NIOSH Hazard Review: Carbonless Copy Paper/Health Effects

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4 Health Effects

4.1 Introduction

During the early 1970s, manufacturers, employers, and occupational safety and health organizations received numerous complaints of skin and mucous membrane symptoms related to handling or working in close proximity to CCP [Calnan 1979; Göthe et al. 1981; Parmeggiani 1983]. The association of CCP with cases of occupational contact dermatitis was first investigated by Calnan [1979], who also reviewed reactions to ordinary carbon paper, which CCP has largely replaced. According to Calnan, proven allergic contact dermatitis from carbon paper was a rarity. Four early outbreaks of CCP health effects were described by Calnan [1979] and Göthe et al. [1981] at a scientific symposium in Stockholm in 1981. Although skin-patch tests were negative and therefore did not support allergic contact dermatitis as the mechanism of CCP health effects, five pieces of evidence indicated an occupational origin for the CCP symptoms:

  • The reporting of symptoms from several workers in a number of unrelated and unconnected companies
  • The receipt of customer complaints by all of the CCP manufacturers
  • The similarity of reported symptoms and signs
  • The similarity of complaints from different countries
  • The absence of reported symptoms before the introduction of CCP

Calnan [1979] concluded that the reactions appeared to be toxic (i.e., irritant) rather than allergic because the affected workers were able to continue working in the same general environment without immediate recurrence of their symptoms and because many of the workers related their symptoms to periods of intensive work handling large amounts of CCP.

Calnan [1979] noted that the CCP manufacturers had reported an absence of skin, oral, ocular, or respiratory tract symptoms among their own workers employed in packing large quantities of CCP. However, subsequent investigations identified health problems in these groups as well. Calnan also pointed out that all CCP complaints were associated with used CCP paper, indicating that the rupture of the microcapsules containing the color formers and solvents may be important—even though only a small proportion of capsules in each sheet of paper are broken. Ultimately, Calnan concluded that the eye, nose, mouth, and throat symptoms were caused not by the color former chemicals but rather by the encapsulated solvents, which would presumably have to evaporate to cause other than dermal symptoms.

In a review of the evidence, Buring and Hennekens [1991] found most of the available studies on CCP health effects to be critically lacking epidemiologically and difficult to interpret. They were able to find no "analytic studies" of CCP health effects for review. However, they concluded that unequivocal evidence was not likely ever to be available, even with great expenditure of effort and resources. They recommended instead that consideration be given to "implementing measures to prevent or reduce the frequency" of the reported effects.

Murray [1991] also conducted a review of the potential health effects of CCP exposure at the request of the Commission of the European Communities. He noted an absence of documented cases of skin disorders among workers in the manufacturing industry—despite the fact that workers in this industry would be expected to have much higher exposures than office workers. On the basis of both his review of the literature and his experiences as a consultant for a manufacturer of CCP, Murray concluded that although individual cases of sensitivity to CCP components would continue to be reported, a "negligible" threat is posed to the health of producers and users.

Since 1991, additional studies (including some that qualify as analytical epidemiology) have appeared in the scientific literature. The following review considers not only information published in the scientific literature but also information that was submitted to NIOSH in response to announcements in the Federal Register in 1987 and 1997. More than 14,000 pages of combined submissions were received in response to the 1987 and 1997 Federal Register notices. Most of the submissions were made after the latter notice. No materials were accepted or reviewed if the submitter considered the items to contain proprietary information that could not be made available to the public. Information that contained personal identifiers was blocked out unless the submitter wanted the information to remain public.

The following review of CCP health effects separately considers the information from human and animal studies.

4.2 Human Studies

Human studies of CCP have dealt mostly with exposures in office settings. Three types of human studies of CCP have been conducted: individual case studies or case series, cross-sectional studies, and laboratory studies in humans. The following sections separately review each type of study.

4.2.1 Published Case Reports and Case Series

The case report is a detailed profile of a single subject; case series describe the characteristics of a number of patients with a given disease. Case reports and series document unusual features of a disease or a patient’s exposure history; they are a type of descriptive epidemiologic assessment. Case reports and series can present a major problem in interpretability because the presence of any risk factor may be simply coincidental. Their usefulness is generally limited by the lack of a comparison group (i.e., persons without such symptoms who had similar opportunity for exposure). The lack of a formal comparison group in these studies can make it difficult to determine whether the observed associations represent more than the normal background rate of disease. Lack of a comparison group is particularly problematic when the cases involve common diseases or symptoms and when the exposure is relatively common (which is clearly the case with these reports for CCP exposures). In the absence of a comparison group, case reports and series can provide the first clues to the identification of new diseases or exposure effects, and they are potentially useful for formulating research questions; however, the evidence usually cannot be used to test hypotheses [Buring and Hennekens 1991]. On the other hand, when characteristic symptoms and clinical signs vary over time in direct correspondence with changing work exposures, it may be possible to reliably discern a causal relationship. Furthermore, some of these reports included individual experiments in which subjects were exposed to CCP or its components and objective signs and symptoms were evaluated following these exposures. These studies can provide stronger evidence for causality than ordinary case reports that are based on subjective reports of past experiences.

Table 4-1 lists 39 currently available, published case reports and case series related to CCP, including a number of series assembled in NIOSH Health Hazard Evaluations (investigations conducted under the authority of the Occupational Safety and Health Act of 1970 [29 USC[1] 1900]). Nine reports provided information about the experience of a single worker. In the case series, ranging from 2 to 276 workers, symptoms were generally clustered within a defined period and involved a number of employees at a single workplace, often situated in a single room or activity. The observed symptoms varied considerably from site to site, but most included skin problems such as itching, rash, dryness, and eczema as well as mucous membrane irritation, particularly of the eyes, mouth, nose, and throat. Lower respiratory problems were less frequent. Headache was also reported as a problem (to a smaller extent), and fatigue was also mentioned.

The following are summaries of the studies outlined in Table 4-1.

Magnusson 1974. Magnusson [1974] conducted his investigation in Sweden at a workplace where 15 of 18 women working with CCP had reported itching and dryness of the skin, lips, tip of nose, and eyes as well as burning sensations or dryness in the mouth. The symptoms mostly appeared a few weeks after the first exposure to CCP. Seven of the 15 women showing symptoms were skin-patch tested using the paper in question and a standard series. All tests were negative but one, which showed reaction to nickel and cobalt. Symptoms disappeared after introduction of a new type of paper containing a resin to bind the clay material.

Hannuksela 1975. A report by Hannuksela [1975] (unavailable to NIOSH but cited by Jeansson et al. [1983]) found 20 workers among several hundred in a Swedish bank who suspected that eczema on their hands was caused by contact with CCP. None of the 19 workers who were skin-patch tested with a CCP bottom sheet emulsion showed an allergic reaction. One later case was reported as positive, with most of the complaints attributed to physical factors (such as abrasiveness) related to CCP.

Wahlberg 1975. In a personal communication reported by Jeansson et al. [1983], Wahlberg found the CCP-related problems to be relatively evenly distributed between two main types of CCP used in Sweden at the time—clay- and polymer-based papers. He suggested that a finely distributed dust arising from leafing through and tearing the paper was a likely explanation of the symptoms.

Hirvonen et al. 1976. Hirvonen et al. [1976] obtained positive skin-patch test reactions for irritation in 4 of 32 cases associated with CCP from a total of 1,050 cases of occupational dermatitis in Sweden during the period 1973 to 1976. In all four cases, the rash began in areas typical of paper contact—the finger tips of one or both hands and the outer edges of the hand. The eyelids of one worker also revealed a rash. Of the four patients, two reacted only to the top side of the paper but not to the CB or CF portions. Two patients reacted to all of the

Table 4–1. Published case reports, case series, and health hazard evaluations involving exposure to CCP or CCP components
Authors Country Number of cases Symptoms[2]
Magnusson 1974 Sweden 15 Itching and dryness of skin, lips, tip of nose, eyes; burning or dryness of mouth
Hannuksela 1975 Sweden 20 Eczema
Wahlberg 1975 Sweden NR[3] "Problems"
Hirvonen et al. 1976 Sweden 32 Skin irritation
Maggio et al. 1978 Italy NR Acne, headaches, nausea
Andanson et al. 1979 France 27 Skin symptoms (pruritus of uncovered areas on hands, face, forearms, thorax, and legs); eye symptoms (pruritus, conjunctival hyperemia with tearing and photophobia); respiratory system symptoms (pruritus, burning, prickling, dysphagia, throat constriction, rhinorrhea, nasal obstruction, glottal edema, asthma)
Calnan 1979, 1981 United Kingdom Several Itchy hands, swollen eyelids, headaches
2 Burning face and forehead, fatigue, thirst, sore throat and tongue, chills, aching limbs, small itchy blisters on palms
4 Burning lips and tongue, sore eyes, dry throat and skin
Japan 1 Nausea, sore eyes and throat, skin irritation
1 Dry throat
1 Facial rash
1 Rash on hands
England 4 Dry, burning lips, and tongue; stinging, running eyes and nose; dry, cracked skin on hands; facial rash; chest tightness
Cronin 1980 United Kingdom 4 Eczema
Dodds and Butler 1981 Belgium 17 Eczema, itching, red spots, itching eyes
Marks 1981 United States 1 Dermatitis on face and neck
Menné et al. 1981 Denmark 38 Skin redness, burning, itching; itching eyes, nose; hoarseness; burning mouth, red face, headache, dizziness
Chrostek and Moshell 1982 United States 21 Eye and nose itching and burning; dry throat; headaches; facial itching; and sinus, skin, and respiratory problems
Levy and Hanoa, 1982 Norway 13 Perception of unpleasant odor; itching eyes, face, and hands; rashes; headaches
Roure et al. 1982 France 28 Pruritis on the hands, face, forearms, or thorax and legs
11 Burning sensation, nasopharyngeal tingling, slight dysphagia, photophobia, eye irritation, and conjunctival pruritus
3 Dryness of the mouth, burning, and taste perturbations
3 Headache
9 Erythematous patches on hands and face
1 Urticaria
1 Migratory edema
1 Conjuntivitis with eyelid edema
2 Conjuctival hyperemia with lacrimation
4 Rhinorrhea
1 Glottal stricture
1 Nasal obstruction
4 Spasmodic cough and asthmatic breathing
Certin and Zissu 1983 France 46[4] Skin, eye, and respiratory irritation; headache; arthralgia
Jeansson et al. 1983, 1984 Sweden 148 Irritation of the eyes, nose, throat, arms, face, and scalp; cold symptoms; hoarseness; sores behind the ears or in the nose; itching, dryness, redness, or eczema of the hands; unpleasant odor or taste; fatigue; headache; nausea; joint pains; a feeling of paralysis
Norbäck et al. 1983a,b Sweden 80 Respiratory tract and eye irritation
Marks et al. 1984; Trautlein et al. 1984 United States 1 Pruritus, eye and throat irritation, hoarseness irregular heartbeat, headache, nausea, tightness of chest, shortness of breath, and fatigue; challenge test with CCP indicated contact urticaria, changes in pulmunary function indicative of upper airway obstruction, and increased prostaglandin PGF2 alpha and thromboxane BE
8 Throat irritation
5 Skin itching
4 Headache
3 Hoarseness
3 Difficult breathing
3 Chest tightness
2 Rash
2 Burning eyes
2 Chest pain
1 Nausea
1 Weakness
1 Rapid heartbeat
Messite and Baker 1984; Messite and Fannick 1980 United States 6 Skin and eye irritation
Menné and Hjorth 1985 Denmark 3 Contact dermatitis, eczema on fingers
Olsen and Mørck 1985 Denmark 1 Skin irritation
Apol and Thoburn 1986 United States NR Voice change, cough, chest tightness and soreness, running sinuses, skin rash
Bennett and Chrostek 1986 United States NA Respiratory problems reported but not attributed to CCP; some mention of formaldehyde exposure that was assumed to originate from CCP
Chovil et. al. 1986 United States 9 Eye irritation, sinusitis, dermatitis, psychological manifestations
Shehade et al. 1987 United Kingdom 1 Allergic contact dermatitis
LaMarte et al. 1988 United States 2 Hoarseness, wheezing, coughing, flushing, pruritus, rash, laryngeal edema, localized angioedema
Norbäck et al. 1983c; 1988 Sweden 276 Skin and mucous membrane and skin irritation
Hammel 1990 United States 2 Hoarseness, cough, flushing, pruritus, rash
1 Nausea, dizziness
1 Redness and itching on hands
Kanerva et al. 1990a,b; 1993 Finland 1 Allergic contact dermatitis
Burton and Malkin 1993 United States 1 Chest tightness, cough
1 Cough, rhinitis, headache, rash
Sim and Echt 1993 United States NA Itchy skin and rashes attributed to fibrous glass
Zimmer and Hadwen 1993 United States 6 Odor in archives area
Ziem and McTamney 1997 United States 2 Multiple chemical sensitivity disorder
Smith et al. 1999 United Kingdom 1 Eczema of the thumbs

Adapted from Buring and Hennekens [1991], with additional references added.

  1. United States Code. See USC in references.
  2. Symptoms were observed in one or more subjects. Exact numbers are supplied in parentheses if they were reported.
  3. Abbreviations: NA=not available; NR=not reported.
  4. Requests for CCP analysis—not cases.
surfaces of the papers. Tests on the ingredients of the papers were negative. The authors attribute the reactions to nonspecific irritation of the skin.

Maggio et al. 1978. Maggio et al. [1978] reported an investigation of the chemical composition of CCP in Italy. They identified organic dyes dissolved in mineral oil or PCBs enclosed in the microcapsules made of urea-formaldehyde resins or gelatin. The symptoms reported by those using CCP were skin complaints such as acne and general complaints such as headache, nausea, and uncomfortable olfactory sensations. The authors assumed the symptoms to be related to the PCB exposure.

Andanson et al. 1979. In France, Andanson et al. [1979] described the chemical composition of CCP and the spectrum of symptoms resulting from handling sheets of CCP directly or possibly from contact with vapor. The onset of symptoms (reported by 27 of 35 exposed workers) varied but generally developed a few weeks after first exposure. The authors mentioned symptoms of the skin (pruritus of uncovered areas on the hands, face, forearms, thorax, and legs), eyes (pruritus, conjunctival hyperemia with tearing and photophobia), and respiratory system (pruritus, burning, prickling, dysphagia, throat constriction accompanied by rhinorrhea, nasal obstruction, glottal edema, and one case of true immediate asthma). The authors noted that chemical information from the manufacturers was inadequate to relate the symptoms to the exposure and that office environments involved nonexistent or inadequate ventilation. The authors reported that symptoms disappeared soon after exposure ended. They considered the irritant symptoms definitive but performed no tests to assess the allergic potential. The authors concluded that while some of the cases were relatively severe, they did not consider them "a great historic pathology."

Calnan 1979, 1981. Calnan [1979, 1981] reported on three episodes of complaints from various types of office workers in the United Kingdom who attributed their symptoms to the use of CCP. The first episode occurred in 1965 in a group of nine women who worked with business forms in an enclosed computer room at an insurance company. Within a few weeks of the introduction of CCP, several of the women complained of itchy hands, swollen eyelids, and headaches. Skin-patch testing to the paper and all of its constituents was negative. At the time, the solvent for the ink was chlorobiphenyl (a PCB), which was suspected as the causal agent. When ventilation in the workroom was improved, the episode subsided. Soon afterwards, the PCB use was discontinued by all manufacturers.

A second episode occurred in 1975 and involved two men working intensively over a long, hot weekend checking a large number of forms in a small office. One reported a burning sensation on his face and forehead, fatigue, thirst, sore throat and tongue, chills, and aching limbs. He recovered in a few days without treatment, returned to the office to continue his work, and suffered a recurrence of the same symptoms. The other man was similarly but less severely affected and had small, itchy blisters on the centers of his palms.

The third episode described by Calnan occurred in 1976 in a small office where all four workers complained of similar symptoms whenever they handled large amounts of CCP. They reported a burning sensation of the lips and tongue, sore eyes, dry throat, and some dryness of the skin.

Calnan [1979] also reported on complaints from three users of CCP made in Japan. The complaints included nausea, sore eyes and throat, and skin irritation (see Table 4–1).

Among all of these reported episodes, no workers changed jobs or were forced to stop work. All skin test investigations were negative, and the CCP came from different manufacturers. Calnan hypothesized that if there was a responsible agent, it was most likely to be the solvent in the microcapsules, which could include kerosene, diarylethanes, alkyl naphthalenes, cyclohexane, and dibutyl phthalate.

Cronin 1980. Cronin [1980] reported that four workers involved in the making of microcapsules for CCP in the United Kingdom were found with eczema of the hand (which had been present in one worker for 4 years) or palms (present in one worker for 10 years). Two Proxel compounds (Imperial Chemical Industries) were used as preservatives for gelatin in a factory making the emulsion for CCP. Both contained the active ingredient 1,2-benzisothiazolin-3-one, and one also contained ethylenediamine. Both the active ingredient and the Proxel provoked positive skin-patch test reactions in all four workers, but the ethylenediamine provoked a response in only two of them [Kanerva et al. 1993]. The author concluded that two of the workers' eczema predated their contact with the agents, and the sensitization was thought to be an aggravating factor in their dermatitis rather than its complete cause. Another dermatitis case was cited in a paper mill worker.

Dodds and Butler 1981. In Belgium in 1975, these investigators described five female workers who handled paper forms and reported skin and eye irritation (specifically eczema, itching, and red spots). An additional 12 workers reported itching of the eyes. The incident coincided with the use of a new desensitizing ink ("D-ink," a coating to disable the color formation process). Before the use of this ink, no symptoms had been reported for 7 years. A hamster cheek-pouch test resulted in transient ischemia that lasted approximately 15 min. Detailed studies of the new desensitizing formula led to the conclusion that one of its ingredients (1-hydroxyethyl-2-oleylimido-azoline) caused the severe effect. In a second case in Denmark, similar symptoms were reported after workers handled paper that contained the same desensitizing ink. The manufacturer was reported to have immediately terminated production of the formulation.

Marks 1981. Marks [1981] reported the following case of a 21-year-old woman in the United States who had a 1.5-year history of an intermittent eruption of the face and neck. She worked as a clerk in a college registrar’s office where CCP forms were used for student registration. Within 24 to 48 hr after using the forms, she developed pruritic, erythematous, and edematous dermatitis. She was skin-patch tested with a standard series of allergens as well as with pieces of paper and the components of the paper backing. She reacted to three of the four colored sheets of CCP. She also tested positive to the color former, identified as paratoluene sulfinate of Michler's hydrol, a component of some CCP. She was further skin-patch tested with paratoluene sulfonic acid (results were negative) and with the Michler's hydrol (4,4N-bis[dimethylamino]benzhydrol) (results were positive). Twelve control subjects tested negative to the paper and coating materials.

Menné et al. 1981. Menné et al. [1981] performed an investigation resulting from 70 complaints at a telephone company in Denmark that employed 2,600 workers who handled up to 900,000 sets of CCP per year (i.e., an average of 1.3 sets per person per day). They first investigated 38 of the complaints and found that 26 workers had skin symptoms only, 9 had skin and mucous membrane symptoms, and 3 had mucous membrane symptoms only. Among the workers with skin symptoms, 22 reported that they started on the hands, and 4 reported that they began on the face. The skin symptoms were temporary redness, burning, and itching that occurred after 2 to 3 hr of work; they disappeared overnight or over the weekend. Itching of the eyes or the nose, hoarseness, and burning in the mouth were the other symptoms recorded. Twenty-nine of the 38 received standard skin-patch tests, and 11 were found with one or more reactions. Twenty-five workers were further skin-patch tested with 17 paper substances and with the paper. Eight workers were tested with the paper components plus the paper, but no reactions were observed. Other tests included prick testing, photo-patch testing, open tests on the forehead (dab testing), and short-term patch testing for 20 min. All results were negative. The three skin-prick tests using the paper components were negative. Eight were photo-patch tested, and eight had open-patch tests to assess phototoxicity, but all reactions were negative. Twenty-six were skin-prick tested with two types of CCP; six reacted to one type, and five reacted to the other type with reactions the size of one histamine equivalent. However, authors considered these responses to be nonimmunological. Among the 35 controls, one had a positive reaction to one of the skin-paper prick tests. The controls were also tested with 17 different components of the CCP; all tests were negative. The authors stated that approximately 4,000 separate tests were carried out without reaching any definite conclusions.

Menné et al. [1981] also reported on the case of a worker from a different company who began experiencing redness of the face, headache, and dizzy spells on the day that a new delivery of CCP was made. The worker's symptoms disappeared 2 hr after he returned home. Two months later, the paper was replaced and his symptoms disappeared.

Chrostek and Moshell 1982. Chrostek and Moshell [1982] conducted a walk-through survey and administered nondirected medical interviews with 21 workers at a U.S. telephone company. These service department workers acted on reports of malfunctioning telephone service and requests for new services, which were printed on yellow CCP. Previously, carbon paper had been used with no complaints. The following health complaints were described after the introduction of CCP: eye itching and burning, nose itching and burning, dry throat, headaches, facial itching, and sinus, skin, and respiratory problems. Some of the workers stated that the adverse health problems existed only when handling yellow CCP—not white CCP. Five air samples were collected for total dust; they ranged from 0.06 to 0.2 mg/m³. The two samples collected for formaldehyde were 0.22 mg/m³. Workers handling the CCP were asked to wear white cotton gloves, which were analyzed. The common contaminant in both the gloves and the CCP was dibutyl phthalate, although other contaminants (diethyl phthalate and dioctyl adipate) were also detected in the gloves. Qualitative analysis of the carbonless paper did not detect formaldehyde. On May 13–14, 1981, a NIOSH dermatologist interviewed and examined 33 workers. Of these, 28 were skin-patch tested with unmarked white and yellow CCP—and a marked yellow CCP. On the basis of the negative skin-patch tests and a lack of skin findings consistent with allergic contact dermatitis, the authors ruled out type IV allergic phenomena as a major problem. However, they allowed that certain individuals might have been allergic to a component of the paper.

Levy and Hanoa 1982. Levy and Hanoa [1982] reported on an isolated epidemic that occurred in northern Norway when a new type of invoice form (30,000 sets) had been introduced by a builder's supply company. During the first week of use, workers complained about an unpleasant odor, rashes, headaches, and itching eyes, face, and hands. Thirteen female workers were examined in June 1979; six had serious symptoms and three exhibited mild symptoms. These workers were again examined in November 1979 when some CCP sets were still in circulation but most had been returned to the supplier. The complaints gradually declined until none of the workers exhibited serious symptoms and eight had only mild symptoms. In September 1980, when none of the original CCP remained in use, only one of the workers (who had a previous history of allergy) complained of itching and irritation of the eyes. The solvent MIPB and associated impurities (which had a characteristic odor) were suspected. Formaldehyde was not thought to be of any importance in the incident.

Roure et al. 1982. Roure et al. [1982] described subjective symptoms and objective signs occurring in 22 of 35 workers exposed in a French company during the introduction of CCP. The following frequencies of subjective symptoms were observed: pruritis localized on the hands (13 cases), face (9 cases), forearms (5 cases), or thorax and legs (1 case); burning sensation, nasopharyngeal tingling, slight dysphagia, photophobia, eye irritation, and conjunctival pruritis (11 cases); dryness of the mouth, burning, and taste perturbations (3 cases); and headache (3 cases). All symptoms appeared as early as the start of the workweek, lessened in the evening, and disappeared on the weekends. Objective signs in 18 workers consisted of erythematous patches on the hands and face (9 cases), urticaria (1 case), migratory edema (1 case), conjunctivitis with edema of the eyelid (1 case), conjunctival hyperemia with lacrimation (2 cases), rhinorrhea (4 cases), glottal stricture (1 case), nasal obstruction (1 case), and spasmodic cough and asthmatic breathing (4 cases). An etiologic survey showed evidence of previous allergies in three subjects and enabled a distinction to be made between the risks due to "transfer-contact" and "chemical-contact" copy papers.

Certin and Zissu 1983. Results of analyses requested of the French National Research and Safety Institute were reported by Certin and Zissu [1983] and compared with other published studies. They reported 51 requests for analysis of CCP during the 10 years preceding publication of the results. Reasons stated in 46 of the requests included cutaneous problems (allergies, irritation, pruritis, and chapping) (41), respiratory problems (12), ocular disorders (lacrimation, conjunctivitis) (10), irritation of the nasal mucosa (2), and others including asthenia, anemia, headache, and arthralgias. According to the authors, dermatological and respiratory problems seemed to be linked to the use of these papers and were more likely to be due to irritation than to allergy.

Norbäck et al. 1983a,b,c; 1988. Norbäck et al. [1983a] summarized conclusions from five studies in Sweden. Studies in 80 office workers observed only eye and respiratory tract irritation caused by CCP. Norbäck et al. [1983b] found no correlations between airborne solvent concentrations from CCP and the occurrence of irritative symptoms. Formaldehyde, glutaraldehyde, and the organic solvents in which the color formers are dissolved were studied under standardized conditions. According to the authors, the emission of aldehydes from CCP was too low to cause the irritative symptoms. The highest airborne concentration was that of kerosene, which could not be related to symptoms.

Norbäck et al. [1983c, 1988] searched for the discomfort-inducing factors in 276 paper samples (233 of which were CCP) submitted by workers claiming to have experienced irritative symptoms while handling the papers. Interviews regarding symptoms and handling volume were conducted with subjects who had submitted 190 of the CCP samples. To distinguish between CCP of different makes, GC of paper extracts was performed, sometimes combined with thin-layer chromatography (TLC) of the color formers. Coded paper samples were used to permit blind analyses of the papers and blind interviews of the exposed persons. The samples were extracted with carbon disulfide, and the extracts were analyzed by GC or TLC. Most correlations of CCP with discomfort were not statistically significant but were found in one brand of paper that used MIPB as the solvent for the color formers. However, the authors concluded that the discomfort-inducing factor was unlikely to be MIPB because two types of MIPB paper were on the market at the time of this study, but patient complaints identified only one of them. CCPs treated with D-ink were more frequently linked to work-related skin symptoms than those not treated with the ink. This correlation was statistically significant (P<0.05). No such correlation was seen for mucous membrane irritation symptoms. The authors concluded that the causal factor was probably two desensitizing inks available on the Swedish market during the investigation period (from January 1 to October 27, 1980)—but not necessarily to D-inks in general. The suspected ingredient in one of the D-inks was 1-hydroxyethyl-2-oleylimidoazoline—the same ink that had previously been associated with skin and eye irritation among office staff in Belgium [Dodds and Butler 1981].

Jeansson et al. 1983, 1984. See Section for a discussion of this study.

Marks et al. 1984; Trautlein et al. 1984. A 27-year-old woman in the United States had an 8-year history of pruritus, eye and throat irritation, hoarseness, irregular heartbeat, headache, nausea, tightness of the chest, shortness of breath, and fatigue within 30 min of exposure to CCP [Marks et al. 1984; Trautlein et al. 1984]. For 10 years, she had worked in the same factory, which printed, cut, collated, and packaged CCP. She reported that her symptoms became progressively worse as she processed greater amounts of CCP in her job of removing and stacking forms from a collating machine. When working with regular paper, she was asymptomatic. Her symptoms disappeared on weekends, nights, and after 1 hr of exposure to fresh air. On two occasions, she was challenged in a controlled-blinded fashion with portions of complete forms of the CCP. Both challenges resulted in contact urticaria of the hand that held the paper and changes in pulmonary function characteristic of upper airway obstruction. To determine whether alterations in prostaglandin (PG) metabolism might explain these findings, plasma PGF2 alpha and thromboxane B2 (both capable of causing these symptoms) were measured before and during the second exposure period. Both PGF2 alpha and thromboxane B2 increased substantially. The authors concluded that the cutaneous and respiratory symptoms induced by CCP were probably related to PG release and caused by a chemical formed from the reaction of the color former with the color developer, since the patient reacted only to the complete forms and not to the single sheets. When the patient was relocated within the factory with no exposure to CCP, she was asymptomatic.

Similar symptoms were found in 9 of 59 workers in a subsequent plant survey. The symptoms reported by the 9 workers included throat irritation (8), skin itching (5), headache (4), hoarseness (3), difficulty breathing (3), chest tightness (3), rash (2), burning eyes (2), chest pain (2), nausea (1), weakness (1), and rapid heartbeat (1). A statistically significant (P<0.01) relationship existed between symptoms and high exposure to CCP (compared with low exposure to CCP).

Messite and Baker 1984; Messite and Fannick 1980. Messite and Baker [1984] summarized a number of NIOSH Health Hazard Evaluations dealing with indoor environmental quality and specifically reported on a previous study involving CCP [Messite and Fannick 1980]. Six complaints of skin and eye irritation among 100 office staff members and faculty at a school were related to heavy CCP exposure during marking periods of 1 to 2 days. Analysis of the paper did not identify the sensitizing agents or significant irritants. The problem was alleviated by spreading the task of marking papers over several days and frequent hand-washing during handling of the paper.

Menné and Hjorth 1985. Menné and Hjorth [1985] reported from Denmark that frictional trauma with CCP to the palms and fingertips can provoke dermatitis. Elimination of the exposure led to healing within 2 to 3 weeks. Three case histories of patients with frictional contact dermatitis were examined.

Case 1 involved a 35-year-old male office worker. Each day for 2 years, he had handled 100 to 200 documents written on CCP. He gradually developed a scaling patch of dermatitis on the left hypothenar, second finger, and tip of the right index finger at areas of contact with paper. Standard skin-patch tests and paper- and glue-patch tests were negative.

In Case 2, a 64-year-old female medical secretary spent long hours handling CCP. She had noted pruritic vesicles on the left palm surface of the thumb that was in contact with the paper. Eruptions decreased when she wore gloves. Standard skin-patch tests and patch tests to the carbonless paper were negative.

In Case 3, a 37-year-old male bus driver had a fissured eczema of the fingertips, apparently caused by tearing CCP tickets from the stub. The eczema cleared during holidays and on night shifts when there were fewer passengers. Standard skin-patch tests and patch tests with the ticket paper were negative. The histopathology of this type of dermatitis was characteristic, showing necrosis of prickle cells with intraepidermal vesicles and an absence of spongiosis, which excludes a diagnosis of chemical dermatitis. The authors concluded that in patients with dermatitis of the palm or fingertips, frictional trauma should be considered.

Olsen and Mørck 1985. See Section for a discussion of this study.

Apol and Thoburn 1986. Apol and Thoburn [1986] reported on an investigation requested by an authorized representative of the Association of Western Pulp and Paper Workers in the United States. They examined employee exposure to diethylenetriamine (DETA), hexamethylene diisocyanate (HMDI), and other chemicals used during the production of CCP at the Boise Cascade facility in Vancouver, Washington. This facility makes paper from pulp and applies CCP coatings to the paper. Personal breathing zone samples and area samples were collected to determine worker exposures to chemicals used by the coater preparation operators, coating operators, and maintenance personnel. The airborne concentrations were as follows: HMDI (<0.7 to 14.0 μg/m³, DETA (<0.01 to <0.35 part per million [ppm]), phenol (<0.02 to 0.15 ppm), formaldehyde (<0.04 to <0.08 ppm), biphenyl (0.003 to <0.02 ppm), butyl biphenyl (0.12 to 0.29 ppm), petroleum solvents (0.7 to 12 mg/m³), and total particulate (one sample was 2.70 mg/m³). All the sample results were less than the regulatory limits for these substances. Symptoms reported as a result of exposure included voice change, cough (sometimes productive), tightness and soreness in the chest, running sinuses, and skin rashes.

Medical interviews with 65 employees suggested that when the process was operating properly, few (number unspecified) health complaints were associated with the coating process. The maintenance workers had symptoms associated with exposure to the coating equipment, with the HMDI equipment reportedly being the worst offender. Four workers reported pulmonary symptoms consistent with exposure to diisocyanates. Breathing zone concentrations of biphenyl were below the limit of detection (i.e., <0.02 ppm), butylobiphenyl concentrations ranged from 0.12 to 0.29 ppm, and HMDI concentrations ranged from 0.7 to 4.5 μg/m³ for coater and assistant coater operators. On the basis of the medical questionnaire data obtained during the investigation, the authors concluded that some workers may have had pulmonary problems related to past diisocyanate exposure. This investigation is one of several that document CCP-attributable health effects at a CCP manufacturing facility.

Bennett and Chrostek 1986. At the request of the management of the Defense Industrial Supply Center in Philadelphia, Pennsylvania, NIOSH evaluated possible excess cancer deaths and respiratory problems encountered among workers [Bennett and Chrostek 1986]. Measurements were taken for carbon dioxide, carbon monoxide, temperature, relative humidity, organic vapors, and airborne dust. Samples were taken of insulation, solvent cleaners, and CCP used at the facility. The amount of outside air being introduced into the building was occasionally in the low range—such that headaches and complaints of respiratory and mucous membrane problems could develop, even though concentrations of carbon monoxide and carbon dioxide were within safe limits. In addition, the building was overcrowded. The authors concluded that hazards were posed by inadequate ventilation, high temperatures, and low humidity. The authors recommended improvements in ventilation and the use of impermeable gloves when using solvents. However, they made no statements or recommendations about the use of CCP—other than the possibility of formaldehyde release.

Chovil et al. 1986. Chovil et al. [1986] reported cases of eye irritation, sinusitis, dermatitis, and psychological manifestations associated with an outbreak of a building-related illness at a U.S. university. As part of a building expansion program in August 1983, the student advisement office was relocated to a renovated area on another floor. Shortly after the move, the nine-member staff began complaining of skin and mucous membrane irritation. The presence of asbestos increased staff concern over their symptoms. Medical histories were taken and clinical examinations were performed. Air flow in the ventilation system was evaluated. Seven staff members reported symptoms that they believed were work related. All claimed that their symptoms occurred when they were in the file storage area or when they handled the files.

Air-flow measurements indicated that any noxious agent originating from the files would tend to stay localized in the filing area instead of being dispersed throughout the work area. An inquiry revealed that the university had changed suppliers of advisement forms composed of CCP in April 1983. The authors suggest that the outbreak was due to low-level environmental pollution, probably originating from the CCP in the forms. Reported symptoms may have been exacerbated by the fear of asbestos. In all but one case, symptoms were mild. The worker who exhibited severe symptoms restricted contact with CCP and had no recurrence. The authors added that informal inquiries revealed at least two workers in other departments who had symptoms of mucous membrane irritation during periods of peak usage of these forms (at the beginning of each semester). A followup 8 months later revealed that the staff members were no longer complaining about symptoms—in spite of the fact that previous recommendations for improving the ventilation and for reducing CCP handling had not been implemented.

Shehade et al. 1987. In the United Kingdom, Shehade et al. [1987] identified a case of allergic contact dermatitis associated with exposure to CVL in CCP. Skin-patch tests were employed to identify the cause of an irritant vesicular rash on the hands and fingers of a female office worker whose occupation entailed the day-long handling of significant quantities of CCP. The symptoms developed within 2 days of the subject's return to work after 18 months of leave. They resulted in the patient's stopping work after 3 weeks. Initial skin-patch tests to nickel sulfate, cobalt chloride, and fragrance mix gave positive results, but there was no reaction to the CCP. The patient improved during 3 months on sick leave, but the condition recurred severely as soon as she returned to work. Subsequent skin-patch tests to the five color formers supplied by the manufacturer of the CCP showed an allergic reaction to CVL at concentrations of 0.01% to 5%. The authors concluded that the patient was allergic to CVL and that CCP skin-patch tests with CCP only are not sufficient to detect allergies to color formers. They therefore suggested that the color formers themselves be used to test patients with hand eczema and regular contact with CCP.

LaMarte et al. 1988. Acute systemic reactions to CCP, including laryngeal edema, were reported in two U.S. office workers by LaMarte et al. [1988]. The first case was a 39-year-old woman with a 2-year history of recurring episodes of hoarseness, coughing, flushing, pruritus, and rash appearing within 30 min of topical exposure to CCP. She was a clerk/typist with frequent exposures to CCP during her working hours. Cutaneous application tests were performed using six chemical ingredients of CCP. Approximately 15 min after 1% alkylphenol novolac resin dispersion was rubbed onto her forearm, she was noted to develop hoarseness, wheezing, and angioedema of both arms. A subsequent challenge with the material was followed by hoarseness, wheezing, and angioedema at the challenge site. Video endoscopy of the larynx was interpreted as showing diffuse swelling and marked edema of the true vocal cords. Plasma histamine levels obtained at the onset and peak of symptoms were sixfold higher than the prechallenge level.

The second case described by LaMarte et al. [1988] was a coworker of the patient in the first case. This 45-year-old woman had a 6-month history of hoarseness, coughing, flushing, and localized angioedema subsequent to skin contact with CCP. She was challenged by rubbing 1% alkylphenol novolac resin onto one arm and was reported to have angioedema of the arm and hoarseness 30 min after the challenge. The authors concluded that the reaction was mast cell/basophil-mediated, that these cases demonstrate a connection to a specific component of CCP, and that they indicate a potentially life-threatening adverse reaction in susceptible patients.

Hammel 1990. Hammel [1990] reported the results of a NIOSH Health Hazard Evaluation of a U.S. consumer refrigeration manufacturer employing 2,600 workers, including 900 office personnel. CCP was used in all departments, but most users were in the export and purchasing departments. Medical interviews were performed for four workers who felt that their health problems were associated with CCP exposure. Two of four workers had developed recurrent episodes of hoarseness, coughing, flushing, pruritis, and rash, which would occur within 30 min of handling CCP. The third worker described having nausea and dizziness when handling one type of CCP form but not other types. The fourth worker developed redness and itching on the edges of both hands when handling CCP forms (a dermatitis that resolved during weekends). Symptoms improved in all four workers when they avoided exposure to CCP. Two of the four workers became so sensitized that they could not be in the vicinity of CCP without being hoarse. Medical evaluations confirmed acute systemic reactions to CCP (laryngeal edema and sixfold increases in plasma histamine levels) after blinded, provocative, cutaneous challenges with alkylphenol novolac resin, a component of CCP. Subsequently, both workers developed hoarseness as a response to other chemicals such as paint, wall paper adhesives, and colognes. Job rotation to positions with minimal or no contact with CCP effectively alleviated health problems in all four workers.

Kanerva et al. 1990a,b; 1993. Kanerva et al. [1990a,b; 1993] investigated the case of a 43-year-old machinist in Finland whose work involved the manufacture of CCP and who developed occupational dermatitis on the hands. The worker was a healthy man with no previous skin disease. He had been employed by the same paper-making company for 23 years. During the last 4 years, he was exposed to the agents used in the CCP manufacturing system—initially, just on the weekends. After a new microcapsule machine was introduced, the patient was given the responsibility of getting the machine into operation. Because of problems with the new machine, his exposure exceeded what would have been expected in normal use. He had direct contact with the microcapsule dispersion and contracted hand dermatitis within a month of the installation of this new machine. Vesicular eczema developed on both hands but cleared over a 3-month sick leave followed by vacation. Upon returning to work, the worker relapsed.

Skin-prick testing was negative for 20 common allergens and natural rubber latex. On skin-patch testing using a series of standard European allergens and CCP, both CCP and one of the chemicals used to produce the microcapsules of CCP provoked a strong (3+) allergic reaction. Analysis of the paper showed that it contained enough DETA to induce allergic contact dermatitis. The patient tested negative to ethylenediamine, para-phenylenediamine, hexamethylenetetramine, 4-tolyldiethanolamine, and triethanolamine; but he cross-reacted to triethylenetetramine and diaminodiphenylmethane. Twenty control subjects were skin-patch tested with the microcapsule dispersion substance, the microcapsule paste, and the paper. They all reacted negatively.

The source of the DETA in this case was its use as a cross-linking agent that was added to a solution of color formers in a suitable organic solvent and then mixed with a polyisocyanate. The authors commented that DETA remained even though the vendor claimed that the process ensures that all of the polyisocyanate has reacted. The authors recommended that workers who handle CCP and develop symptoms of contact dermatitis be skin-patch tested with DETA. This patient was the only one who reacted to DETA among the 20 to 30 subjects tested each year since 1986 at the facility–except for a painter who also tested positive to ethylenediaminetetraacetic acid (EDTA), which was a component of the hardener in an epoxy resin paint.

Burton and Malkin 1993. Burton and Malkin [1993] responded to a management request based on a report that a former worker at the Michigan Printers in Chicago, Illinois, had suffered adverse reactions to CCP and solvents. They conducted an industrial hygiene and medical survey. The facility employed 12 workers in check printing and other offset printing on CCP. Samples of personal breathing zone and area air quality were analyzed for printing solvents and metal particles. Workers were interviewed and work practices were observed. The ventilation units appeared to be operating well and were well maintained. The authors concluded that workers were not overexposed to organic solvents or metals at the time of the survey. Of the 11 workers interviewed, 1 reported chest tightness and cough. The former employee (on which the investigation was based) had reportedly experienced cough, rhinitis, headache, and rash when using CCP; however, management reported that the current CCP was a different brand than that used by the former worker. The authors were unable to evaluate the effects of the previously used CCP and concluded that no symptoms were related to the current use of CCP.

Sim and Echt 1993. In response to a request from the Health Commissioner for Kentucky, Sim and Echt [1993] investigated an outbreak of skin disorders among 10 laboratory workers at the Health Services Building in Frankfort, Kentucky. Workers were concerned about their symptoms, which they felt resulted from contact with CCP forms that accompanied the biological specimens analyzed in the laboratories. Itchy skin and rashes on exposed skin and areas where clothes rub were reported in early May of 1993, soon after the start of fibrous glass insulation installation in the mechanical rooms that housed the air-handling units for the laboratories. Symptoms were reported more often in the early part of the week, were less severe in the latter part of the week, and usually resolved on the weekends. The symptoms tended to recur upon returning to work the following week. Several nonskin symptoms were reported during medical interviews with some workers, including breathing difficulties, headaches, sinus infections, irritated eyes, and a tingling sensation of the nose and lips. Three of the workers reporting skin symptoms did not handle CCP forms. The number of workers with symptoms who handled CCP was not reported. Although a new printing of CCP forms occurred at the beginning of 1993, the manufacturer indicated that no change to the forms had recently occurred. The nature of some of the symptoms was consistent with the irritant dermatitis caused by exposure to insulation, and the onset of symptoms also coordinated well with the timing of this operation. The authors concluded that the most likely cause of the symptoms was irritant dermatitis due to contact with glass fibers.

Zimmer and Hadwen 1993. See Section 3.2.1 for a description of this study.

'Ziem and McTamney 1997.' In the United States, Ziem and McTamney [1997] published a case series of patients assigned the diagnosis of multiple chemical sensitivity (MCS). MCS is a controversial diagnosis used by some practitioners to refer to illness in persons who typically describe multiple symptoms attributed to numerous and varied environmental chemical exposures in the absence of objective, diagnostic physical findings or laboratory test abnormalities that define an illness. A new name for the condition—idiopathic environmental intolerances—was recommended in 1996 by a workshop organized by the International Programme on Chemical Safety of the World Health Organization [American Academy of Allergy, Asthma, and Immunology 1999; Miller 1997]. Cullen [1987] proposed the most commonly referenced definition of MCS: an acquired disorder characterized by recurrent symptoms that (1) are referable to multiple organ systems, (2) occur in response to demonstrable exposure to many chemically unrelated compounds at doses far below those known to cause harmful effects in the general population, and (3) do not correlate with any single widely accepted test of physiological function. The Interagency Workgroup on Multiple Chemical Sensitivity [1998], in reviewing three categories of proposed theories of causation (immunological, neurological, and psychological), found many variations and theories that were interrelated.

Two of 91 patients attributed their conditions to CCP. For one of these patients, few immunologic changes were demonstrated, and most of the values were within normal limits. The authors believed that immune measures preand post-challenge testing were unlikely to show major changes and were therefore not diagnostic of specific MCS etiologies. They reported that after being away from exposure for many months, this patient showed significant clinical improvement. They also mentioned that another investigator had seen chemical sensitivity in about 100 patients with substantial occupational exposure to CCP, but this information was unpublished.

Smith et al. 1999. In the United Kingdom, a 49-year-old male forklift driver at a paper mill producing CCP described a 2-year history of hand dermatitis and was diagnosed as having fissured hyperkeratotic eczema of the thumbs. He responded positively to patch testing with para-phenylenediamine in a standard series; and when tested with a dye series, he reacted to the azo dye Disperse Orange 3. Several azo dyes were used at the mill to produce colored paper; the patient’s job entailed transportation of dye containers. Skin contamination was thought to have occurred during the collection of the used dye containers. Work restrictions from handling the dyes led to resolution of the hand dermatitis. The azo dyes were not likely to have been part of the CCP system, but they were used as a background color for the paper; the authors did not explain the use of the dyes.

4.2.2 NIOSH Docket Submissions

4.2.1 Unpublished Case Reports andCase Series Submitted by Individuals

This subsection describes case reports or case series that were submitted to the NIOSH docket from sources other than CCP manufacturers in response to the 1987 and 1997 Federal Register notices regarding CCP [52 Fed. Reg. 22534 (1987); 62 Fed. Reg. 8023 (1997)]. Twenty-six cases involving health effects attributed to CCP were submitted. The sex of the respondent is mentioned in 14 cases, all of which were female. Age was mentioned in 11 cases. Mean age was 43, with a range from 32 to 55. Symptoms were reported in 23 cases. Multiple symptoms were attributed to CCP in many cases, with 5 or more symptoms reported in 14 of the 23 cases. The most common symptoms attributed by patients or their doctors to CCP included skin symptoms (irritation, rash), respiratory symptoms (breathing difficulty/shortness of breath, nasal/respiratory irritation, lip sores, frequent colds, hoarseness or loss of voice), eye symptoms (eye irritation, blurred vision, eyes feeling swollen and hurt), and general symptoms (fatigue, dizziness, vertigo, lack of energy, fever, malaise, trouble thinking/focusing, and weakness/pain of muscles in general or specifically of the legs, back, or arms). Some information about laboratory workup was provided in eight cases. Immunologic testing, performed in six cases, was extensive but used tests of unknown utility. Small deviations from laboratory normal ranges were attributed to or said to be compatible with immunotoxicity. Extensive neuropsychiatric testing was reported in seven cases, and abnormal results were attributed to or said to be compatible with neurotoxicity. Sophisticated neuroimaging studies such as magnetic resonance imaging (MRI) scans of the brain and single positron emission computed tomography (SPECT) scans of the brain were reported in three cases. Abnormalities in SPECT scans of unknown importance were often attributed to or said to be compatible with neurotoxicity. Eleven of the subjects were characterized as suffering from MCS or "chemical sensitivity." In four cases, symptoms were attributed to formaldehyde sensitivity. Diagnoses of chronic Epstein-Barr virus infection and chronic fatigue syndrome were each made in one case. One subject reported having been treated with "drops under tongue of formaldehyde and petrochemicals." Another reported having been treated with "antigen." Inquiries about Health Effects Submitted by CCP Manufacturers

NIOSH also received docket submissions from CCP manufacturers describing inquiries they had received about alleged adverse health effects associated with use of CCP. These inquiries are summarized in this section.

Appleton Papers, Inc. 1987. A letter from Duane Jones at Appleton Papers, Inc. (dated August 18, 1987, and submitted to the NIOSH docket) reported that from 1976 to 1986, Appleton received an average of six inquiries per month (with a range of one to nine per month) regarding skin, headache, nausea, odor, breathing, eyes, nose, mouth, and unspecified symptoms. No seasonal or other patterns were reported in the frequency of symptoms. Table 4–2 summarizes these data. Other details are contained in the NIOSH docket submission.

Moore Business Forms, Inc. 1987. An August 24, 1987, letter to Richard Lemen from Dr. Norman Macaulay of Moore Business Forms, Inc., noted that in the past 5 years (1982 to 1987), Moore had received only 23 inquiries concerning CCP, and only 6 of 7,500 customers had inquired about skin irritation that they thought was associated with CCP. Also, Moore had produced 13 billion CCP forms during the previous year.

CCP Manufacturers 1998. A letter dated October 6, 1998, was received from Robert G. Tardiff, Ph.D. (representing the CCP manufacturers in the United States) in response to a query from NIOSH. The Institute had asked whether the end users of CCP were reporting to the CCP manufacturers and sellers any health-related symptoms that might be perceived to be associated with CCP in the workplace over the last 10 years (1987–1996). Each of the five U.S. manufacturers contributed data, which were normalized to the amount of paper sold yearly. The letter stated that the figure might be overestimated, based on the following rationale: (1) customers, unsure of which manufacturer’s paper was and is being used, might have addressed the same inquiry to several different companies; (2) a customer might inquire at different levels within the manufacturing and distribution chain, with each contact being treated as a separate report; (3) a consumer might

Table 4–2. Summary of health-related inquiries from customers to Appleton Papers, Inc., May 1976 to December 1986
Item Number %
Focus of inquiry:
Skin 246 28.3
Headache, nausea 46 5.2
Odor 151 17.4
Breathing 33 3.3
Eyes, nose, throat 108 12.4
Unspecified 284 32.7
Total 868 99.3
inquire repeatedly over time to the same company regarding the claim of a single health-related symptom; and (4) inquiries received at one CCP company might not relate to that company’s products, since some sample CCP forms submitted were those of manufacturers.

The letter further explained that most of the information they receive is anecdotal and inconsistent in terms of type, quantity, and quality of information, including the circumstances of product use. Most often the inquiry is received indirectly from merchants, printers, brokers, etc. The yearly average of health-based inquiries is stated to include claims from companies alleging health symptoms and may or may not have included the regular inquiries. Furthermore, some inquiries do not state the number of workers affected and are thus treated as a single inquiry. Some of the inquiries result from odors associated with CCP. Also, some inquiries result from news articles and may have no temporal relationship with actual exposure. For the years 1987 to 1996, the yearly average (±standard deviation) for health-based inquiries for all U.S. CCP manufacturers was 113 (±4) for 960,115 (±6,473) tons of paper sold—or approximately 1 inquiry per 10,000 tons of CCP sold (equivalent to less than 1 inquiry per 1 billion 8.5- X 11-in. sheets). The information was examined for trends by the companies. They found an increasing volume of CCP sold during the period 1987-1992, with a corresponding increasing rate of inquiries followed by an apparent sharp decrease in health inquiries over the last 5 years (1992-1996) (see Figure 4-1). CCP manufacturers have provided no descriptive details (such as conditions of work or volume of CCP used) for the health complaints that led to the reported inquiries.

NIOSH Hazard review of Carbonless Copy Paper image from p. 48.png
Figure 4-1. Production of CCP and number of inquiries per year for all U.S. manufacturers from 1987 to 1996. (Source: Graves et al. [2000]. Reprinted with permission. Copyright by Academic Press.)

4.2.3 Cross-Sectional Studies

The cross-sectional studies reviewed in this section were conducted to evaluate either the potential health effects of indoor air contaminants in general or those of CCP specifically. Both types of studies are summarized in Table 4-3. In both cases, the information about

Table 4–3. Summary of cross-sectional studies that used questionnaires to assess the health effects of indoor air contaminants in general or CCP specifically
Study Country Methods CCP-exposed workers Results
Number responding to survey[1] Workers with complaints
Number %
Studies of indoor air contaminants:
Skov et al. 1987, 1989 Denmark Questionnaires were sent to 4,369 municipal workers in different buildings. Ambient measurements were taken for a large number of factors. 424 men 110 26 Clerks had the highest frequency of mucosal irritation; social workers had the highest frequency of general symptoms. Other significant correlations with mucosal irritation and general symptoms included sex, job category, photoprinting, and VDTs. Older buildings had lower incidences, but no relationship was found between naturally and mechanically ventilated buildings. Handling CCP was related to mucous membrane symptoms (OR=1.3; P<0.0001) and general symptoms (OR=1.6; P<0.0001).
1,102 women 397 36
Zweers et al. 1992 Netherlands Authors surveyed 10,500 workers in 61 office buildings. Unknown Unknown Unknown The study found statistically significant associations of handling CCP with oronasal symptoms (OR=1.18), perception of air contaminants (OR=1.48), air quality complaints (OR=1.21), and lighting complaints (OR=1.30). Near-significant elevations found for eye and fever symptoms.
Mendellet 1991 and Fisk et al. 1993 United States Authors surveyed 880 workers in 12 office buildings. Building characteristics were described, and ambient measures of air quality were taken. 142 82 58 Increased prevalence of some symptoms was associated with several job and workspace factors—including presence of carpet, the use of CCP and photocopiers, air quality spacesharing, and distance from a window. Statistically significant observed between use of CCP and symptoms such as eye, nose, or throat (OR=1.6) and chest tightness/difficulty breathing (OR=2.3).
Jaakkola and Jaakkola 1999 Finland Authors conducted a population-based, crosssectional questionnaire study of workers in 41 office buildings working with CCP, photocopying, and using VDT’s. 910 Unknown Unknown Statistically significant associations (ORs) observed between work with CCP (34% of population) and symptoms such as eye (OR=1.56), nose (OR=1.48), pharyngeal (OR=1.89), and skin symptoms (OR=1.68); headache (OR=1.66); and lethargy (OR=1.38). The ORs for chronic respiratory symptoms and some measures of respiratory infection (acute bronchitis and sinusitis) were significantly elevated (ORs=1.3–1.8). In contrast, only the OR for the common cold was significantly elevated in those performing photo-copying, as were the ORs for otitis and general symptoms in those using VDTs.
Studies of CCP:
Fristedt and Pettersson 1980 Sweden Authors surveyed 3,000 workers and described those with complaints. 180 122 68 A greater incidence of skin symptoms was reported with clay-based CF than with phenolic-based CF. A greater incidence of mucous membrane symptoms was reported with phenolic-based CF than with clay-based CF.
Andersson et al. 1980 Sweden Authors surveyed subjects at 5 sites comparing atopics and nonatopics exposed to CCP: 341 Increased complaints of skin, eye, and mucous membrane irritation were associated with CCP. More frequent itching and dry skin were reported in atopic patients or those with existing skin disease than in nonatopic patients or those lacking prior skin symptoms.
Atopics 29 9 12–52
Nonatopics 194 39 8–7
Öberg 1980 (cited in Murray 1991[2]) Sweden Authors surveyed 205 workers; 74% handled more than 10 CCP forms daily. 205 82 40 Respondents complained of itching and dryness of the hands, eyes, and mouth; 4 reported eczema.
Sondergard 1981 (cited by Murray 1991 and Olsen and Mørck 1985[2]) Sweden Surveyed offices of an airline. 93 68 73 Symptoms not described; dose-response connection was not statistically significant because of small numbers of workers in two groups.
Menné et al. 1981 Denmark Authors surveyed those with CCP exposure at telephone company by asking about symptoms caused by CCP. 1,855 208 11 5.1 % of men (32 of 624) and 14.3% of women (176 of 1,231) reported skin symptoms or mucous membrane irritation. Symptoms were unrelated to the type of building in which subjects worked. A dose-response relationship was noted.
Göthe et al. 1981 and Norbäck et al. 1983b Sweden Authors described complaints from handling CCP, ordinary bond paper, or carbon paper; used a comparison group of 22. Unknown 58 Unknown The prevalence of mucous membrane symptoms (P<0.01) was greater with CCP than with ordinary bond or carbon paper.
Kolmodin-Hedman et al. 1981 Sweden Authors surveyed the following: Laboratory workers handled >1,000 CCP sheets/day compared with insurance workers handling fewer sheets (unspecified no.) and office controls who handled no CCP. Symptom prevalence: 92%, 32%, and 10%, respectively.
Insurance workers 145 46 32
Hospital laboratory workers 12 11 92
Hospital office workers (controls) 20 2 10
Kleinman and Horstman 1982 United States Authors surveyed workers in 61 U. of Washington offices with heavy CCP use. Subjects were asked about symptoms caused by CCP; respondents had a physical examination. 265 71 27 Significant dose-response relationship reported between CCP use and health complaints. Estimated minimum rate of complaints across different offices was 11%.
Pryor et al. 1983 United States Authors surveyed 8 workers in municipal court office and 8 age and sex-matched controls in accounting office. 8 Unknown Unknown Eye, nasal, and throat complaints were higher in CCP exposed workers than in controls, but numbers were too small for meaningful comparison.
Olsen and Mørck 1985 Denmark Authors surveyed employees of 2 form-printing shops. 129 40 31 31% reported skin and mucous membrane symptoms; 22.5% reported skin symptoms only.
Omland et al. 1993 Denmark Authors surveyed 20 government office workers handling large amounts of CCP and a comparison group of 20. 20 10 50 Increased incidences of pruritus (P=0.007) and skin irritation (P=0.03) were associated with CCP. A dose-response relationship was established between pruritus and increased handling of CCP (P=0.049).
Apol and Thoburn 1986 United States Authors surveyed 65 employees making CCP. Ambient evaluation was also performed. 65 Unknown No numbers were presented. Maintenance workers in the coater area reported the most problems; 4 men reported pulmonary symptoms consistent with exposure to diisocyanates.
  1. The number of CCP-exposed workers surveyed was not generally known except for those responding to the surveys; therefore, response rates were unknown.
  2. 2.0 2.1 Original reference was not retrievable by NIOSH.
health effects (symptoms) was generally identified by surveys of workers using a questionnaire. A major concern with studies based on questionnaires is the potential for overreporting of symptoms, particularly when the study subjects are already concerned about the exposure being studied.

This concern is greater for the CCP studies than for the indoor air quality studies because the CCP studies were generally conducted at facilities where complaints of symptoms were allegedly related to CCP. The indoor air quality studies were not conducted in facilities where complaints were related to CCP, and thus they are generally considered to provide better information than the CCP cross-sectional studies. The indoor air quality studies and the CCP studies are considered separately below. Cross-Sectional Studies of Indoor Air Contaminants

A number of studies on indoor air quality have associated CCP exposure (and other factors) with workers’ symptoms (Table 4-3). Three indoor air quality studies—Knave et al. [1985], Reinikainen et al. [1990], and Thompson [l996]—are not included in this review because they were judged to be largely uninformative with respect to potential health effects associated with CCP exposure. One common limitation of the studies described below is that they generally include only two or at most three categories of CCP exposure and thus provide a very limited assessment of exposure-response.

Skov et al. 1987, 1989. Skov et al. [1987] conducted a cross-sectional survey of office workers and indoor climates in 14 town halls and other affiliated buildings in Copenhagen. Researchers administered a questionnaire to 4,369 workers and measured indoor climate factors in town halls. The return rate for the questionnaire was 80%. Measurements of the many indoor climate factors yielded values considered acceptable or within a typical range for office buildings as previously reported. The analysis showed that the following tasks were significantly correlated with the presence of mucosal and general symptoms: photocopying, working at video display terminals (VDTs), and handling CCP. However, in this univariate analysis the potential exists for confounding between CCP, photo-copying, and VDT exposures.

Subsequently, Skov et al. [1989] described the influence of personal characteristics as well as job-related and psychosocial factors on indoor air quality complaints in the same population. Of the 3,507 respondents (2,347 women), the CCP-exposed included 1,102 women and 424 men. For the 19 buildings studied, numbers were sufficient for multi-variate analyses. The questionnaire provided information about work activity, previous and present diseases, the presence of mucous membrane and general symptoms (headache, fatigue, and malaise), indoor climate, family and housing conditions, exercise habits, smoking, and consumption of alcohol and other beverages. Thirty-six percent (397) of these women reported complaints, as did 26% (110) of the men. In logistic regression analyses, sex, type of job, and the following job activities were significantly related to mucous membrane symptoms: handling CCP (P<0.0001), handling carbon papers (P<0.0001), photo-copying (P<0.0001), working at VDT's (P<0.0001), dissatisfaction with one’s superiors (P<0.0001), and work overload (P<0.0001). Crude prevalence rates showed a dose-response between frequency of CCP exposure and mucous membrane symptoms:

Monthly or less frequent use 24
Weekly use of 25 sheets or fewer 32
Weekly use ofmore than 25 sheets 43

With multiple logistic regression analysis, handling CCP weekly or daily had a significant effect on mucosal irritation (odds ratio [OR]=1.3, 95% confidence interval [CI]=1.1–1.6), and handling CCP was the only exposure with a significant effect on general symptoms (see above; OR=1.6, 95% CI=1.1–1.7). Also the authors commented that these office workers handled relatively small quantities of CCP.

Zweers et al. 1992. Zweers et al. [1992] conducted a cross-sectional epidemiologic study of indoor air quality and health effects in the Netherlands. Approximately 10,500 workers in 61 office buildings were studied. CCP usage, which was not the primary focus of the study, was ascertained in a questionnaire and analyzed as a dichotomous variable—handling "more than zero CCP per day" versus handling "zero." No usage prevalence was reported. Multivariate logistic regression models adjusted for personal variables, type of air-handling system, and various job and workspace variables. Controlling for some variables in the multivariate models (e.g., allergic or respiratory symptoms) may have underestimated actual CCP effects, as these factors may themselves have resulted from CCP exposures. Despite these limitations, the authors found associations of CCP handling with oronasal symptoms (OR=1.18, 95% CI=1.00–1.39), perception of air contaminants (OR=1.48, 95% CI=1.15–1.89), air quality complaints (OR=1.21, 95% CI=1.05–1.40), and lighting complaints (OR=1.30, 95% CI=1.12–1.51).

Mendell 1991 and Fiske et al. 1993. Mendell [1991] and Fiske et al. [1993] conducted a cross-sectional epidemiologic study in Northern California among 880 office workers in 12 office buildings. A strength of this study, unlike previous studies, was that the study facilities were selected without regard to worker complaints. Work-related symptoms used in the analyses were defined as those that "occurred often or always in the last year and improved when away from work." The questionnaire response rate was 85%. A number of factors (including CCP) were associated with the prevalence of work-related symptoms after adjustment in a logistic regression model for personal, psychosocial, job, workspace, and building factors (Table 4–4). The OR was not increased for a set of control symptoms included to detect overreporting associated with risk factors of possible concern (such as air-conditioning or CCP). In multivariate analyses adjusted for other workplace exposures, the authors reported that the use of CCP for more than 1 hr/day was associated with increased ORs for the following: eye, nose, and throat symptoms (OR=1.6, 95% CI=1.0–2.6); chest tightness or difficult breathing (OR=2.3, 95% CI=1.1–4.9); and fatigue or sleepiness (OR=2.1, 95% CI=1.3–3.5).

Omland et al. 1993. See Section for a discussion of this study.

Jaakkola and Jaakkola 1999. Jaakkola and Jaakkola [1999] conducted a cross-sectional epidemiologic study of office workers in 41 randomly selected buildings in Helsinki in 1991. They used a questionnaire to investigate associations of health effects with work involving CCP, photocopying, and VDT use. The populations studied had not been selected on the basis of prior complaints or concerns about CCP. The response rate to the questionnaire was 81%, representing a study population of 2,678 (1,119 men and 1,559 women). Of these workers, 910 were exposed to CCP. The outcomes studied included the work-related symptoms often associated with sick building syndrome as well as chronic respiratory symptoms and respiratory infections. Multivariate analyses controlled for building ventilation type in addition to a number of demographic, psychosocial, and other environmental factors. Blinding to the specific study hypotheses reduced the likelihood of information bias in reporting exposure. Known confounders
Table 4–4. Job or workspace factors associated with the prevalence of work-related symptoms after adjustment[1] for other personal, psychological, job, workspace, and building factors in northern California office workers, June–September 1990
Job or workspace factor Work-related symptoms
Eye, nose, or throat symptoms Chest tightness or difficult breathing Chills or fevers Fatigue or sleepiness Headache Dry or itchy skin Non-indoor-air-related symptoms
OR[2] 95% CI OR 95% CI OR 95% CI OR 95% CI OR 95% CI OR 95% CI OR 95% CI
Managerial job 1.2 0.7-2.2 0.8 0.2-3.2 1.7 0.2-1.3 0.8 0.4-1.6 0.6 0.2-1.4 1.2 0.4-3.8 1.2 0.5-2.9
Case worker job 1.2 0.6-2.5 0.8 0.2-3.0 1.0 0.1–7.5 1.2 0.6–2.4 0.6 0.3-1.5 2.2 0.7-7.3 1.7 0.7–4.3
Technical job 1.9 0.9-4.0 0.5 0.1-3.1 3.1 0.4-2.3 0.5 0.2-1.1 1.3 0.5-3.2 2.5 0.8-8.2 1.6 0.6–4.6
Clerical job 1.3 0.8-2.1 1.3 0.4-3.8 2.9 0.5–1.7 0.9 0.5-1.5 1.2 0.6-2.4 1.5 0.6-3.9 1.7 0.8-3.5
CCP use more than 1 hr/day 1.6† 1.0–2.6 2.3 1.1–4.9 1.7 0.7–4.6 2.1 1.3–3.5 1.4 0.8–2.4 0.9 0.5–1.9 1.4 0.8–2.4
Photocopier use more than 1 hr/day 1.6 0.8–3.1 1.7 0.6–4.7 0.4 0.1–2.1 1.4 0.7–2.8 1.5 0.7–3.1 3.1 1.4–6.9 1.4 0.6-2.9
Space-sharing with 2 or more workers 1.3 0.9-1.9 2.0 1.0-3.9 1.3 0.1-2.1 1.6 1.1-2.3 1.8 1.2-2.7 1.6 0.9-2.8 1.4 0.9-2.2
New paint within 15 ft of workstation 0.6 0.3–1.1 0.5 0.2–1.6 0.9 0.2–3.5 0.4 0.2–0.8 0.7 0.4–1.4 0.5 0.2–1.2 1.0 0.5–2.0
New walls within 15 ft of workstation 1.4 0.8-2.4 1.9 0.7–5.0 2.2 0.7–7.0 1.3 0.7-2.3 1.8 0.9-3.4 1.5 0.7-3.4 0.8 0.4-1.7
New carpet within 15 ft of workstation 3.0 1.0–8.8 14.2 3.2–63 1.2 0.1–15 1.4 0.4–4.4 2.6 0.8–9.2 0.5 0.0–6.0 2.8 0.8–9.5
Carpet—any in study space 1.7 1.1–2.6 2.5 1.0–6.2 1.4 0.5–3.7 1.1 0.7–1.7 2.0 1.1–3.4 0.9 0.5–1.8 1.1 0.6–1.9
Cloth partitions—any in study space 0.5 0.3–0.8 0.2 0.1–6.2 0.5 0.1–1.6 0.5 0.1–1.6 0.6 0.4–1.1 0.5 0.2–1.0 1.2 0.7–2.0
No windows within 15 ft of workstation 1.6 1.1–2.3 1.6 0.8–3.2 2.4 1.1–5.6 1.5 1.0–2.5 2.1 1.3–3.3 1.6 0.9–2.7 1.3 0.8–2.1
Inability to see out of window from workstation 0.8 0.5–1.3 0.8 0.3–1.7 0.4 0.2–1.2 1.6 1.0–2.5 1.0 0.6–1.7 1.1 0.6–2.1 1.0 0.6–1.7

Source: Mendell [1991].

  1. ORs and 95% CIs were adjusted in a logistic regression model.
  2. Abbreviations: OR=odds ratio; CI=confidence interval.
(including personal characteristics, smoking, socioeconomic status, and psychological and social factors at work) were controlled in the analysis. CCP use was analyzed as "any" versus "none."

Statistically significant associations were observed between work with CCP (involving 34% of the population) and most of the outcomes studied—including weekly work-related eye, nose, pharyngeal, and skin symptoms,headache, and lethargy (ORs=1.56, 1.48, 1.83, 1.68, 1.66, and 1.38, respectively); chronic respiratory symptoms including wheeze, cough, mucus, and chronic bronchitis (ORs=1.29, 1.43, 1.41, and 1.79, respectively); and respiratory infections including sinusitis and acute bronchitis (ORs=1.46 and 1.54, respectively). In contrast, only one of the 20 or so outcomes assessed (the common cold) was significantly elevated among workers with light or heavy photocopying work, and two symptom categories (otitis and general symptoms) were elevated for light or heavy VDT users. Additional analyses focused only on VDT and photocopier users; they identified several additional outcomes related specifically to these activities. This study provides strong support for the CCP health effects hypothesis. The numerous relationships found between health outcomes and CCP use (but not between health outcomes and photocopying or VDT work) make overreporting due to health concerns in the randomly selected buildings an unlikely explanation for these findings. Cross-Sectional Studies of CCP Exposures

Sixteen cross-sectional studies using questionnaires to assess health problems in relation to CCP exposure were conducted in Sweden, Denmark, and the United States (see Table 4–3). These studies attempted to describe and estimate the prevalences of various symptoms, primarily mucous membrane and skin irritation associated with the handling or manufacturing of CCP. A few of these studies had strong cross-sectional designs with appropriate unexposed comparison groups, ascertainment of symptoms independent of workers' opinions on their association with CCP use, and multivariate analysis allowing determination of the association with CCP exposures independent of other factors. In surveys with data on self-reported and unconfirmed symptoms that respondents subjectively attributed to CCP handling, concern about the use of CCP might (through hypervigilance or enhanced recall) upwardly bias estimates of symptom prevalence.

Fristedt and Pettersson 1980. Fristedt and Pettersson [1980] conducted a questionnaire survey of 180 persons (88% were women) in Sweden. Of these 180 study subjects, 135 had been identified in a previous survey[1] of the Swedish Association of Municipal Technology (SKTF) union as having reported symptoms related to CCP exposure. An additional 45 cases were identified from interview referrals (i.e., workers who had not previously disclosed symptoms but were mentioned in interviews with other workers). The average duration of CCP exposure was 5 years (maximum of 18 years), with 87% handling paper for more than 50% of their working time.

By correlating the time and use patterns, 68% (122 workers) were thought to have symptoms related to work with CCP, including some workers in printing operations. Fifty-three percent of this group with symptoms reported mucous membrane symptoms (primarily of the nose and eyes), and 47% reported skin symptoms (see Table 4–5). The skin disorders consisted mainly of dryness that occurred first on the hands and later on the face. The latter is localized around the eyes and sometimes combined with irritation of the eyes (assumed to be caused by touching the face with the hands). According to the authors, the most striking disorders occurred among the 67 who had a history of similar complaints or "a tendency to allergy." Of the 180 interviewees, 22 complained of an unpleasant smell that could not be linked to a specific CCP. One interviewee lost the sense of smell and taste, and two stated that they no longer had feeling in their tongues.

The authors stated that in the original survey of 3,000 workers, 30% to 50% of the employees at some workplaces had complained; but at others, no one had complained in spite of massive handling of CCP. Workers who handled clay-based papers reported skin disorders more frequently than those who handled polymer-based (phenolic) papers (71% [29/41]

Table 4–5. Types and locations of skin and mucous membrane symptoms in a Swedish questionnaire study
Type and location of symptom Number of workers reporting symptoms % workers linking symptoms with CCP
Type of skin symptom
Dryness 39 36
Itchng 16 94
Dryness and itching 26 62
Redness and rash 20 55
Eczema 7 14
Total 108
Location of symptom:
Hands 66 53
Arms 11 64
Face 29 69
Other 12 67
Total 118
Type of mucous memrane symptom:
Dryness 18 50
Irritation 28 58
Dryness and irritation 18 6
Allergy 6 17
Total 120
Location of symptom:
Eyes 57 54
Nose 86 63
Mouth 23 57
Throat 29 66
Total 195

Source: Fristedt and Pettersson [1980].

compared with 52% [36/69]). But those who worked with polymer-based (phenolic) papers reported mucous membrane disorders more often (81% [56/69] compared with 68% [28/41]). Solvents used in the clay paper consisted of hydrogenated terphenyls plus kerosene, and those in the polymer paper consisted of phenylxylylethane plus diisopropylnaphthalene [Norbäck et al. 1988]. Other numbers of symptoms were too small to discern patterns. Of the 35 workers who were skin-patch tested with

CCP, none had positive reactions. Environmental factors such as high temperature, low humidity, and dust were thought to be contributing. The authors concluded that it was difficult to decide which symptoms could definitely be correlated with CCP. The prevalence of complaints was 4% of the 3,000 workers who came in contact with CCP; but if slight complaints of doubtful origin were ignored, the prevalence was 2.4%. Symptoms were more severe in those predisposed to allergy, but no allergy to CCP components was demonstrated. Also, the authors remarked that most of the workers interviewed had reported ill health symptoms only after the newspaper publicity had appeared.

Andersson et al. 1980. This Swedish study used a questionnaire to address CCP effects among 158 workers at an insurance office who had reported symptoms of the skin (irritation and itching of hands, forearms, and face), eyes (itching and burning), and mucous membranes (dryness of mouth and throat, nasal stuffiness, and catarrh). To obtain comparative data, the same kind of questionnaire was distributed to four other office places (183 persons). The authors examined the type of paper in question as well as other environmental factors. The prevalence of symptoms increased when subjects were exposed to CCP or to wall-to-wall carpeting. This increase was observed in both atopic and nonatopic patients.

Öberg 1980. As cited in Murray [1991], Öberg conducted a questionnaire study of 205 people; 74% handled more than 10 CCP forms per day. Forty percent of the study population reported symptoms, including itching and dryness of the hands, eyes, and mouth. Four cases of eczema were found. The author reports a dose-response relationship, but Murray suggests that information was inadequate to verify this result.

Sondergard 1981. Sondergard [1981], as cited by Murray [1991] and Olsen and Mørck [1985], conducted a questionnaire study of workers at two locations of Scandinavian Airlines Systems. The frequency of symptoms reported was 73% (68 of 93 workers studied), and the symptom frequency increased with the amount of CCP handled daily (see Table 4–6). The author noted that the dose-response connection was not statistically significant because of the small number of workers in Groups 2 and 4 (numbers were not reported by the reviewers).

Menné et al. 1981. Menné et al. [1981] administered a questionnaire survey to workers at the Danish telephone company; the authors also performed a clinical evaluation of the cases (see Section 4.2.1). Approximately 77% of the workers responded to the questionnaire. Of these, some were eliminated because they did not handle CCP. Of the remaining 1,855 respondents, 208 (11%) indicated that they had experienced skin and/or mucous membrane irritation. Analysis revealed that the symptoms were not related to the type of building in which the subjects worked. According to the authors, the number of CCP contacts per day appeared to be clearly related to the frequency of symptoms:

Contacts: Symptom frequency (%)
0–10 5 10–50 15 20
Table 4–6. Dose-response relationship of CCP handling frequency with symptoms reported by respondents
Group Number of CCP sheets handled per day % Respondents with symptoms
1 <100 57.6
2 100–250 66.7
3 250–1,000 93.5
4 >1,000 100.0

Source: Sondergard [1981] as cited by Murray [1991] and Olsen and Mrrck [1985].

The authors suggested that mass psychosis was an unlikely explanation for their findings since an exposure-response relationship was identified—not the all or nothing response expected with mass psychosis. The authors also suggested that mass psychosis was inconsistent with the fact that no relationship existed between the age of the workers and the number of complaints: they would expect younger workers to have the weakest ties to the company and thus to be more likely to report symptoms. In rejecting mass psychosis as an explanation for their findings, the authors suggested that some component of the paper was responsible for the observed symptoms.

Göthe et al. 1981 and Norbäck et al. 1983b. Göthe et al. [1981] and Norbäck et al. [1983b] presented findings about the frequency of respiratory symptoms in three groups of Swedish patients:

  • Group A: 19 patients referred to the Clinic of Occupational Medicine at South Hospital
  • Group B: 38 patients at the Karolinska Clinic of Occupational Dermatology
  • Group C: a random sample of 22 patients with no CCP exposure
The patients in Groups A and B were referred during the period January 1976 to October 1980 because of health problems associated with occupational handling of CCP. However, because the authors did not describe the population from which the patients were referred, population prevalence rates could not be calculated. Among patients with health complaints from handling CCP, roughly half reported irritative symptoms involving the eyes or upper respiratory tract, and 11% (Group A) to 28% (Group B) experienced nasal catarrh or congestion. In the unexposed group (Group C), 14% experienced ocular or upper respiratory irritation, and there were no cases of nasal catarrh or congestion. The difference in incidence between the exposed groups (A and B) and the unexposed group (C) was statistically significant (P<0.01) for eye and upper respiratory irritation. The elevated incidence of nasal catarrh or congestion was statistically significant (P<0.01) in Group B but not in Group A relative to the unexposed Group C. Symptoms such as headache, fatigue, nausea, and a metallic taste in the mouth occurred at a low rate (1% to 9%), with no statistically demonstrable correlation with the type of exposure or the volume of CCP handled. The results in Table 4-7 contrast patients in a high-exposure group (≥150 sheets per day) with those in a low-exposure group
Table 4–7. Frequency of respiratory tract symptoms by type of paper and exposure level[2]
Type of paper Workers exposed to <150 sheets per day Workers exposed to ≥150 sheets per day
Total number in group Workers reporting symptoms Total number in group Workers reporting symptoms
Number % Total Number % Total
Paper containing MIPB 6 3 50 5 5 100
Other CCP 21 4 19 26 13 50
Ordinary paper and carbon paper 7 0 0 15 3 20

Source: Göthe et al. [1981] and Norbäck et al. [1983b].

  1. In this previous survey, only 243 (8%) of the 3,000 persons surveyed responded to the questionnaire, which raises serious concerns about the representativeness of the respondents.
  2. Note: These values vary slightly in the earlier publication.

(<150 sheets per day). Patients were excluded if they had irritation of the respiratory tract that was not specifically related to work with paper. The data show that throughout, the frequency of complaints was higher in the high-exposure groups than in the corresponding low-exposure groups for all types of paper, including ordinary paper. These data also demonstrated a higher prevalence of work-related respiratory symptoms in patients seen at the clinic and exposed to CCP containing MIPB—a solvent used in the microcapsules. This prevalence rate was 100% in the high-exposure group.

Norbäck et al. [1983b] also investigated whether the dose-response associations might be due to an increased proportion of sensitive workers among those who handle large amounts of paper. They determined whether patients with atopy or nonspecific hyperreactivity of the respiratory tract were concentrated among these highly exposed individuals. Atopy was assumed to be present if the patient had a history of asthma or hay fever or a tendency to develop eczema.

Nonspecific hyperreactivity was assumed to be present if the patient had reported experiencing respiratory tract irritation when exposed to nonspecific irritants such as perfume, cigarette smoke, and vehicle exhaust in the everyday environment. Fewer sensitive patients (P<0.05) were identified among those who handled large volumes of paper than among those who handled small volumes of paper, indicating that confounding by atopy could not explain the observed exposure-response relationships.

These authors also investigated the role of D-inks, which were present in about 20% of the CCP. A significant increase (P=0.00009) occurred in the prevalence of work-related pruritus combined with erythema in those working with CCP treated with D-ink versus those not working with these inks (39% versus 0%).

Analysis of other contributing factors in this population revealed that work involving photocopies or the presence of wall-to-wall carpeting was not significantly correlated with skin or mucous membrane symptoms. The authors concluded that a significant dose-response relationship could be shown only between exposure to CCP and mucous membrane irritation of the upper respiratory tract. The authors stated that the same phenomenon occurs with ordinary paper and carbon paper but that CCP can produce symptoms when lower volumes of paper are handled.

Kolmodin-Hedman et al. 1981. At a clinic for occupational medicine in Uppsala, Sweden, Kolmodin-Hedman et al. [1981] conducted an inquiry among those employed by an insurance office (total of 145 workers) and a hospital laboratory (12 workers). A comparison group of 20 was composed of hospital office staff who did not handle CCP. The investigation was triggered by six cases in an insurance office; the main symptoms were irritation of the upper respiratory tract. The prevalence of symptoms was greatest in the hospital laboratory (92%), where about 1,000 forms were handled per day by each of the five receptionists and seven computer operators. The insurance office workers worked with fewer forms (number not given) than the laboratory workers; they reported a 32% prevalence. The comparison group reported a 10% prevalence of symptoms. Of those in the insurance group who complained of symptoms (46), 17 were diagnosed as atopic and 6 with underlying allergic or eczematous conditions. Of the remaining 23, one had symptoms connected with handling "wet copies," and another had a complaint that was clearly linked to the use of a certain type of stamp pad. The remaining 21 had skin and/or mucous membrane complaints: 13 stated that they had the most trouble at work, and 8 stated that their symptoms were independent of where they were. None of the six types of CCP forms used were known to contain D-inks, and three contained hydrogenated terphenyls, diethylethane, and diisopropylnaphthalenes. Two contained unknown solvents. Among the workers who handled only clay-based paper at the insurance office, the frequency of mucous membrane symptoms was approximately equal to that of the comparison group. The skin (hands and face) and eye symptoms were considered likely to be related to CCP exposure, since their frequency (21% among insurance workers versus 67% in laboratory workers) was much higher than that of the comparison group (5%).

Kleinman and Horstman 1982. In the United States, persistent health complaints attributed to the use of CCP by office workers on the campus of the University of Washington led to a preliminary study by Kleinman and Horstman [1982]. The goals were (1) to estimate the extent of the problem in a population of known CCP users, (2) to describe the health problems that the users attributed to CCP, and (3) to make a preliminary determination of the chemical constituents of the paper. An unknown number of office workers were asked to complete a health questionnaire and to attach to it copies of the forms they used. Among the 265 subjects respondng to the survey, 71 (27%) reported complaints. Across different offices, the minimum estimate was 10.7 health complainants per 100 users, similar to that found by investigators in the United Kingdom and Denmark [Calnan 1979; Menne' et al. 1981], but this estimate was lower than that reported by other investigators and by anecdotal material. Of the 108 respondents who answered "yes" (n=71) or "don't know" (n=37) to the question relating symptoms to CCP, 53 participated in a medical exam. The positive findings are tabulated in Table 4-8. Kleinman and Horstman [1982] also reported a significant relationship (X12-0.0002) between the amount of CCP used daily and worker reports of health effects they attributed to CCP: 41.3% of the heavy users of CCP (those who handled 51 or more forms/day) responded "yes" to the question relating health effects with CCP, compared with 29.9% of moderate users (11 to 50 forms/day) and 18.8% of minimal users (1 to 10 forrns/day). The authors hypothesized that concurrent factors such as poor
Table 4-8. Positive findings from physician interviews of 53 respondents to a health questionnaire
Finding % total
Red, swollen, scaly hands 41.5
Stuffed nose 39.6
Sneezing 37.5
Headaches 35.8
Running nose 30.2
Infected, itching, red conjunctiva 29.6
Red, swollen eyelids 20.4
Red face 17.0
Shortness of breath 15.1
Coughing 13.2
Red, crusted skin 7.5
Wheezing 7.5
Red arms 5.7

Adapted from Kleinman and Horstman [1982].

ventilation, high temperature, and/or low humidity might play a role in the clinical expression of CCP effects.

Pryor et al. 1983. In response to a request for a NIOSH Health Hazard Evaluation, Pryor et al. [1983] investigated complaints of respiratory, eye, and skin irritation and one case of thrombocytopenia at a Colorado municipal court house. A questionnaire was administered to eight employees who worked in an area with intensive storage and use of CCP forms and also to eight others who worked in an area with little CCP contact. The CCP storage was immediately next to 2- and 4-inch pipes carrying hot water during the winter for heating the building; these pipes were believed to be causing increased emissions from the CCP. Heating CCP paper samples in the NIOSH laboratory produced formaldehyde and also substituted biphenyls and terphenyls typical of CCP. However, air samples taken in the office at various times during the months of December and March identified only formaldehyde. CCP-exposed workers during the month of April had somewhat higher prevalences of eye, nasal, and throat complaints (ranging from 25% to 75%) than non-CCP-exposed workers, whose symptoms ranged from 0% to 50%. However, small numbers precluded a statistical test.

Olsen and Merck 1985. Olsen and Morck [1985] administered a questionnaire and physical exams to the 129 workers at two Danish form-printing shops. The authors confirmed complaints that the CCP-exposed parts of the skin exhibited "heavy erythema, combined with irritative itching, vesicles, and wounds together with more chronic changes with lichenification, furrows, and chaps." The frequency of symptoms increased significantly (P<0.01) with the volume of CCP handling (see Table 4-9).

Omland et al. 1993. Omland et al. [1993] investigated the extent to which handling large amounts of CCP caused skin and mucous
Table 4-9. Dose-response relationship between CCP handling and mucous membrane and skin symptoms in two form-printing shops
CCP handling frequency
(sheets per day)
Total number of workers Workers with symptoms
Skin and mucous membrane symptoms Skin symptoms
Number % Number %
0-5 26 0 0 0 0
6-20 26 0 0 0 0
21-75 28 9 32.1 5 17.9
76-250 25 14 56.0 10 40.0
251-2000 24 17 70.8 14 58
Total 129 40 31.0 29 22.5

Source: Olsen and Mørck [1985].

membrane symptoms in a cross-sectional study of 20 Danish government workers who were highly exposed to CCP and a comparison group of 20 workers who were generally not exposed. These groups were matched for sex, age, location of workplace, known skin diseases, history of childhood asthma, known allergy to nickel, asthmatic conditions, chronic bronchitis, eye diseases, nettle rash, and use of tanning facilities. Double-blind dermatological exams included observations and histories, skin-prick tests for allergens, scratch tests for CCP and its components versus ordinary paper, objective measures of dermal erythema after occluded testing, and skin-patch tests. Temperature, humidity, formaldehyde, and total dust were measured. Two groups of workers were exposed to CCP. Over a period of 4 weeks, the first group of 5 sent out 120,000 identical forms printed on CCP that had been stored in the work area. Their work consisted of tearing off forms from a continuous paper web and stuffing the forms into envelopes (about 1,200 per day per worker). The second exposure group of 15 workers processed the 42,000 returned forms over a 2-week period, checking and entering information into computers (about 280 per day per worker). The comparison group was selected from 122 employees who worked in the same large office building and had returned completed questionnaires about symptoms and exposure to CCP. These questionnaires were administered weekly during the exposure periods. They included questions about CCP exposure, work with computers and photocopying, and subjective symptoms of skin and respiratory irritation. Temperature was 23.5 °C and humidity was about 40% in both offices. These were reported along with six formaldehyde measurements, (including both area and personal samples) ranging from 0.1 to 0.62 mg/m³. Total dust measurements were 0.34 mg/m³ in the study office and 0.28 mg/m³ in the comparison group office. Table 4-10 shows the incidence of symptoms during both exposure periods among the exposed workers and their matched comparison workers. A significantly greater incidence of skin irritation (P=0.03) and pruritus (P=0.007) occurred in the exposed group during the first exposure period. However, no differences occurred in the incidence of

Table 4-10. Incidence of symptoms in exposed workers and their matched comparison workers during two exposure periods
Exposure period and type of worker Number of responses[1] Symptoms (%)
Eye irritation Red eyes Skin irritation Facial erythema Erythema of the hands Pruritus Rash Nasal Congestion Runny nose Nosebleed Cough
Exposure period 1:[2]
Comparison worker 18 33.3 22.2 16.7 11.1 0 22.2 11.1 11.1 5.6 0 11.1
Exposed worker 5 60.0 20.0 80.0 0 20.0 100.0 0 60.0 0 20.0 60.0
Exposure period 2:[3]
Comparison worker 16 25.0 25.0 25.0 6.3 6.3 18.8 12.5 6.3 18.8 0 12.5
Exposed worker 15 20.0 20.0 13.3 20.0 13.3 33.3 6.7 20.0 20.0 6.7 20.0

Source: Omland et al. [1993].

  1. Some comparison workers were unable to respond because they were absent from work.
  2. Workers were exposed to 1,200 fresh forms per day during period 1.
  3. Workers were exposed to 280 forms (with broken microcapsules) per day during period 2.
symptoms reported by the exposed and comparison workers during the second exposure period, which involved processing forms that were several months old. Exposed workers reported large decreases in most symptoms during the second period, when they handled the completed forms with broken microcapsules (280/day) rather than the fresh forms (1,200 per day) during the first period. These symptom decreases during the second period included a sixfold decrease in skin irritation and threefold decreases in eye irritation, pruritus, nasal congestion, nose-bleed, and cough. However, increases occurred in facial erythema, rash, and runny nose.

Figure 4-2 shows the relationship between pruritus and increasing CCP exposure. Four of the 18 comparison workers (22.2%) during the first exposure period and 3 of the 16 comparison workers (18.8%) during the second exposure period reported pruritus. Ten of the 20 workers (50%) exposed to CCP experienced pruritus: 4 of 10 employees (40%) who worked daily with 101 to 750 form sets, and 6 of 10 employees (60%) who worked with >750 form sets reported pruritus. These results show a statistically significant increase in the prevalence of pruritus with increasing exposure to CCP, regardless of whether the responses were used from the first exposure period (P=0.049) or the second exposure period (P=0.03). Clinical ex- amination revealed no significant differences between atopic workers in the exposed and comparison groups. The duration of pruritus after histamine provocation was also the same in both groups. Erythema index measurements showed large variations, and no significant differences existed between the reactions of workers in the exposed and the comparison groups to contact with paper, CCP, the contents of the microcapsules, or a damping solution from CCP. Scratch tests with CCP were negative, and skin patch tests with nickel yielded four reactions in the exposed group and one reaction in the comparison group. Al- though these differences were not statistically

significant, the authors noted that the higher number of nickel reactions in the exposed group may indicate a higher prevalence of atopic workers in that group and thus a potential bias in the study. No increased skin dryness or desiccation was noted in the exposed or comparison groups. Possible shortcomings of this otherwise well-designed study are that (1) the matched comparison workers were not matched for the amount of ordinary paper they handled, and (2) the matching does not appear to have been considered in the analysis of the data. Thus the study results may be potentially confounded by the matching factors and by ordinary paper exposure. On the other hand, the strength of the association (P<0.007) and the evidence of an exposure-response relationship (P=0.049) support an association of some types of CCP with pruritus.

Apol and Thoborn 1986. See Section 4.2.1 for a discussion of this study.

4.2.4 Laboratory Studies in Humans

This section reviews studies that used some form of experimental testing in humans (such as patch or prick tests) under controlled laboratory conditions to assess the potential health effects of exposure to CCP or its components. These studies are distinct from the laboratory studies performed in some of the case studies and cross-sectional studies reviewed earlier in this chapter (see Sections 4.2.1 and 4.2.3), which generally involved a few cases from a specific company and did not employ a rigorous experimental design. In addition to the peer-reviewed literature, this section examines unpublished experimental studies that were usually sponsored by the U.S. manufacturers of CCP and were submitted to the NIOSH docket.

The experimental nature of laboratory studies offers advantages over the observational studies described in earlier sections. These studies do not have the potential for confounding or recall bias that the observational studies had. However, laboratory studies also have limitations that undermine their usefulness for judging the causal relationship between CCP exposure and health effects. First, these studies are largely limited to the inclusion of healthy volunteers. A consequence of this approach is that persons with a history of allergy or irritation reaction might be less likely to volunteer than those with no symptoms, thus creating selection bias. Second, it is unclear whether the exposures in laboratory studies are representative of those actually experienced by workers in the field. Third, most of the laboratory studies did not include ordinary paper as a control. Thus it is not possible to determine whether the effects observed in some studies result from chemical components of CCP or from the paper itself. Peer-Reviewed Literature Studies

Table 4-11 summarizes the three experimental studies in humans that have appeared in the peer-reviewed literature. These studies are discussed below.

Nilzen 1975. At the request of a CCP manufacturer, Nilzen [1975] of Sweden conducted provocative tests (including patch, prick, eye, and nose irritation tests with water extracts) and vapor inhalation studies with crushed CCP and ordinary bond paper. The patch tests in eight subjects were negative, but prick tests resulted in an unspecified number of weak and medium-strong reactions to both CCP and ordinary bond paper. Two subjects were tested by inhalation of vapors from CCP or bond paper, and both resulted in irritation; however, the CCP caused a greater reaction. The author concluded that (1) certain persons with a history of allergy or irritative reactions may react to CCP as well as to ordinary bond paper and a variety of other materials and (2) despite evidence of

Table 4–11. Experimental laboratory investigations of allergic and irritative reactions in humans exposed to CCP
Authors Country Number tested Agents Type of test Comparison workers Results
Nilzen 1975 Sweden 16[1] CCP, nose and eye administration of extracts Patch and prick tests, eye and nose irritation, inhalation of vapors from pulverized paper 8 matched comparison workers No positive patch tests; some weak and moderate reactions to prick test with CCP and ordinary paper; two subjects had irritation reactions to vapors from CCP and ordinary bond paper.
Jeansson et al. 1983, 1984 Sweden 148 CCP, non-CCP paper components, specific chemicals in CCP Patch and scratch tests and other examinations None Positive reactions to 2 types of carbon paper. Slight irritation from 50% kerosene (1/59), 50% isoparaffins (1/59). Slight redness from 100% alkylated benzene (1/1), but no reaction with a 50% concentration (0/54). Primary irritation from 2 D-inks (1 at 5% concentration [19/44] and 1at 1% [26/44]). CCP-exposed patients had a longer duration of itch in tests assessing skin response to histamine. Two probable allergic reactions to synthetic resin components (1 to melamine formaldehyde and 1 to resorcin). No specific reactions to subjects’ exposures to their own CCP.
Morgan and Camp 1986 United States 28 Vapors from CCP and bond paper Nasal impedance None In clerical workers, nasal impedance increased 34% (P<0.025) after exposure to CCP vapors and 8% after exposure to plain paper (P>0.01). In atopic workers, nasal impedance increased significantly after exposure to both CCP vapors (30% to 40%) and plain paper.
  1. Eight test subjects and 8 comparison workers.
CCP reactions, nonreacting persons (those without a history of allergy or irritative reactions) can handle CCP without risk.

Jeansson et al. 1983, 1984. During patient followup visits, the authors investigated patients who had complaints related to any type of paper and who had been referred to an occupational dermatitis clinic in Sweden from January 1974 to December 1980. Their complaints included irritation of the eyes, nose, throat, arms, face, and scalp; cold symptoms; hoarseness; sores; itching, dryness, redness, or eczema of the hands; unpleasant odor or taste; fatigue; headache; nausea; joint pains; and a feeling of paralysis.

Jeansson et al. [1983] appraised the chemical contents of the papers by skin tests (patch and scratch) and by other examinations of 148 patients. No controls were included in this study. Three of the original 151 complainants were lost to followup. The focus of the study was to find the triggering chemical factor by (1) examining the chemical content and the toxicological effects of the paper, (2) examining the distribution of patients according to the suspected cause of problems, and (3) investigating the relative prevalence of contact allergies. The complaints involved multiple brands of CCP. Manufacturers submitted lists of the composition of 13 brands of CCP on the Swedish market along with samples of the chemicals from the production process. The authors applied a series of patch tests using a standard panel of 30 known antigens as well as samples of paper (CCP, data paper, carbon paper, and photocopying paper) and CCP components. The tests were performed on 134 patients (those with CCP-related complaints) using the CCP with which they worked. Of these patients, about 50 were also tested with approximately 60 chemicals from the paper production process. The authors tested the following CCP components: those in the CB and CF surfaces in both wet and dry preparations, saline extracts of CCP, 62 chemical components (representing about 95% of the components on the Swedish market), 7 desensitizing chemicals, and 3 adhesive products.

Specific antibodies (IgE, RAST) against dust and molds were identified in 4 of 35 cases, none of whom were among the patients with CCP complaints. The authors noted that this number was not an overrepresentation for a group such as this. The only positive reactions that occurred from any of the test materials other than the standard ones were from two types of carbon paper (not CCP). Slight irritation occurred when testing 50% kerosene (1 of 59) and 50% isoparaffins (1 of 59). Slight redness (1 of 1) occurred with 100% alkylated benzene, but no reaction occurred at repeat testing with a 50% concentration in 54 test subjects. Two of five D-inks produced primary irritation at 5% concentration: the first ink resulted in a slight redness in 43% of patients (19 of 44); and at 1% concentration, the second caused slight redness in 59% of those tested (26 of 44). "Itch" tests assessing skin response to a nonantigenic stimulus (histamine) were performed. Responses were measured as the duration of the sensation of itch and the size of the reddened area after administration of 3 concentrations of histamine below the epidermis. Twenty patients having CCP-related complaints were compared with 17 patients having previous complaints about non-CCP paper . The CCP patients suffered a significantly longer duration of itch (0.05>P>0.01 [Göthe et al. 1981]) than the matched comparisons; however, the area of redness did not differ between the two groups. The authors commented that the longer-lasting itch correlated with the higher prevalence of mucous membrane irritation on exposure to CCP (65% versus 50%).

Among the patients examined with possible CCP-related symptoms, no allergic or single irritant mechanism was found to explain how the handling of CCP directly resulted in medical problems. On the basis of the available assays of irritant or allergenic potency, the authors were unable to conclude that a specific chemical was common to CCP complaints. Two patients had probable allergic reactions to components in the synthetic resins (one to melamine formaldehyde and one to resorcin), but those reacting to resins or solvents did not react in patch tests to their own CCP. Other contributing factors were mentioned, such as the handling of paper generally (i.e., carbon paper, plain paper, CCP, etc.) and atopy. The authors asserted that there were no differences by CCP brand; however, because of the design of the study (only symptomatic workers were included) differences in prevalence or incidence of symptoms across CCP brands could not be assessed. The authors concluded (based on the absence of a causal agent) that CCP was not the leading suspect responsible for symptoms in most of the patients exposed to CCP.

Morgan and Camp 1986. Morgan and Camp [1986] conducted an experiment in the United States under controlled laboratory conditions to quantify upper respiratory congestion in clerical workers reporting prior sensitivity when exposed to CCP. Seventy percent of the subjects reported having symptoms associated with CCP use. These symptoms included dryness, light-headedness, headache, dry mouth, burning sinuses, dizziness, sore throat, tickle in throat, sneezing, irritation, itching nose, congestion in throat, and flushed face. The symptoms reportedly increased with increased use of CCP and tended to dissipate rapidly when the worker was removed from the exposure. The authors used an objective measure of nasal congestion—measurement of the nasal contribution to the work of breathing (nasal impedence) by posterior rhinomanometry. The subjects were 28 clerical workers who reported handling 1 to 200 CCP forms per day, with an average of 90 forms per day. These workers were subjected in random, single-blind fashion to controlled exposures of vapors from two sets of three-page, blue-dye CCP forms and to vapors from plain bond paper. Any particles released by the paper were removed by a 0.3-µm particle filter. Total hydrocarbon concentration during CCP exposure averaged 1 ppm. Nasal impedance increased 34% after exposure to CCP forms (P<0.025) and 8% after exposure to plain paper (P>0.10). However, frequency of symptoms did not differ between exposure to CCP and plain paper, and they were not correlated with the nasal measurements. The authors concluded that quantitation of nasal congestion by this technique may be a sensitive measure of short-term reaction to inhalation of irritants. In subjects with a history of allergy, changes in nasal function were reported after exposure to both paper types, but only the change after CCP exposure was statistically significant (paired t-test, P<0.05). In these patients, nasal aerodynamic response to CCP vapor was significant even with low concentrations of hydrocarbon exposure, and objective changes were measured in the absence of consistent subjective complaints. NIOSH Docket Submissions

RIPT Studies. NIOSH reviewed all of the industry-sponsored laboratory studies in humans submitted to its docket as a result of the Federal Register notices in 1987 and 1997. Most of these studies were RIPT studies, which are summarized in Table 4–12. The RIPT is a test method designed to evaluate the potential of a material to induce and elicit type IV skin sensitization reactions (allergic contact dermatitis) in humans [ASTM 1999]. In general, these tests were performed by administering multiple potentially sensitizing doses of study material as occlusive patch tests over a several-week period. After 2 to 3 weeks, subjects were challenged with an additional diagnostic patch test and evaluated for responses consistent with allergic contact dermatitis.

Table 4–12. Analysis of repeated insult patch test (RIPT) studies submitted by industry clients in response to 1987 and 1997 Federal Register notices on CCP and its components
Study year Report number[1] Laboratory Test material Response rate[2] Score[3] No. of subjects with score Classification as irritant (Y/N)[4][5] Current use of material
1955 E–107 Hill Top Research, Inc. "Internal phase" diluted 50% w/oil, CB, CF, carbon, and base paper ND ND N Solution of CCP component; end-user not exposed; discontinued[6] after 1971
1972 SH–72–4 Shelanski Holding Co. Monsanto Co. Lot QA-I-SHC No. M–77 (100% Santosol 100 solvent only) 1/50 ND N[7] Component of CCP; end-user would not be exposed
1977 77–512–70 Hill Top Research, Inc. A. Paper, CF surface colored by transfer from ruptured CB surface 0/71 NR N Test materials discontinued in late 1970s
B. Paper, CF surface not colored 0/71 NR N
C. Blue liquid 5/71   Y[7]
1 3
2 1
5 1
D. Dark liquid 3/71   N
1 1
2 2
E. Brown granules 7/71[8]   Y
1 1
2 2
6 4
F. Purple granules 1/71 5 1 Y[7]
G. No sample
H. Brown liquid 0/71[9] NR N
I. Amber liquid 1/71 1 1 N
J. Paper, CB surface with ruptured capsules 1/71 2 1 N
K. Paper, CB surface with intact capsules 0/71 NR N
1977 77–513–70 Hill Top Research, Inc. A. Code 29 CFB, sheets of paper (CF surface colored from ruptured capsules of CB surface) 0/12 NR N Test materials discontinued in late 1970s
B. Code 29 CFB, sheets of paper (uncolored CF surface) 0/12 NR N
C. 24W CB (E73–8) plus, blue liquid 0/12 NR N
D. Code 23 oil plus, blue liquid 1/12 1 1 N
E. Code 24 CB (E73–8) dried, white powder 0/12 NR N
F. Code 24 CB (E73–8) plus, light blue powder 1/12 1 1 N
G. No G sample N/A NR N
H. Code 28 oil, blue liquid 0/12 NR N
I. Code 27 oils, amber liquid 0/12 NR N
J. Code 29 CFB, sheets of paper (CB surface with ruptured capsules) 0/12 NR N
K. Code 29 CFB, sheets of paper (CB surface with intact capsules) 0/12 NR N
1977 77–896–71 Hill Top Research, Inc. A. CF surface colored by transfer from CB surface 3/97   N[7] Test materials discontinued in late 1970s
1 1
2 2
B. CF surface uncolored 5/97   N
1 2
2 2
4 1
C. No description 6/97   Y
2 3
3 1
4 1
5 1
D. No description 3/97   N
1 1
3 2
E. Code 24 CB (E73 dried) 2/97   N
1 1
2 1
F. No description 3/97   Y
1 1
3 1
5 1
G. No G sample
H. Code 28 oil 0/97 NR N
I. No description 1/97 2 1 N
J. CB surface used in developing color 5/97   N
1 1
2 1
3 1
4 2 K. CB surface with intact capsules 3/97   Y
2 1
4 1
5 1
1977 77–926–71 Hill Top Research, Inc. A. Not identified 1/163 1 1 N Test materials discontinued in late 1970s
J. Not identified 2/163 1 2 N
K. Not identified 4/163   N
1 3
4 1
1978 78–557–71 Hill Top Research, Inc. A. Blue print internal phase, liquid 85/211   N Solution of CCP component; end-user not exposed; test materials discontinued in mid-1980s
1 61
2 15
3 3
4 6
B. Blue print emulsion, lavender liquid 0/211 NR N
C. Blue transfer paper, off-white paper 2/211 1 2 N
D. Black print internal phase, liquid 0/211 NR N
E. Black print capsule slurry, lavender liquid 0/211 NR N
F. Black transfer paper, off-white paper 2/211 1 2 N
G. Internal phase black print, liquid 1/211 1 1 N
H. Black print self-contained capsules, lavender liquid 1/211 2 1 N
I. Self-contained black, off-white paper 5/211 1 5 N
1978 78–578–70 Hill Top Research, Inc. A. CF surface colored by transfer from CB surface 1/152 2 1 N Test materials discontinued in mid-1980s
B. CF surface uncolored[10] 1/152 1 1 N
J. CB surface used in developing color 0/152 NR N
K. CB surface with intact capsules 0/152 NR N
1979 79–512B–70 Hill Top Research, Inc. A. Imaged CF colored ruptured capsules of CB surface 1/2 ND N[7] Not known
B. Unimaged CF surface 0/2 ND N
1979 79–0002–73 Hill Top Research, Inc. A. CFB CF surface colored 1/166 2 1 N Test materials discontinued in mid-1980s
B. CF surface uncolored 1/166 2 2 N
C. CB surface ruptured capsules 2/166   N
1 1
2 1
D. CF surface colored 0/166 NR N
E. CF surface uncolored 1/166 2 1 N
F. CB surface ruptured capsules 0/166 NR N
1979 79–0085–73 Hill Top Research, Inc. A. CF surface, colored 1/151 3 1 N[7] Test materials discontinued in mid-1980s
B. CF surface uncolored 1/151 3 1 N[7]
C. CB surface ruptured capsules 0/151 NR N
D. CB surface capsule not ruptured 0/151 NR N
E. CF surface colored, code 94 2/151   Y[7]
1 1
5 1
F. Code 94 CF surface uncolored 5/151   Y[7]
1 4
5 1
G. Code 94 CB, ruptured capsule 2/151   N
2 1
4 1
H. Code 94 CB, capsules not ruptured 1/151 4 1 N
1979 79–0246–73 Hill Top Research, Inc. A. CF surface colored 2/136   N Test materials discontinued in mid-1980s
1 1
4 1
B. CF surface uncolored 2/136   N
3 1
4 1
C. CB surface, ruptured capsules 1/136 2 1 N
D. CB, unruptured capsules, code 95 2/136   N
1 1
4 1
E. CF colored 2/136 1 2 N
F. CF uncolored 1/136 4 1 N
G. CB ruptured capsules, code 96 2/136   N
1 1
2 1
H. CB, unruptured capsules, code 96 0/136 NR N
1979 79–0801–73 Hill Top Research, Inc. A. Yellow paper CB surface unruptured capsules 7/122   N Test materials discontinued in mid-1980s
1 3
2 3
4 1
B. Yellow paper CF surface imaged by ruptured capsules 2/122   N
1 1
2 1
C. Yellow paper uncolored CF surface 1/122 1 1 N
D. Yellow paper CB surface ruptured capsules 5/122   N
1 1
2 4
E. White paper self-contained surface of paper imaged 2/122 2 2 N
F. White paper self-contained surface of paper unimaged 3/122   N
1 2
2 1
1980 80–0079–73 Hill Top Research, Inc. A. 118 CF surface uncolored (unimaged) 0/99 NR N Test materials never marketed
B. 118 CF surface colored (imaged) 1/99 1 1 N
C. 121 CB surface unruptured capsules 0/99 NR N
D. 121 CF surface uncolored (unimaged) 0/99 NR N
E. 121 CB surface ruptured capsules 0/99 NR N
F. 121 CB surface colored (imaged) 0/99 NR N
G. 122 CB surface unruptured capsules 0/99 NR N
H. 122 CF surface uncolored (unimaged) 0/99 NR N
I. 122 CB surface ruptured capsules 0/99 NR N
J. 122 CF surface colored (imaged) 0/99 NR N
1981 81–0138–73(2) Hill Top Research, Inc. B. T–3012PP—White paper 0/207 [11] [11] N Discontinued in mid-1980s
C. T–3013PP—Pink paper 0/207 [12] [12] N
1983 83–0305–70 Hill Top Research, Inc. C1. Pink paper, CB surface with unruptured capsules 0/93 NR N Not repeatable results; test materials discontinued in mid-1980s
C2. Pink paper, CF uncolored surface 0/93 NR N
C3. Pink paper, CB ruptured capsules 0/93 NR N
C4. Blue and imaged pink paper CF (blue) surface with color transferred from ruptured capsules 0/93 NR N
D1. White paper, CB surface with unruptured capsules 0/93 NR N
D2. White paper, CF uncolored surface 1/93 1 1 N
D3. White paper, ruptured capsules, CB surface 0/93 NR N
D4. Blue and imaged white paper CF (blue) surface with color transferred from ruptured capsules 0/93 NR N
1983 83–3592H Biosearch Moore Business forms, MCP 2010 0/200 NR N Test material discontinued in early 1980s
1983 83–0771–70 Hill Top Research, Inc. "Sample A" - no other information given 1/14 ND Y Solution of CCP formulation; end-users not exposed
1986 3683 Inveresk Research International A. Resin CF based on Durez resin 32131 24/27[13]   N Test material never used in United States
1 7
2 10
3 6
4 1
B. CF control, standard production paper, S/K/Dow 675 formulation 27/27[14]   N
1 10
2 9
3 5
4 3
C. CB, E20 formulation in 1:2 HB 40/alkylbenzenes in Gel-CMC microcapsules 25/27[15]   Y
1 11
2 8
3 4
4 1
5 1
D. CB, SF2 formulation in 100% alkylbenzenes in Gel-CMC microcapsules 25/27[16]   N
1 10
2 7
3 6
4 2
E. CB control, E20 formulation in 2:1 HB 40/kerosene in BW1 microcapsules 26/27[17]   N
1 12
2 9
3 4
4 1
F. Bond control, Dartford Systems Paper, 60 g/m2 25/27[18]   N
1 7
2 9
3 7
4 2
1987 83–0091–70 Hill Top Research, Inc. CB and CF paper, crushed and uncrushed, aqueous and intact ND ND ND Test materials discontinued since sponsor no longer in this business
1987 86–5436H Biosearch MCP 1010— "#1 formulation" CFB sheet CB side, white paper 0/206 NR N Test materials discontinued in late 1980s
MCP 1010— "#4 formulation" CFB sheet CF side, white paper 0/206 NR N
MCP 2010— "#1 formulation" CFB sheet CF side, white paper 0/206 NR N
MCP 2010— "#1 formulation" CFB sheet CB side, white paper 0/206 NR N
MCP 2010— "#2 formulation" CFB sheet CF side, yellow paper 0/206 NR N
MCP 2010— "#4 formulation" CFB sheet CB side, white paper 0/206 NR N
White paper 0/206 NR N
1989 89–1107–70 Hill Top Research, Inc. T/R CB from No. 12 coater 2/103 1 N Test materials discontinued in mid-1990s
Imaged T/R CB 3/103 1 N
Fraser CF 1/103 3[19] Y
Fraser CF imaged by T/R CB 1/103 2[19] N
Georgia Pacific CF 1/103 2[19] N
Georgia Pacific CF imaged by T/R CB 1/103 3[19] Y
James River CF 1/103 3[19] Y
James River CF imaged with T/R CB 3/103   Y
1 2
3[19] 1
1989 89–1106–70 Hill Top Research, Inc. 304. OPAS CF ink FH–378 1/10 1 N Test materials discontinued in mid-1990s
305. OPAS CB activator 1/10 1 N
1989 89–1105–70 Hill Top Research, Inc. 308a. CB of CFB 2/105 1 N Test materials discontinued in mid-1990s
308b. Imaged CF of CFB 4/105 1 N
308c. CF of CFB 3/105 1 N
308d. CB of CFB after imaging w/CF 1/105 1 N
309a. CB of CFB 4/105 1 N
309b. Imaged CF of CFB 5/105 1 N
309c. CF of CFB 3/105 1 N
309d. CB of CFB after imaging w/CF 3/105 1 N
1989 89–6733H Biosearch 151. Unimaged CB 0/99 0 N Test materials in use
152. Imaged CB 0/99 0 N
153. Unimaged CF 1/99 +[20] N
154. Imaged CF 0/99 0 N
157. Unimaged CB 0/99 0 N
1989 89–1359–70 Hill Top Research, Inc. 161. Unimaged CB 0/109 0 N Test materials in use
162. Imaged CB 0/109 0 N
163. Unimaged CF 0/109 0 N
166. Imaged CF 0/109 0 N
1990 K23–33T–3E Keyline Research T–5205 carbonless blue image paper, EM0571 0/204 0 N Test materials in use
1990 90–2826–70 Hill Top Research, Inc. 182. Imaged CB 0/110 0 N Text materials in use
183. Unimaged CB 0/110 0 N
184. Imaged CF 0/110 0 N
185. Unimaged CF 0/110 0 N
186. Imaged self-contained CB 0/110 0 N
1991 90–2846–70 Hill Top Research, Inc. 325. Thick, gray, opaque liquid 0/107 0 N Test materials discontinued mid-1990s
325AD Thick, gray, opaque liquid 0/107 0 N
326A Paper 2/107 2 N
326B Paper 0/107 0 N
1991 91–1141–70 Hill Top Research, Inc. 343a. Unimaged CF 0/117 0 N Test materials discontinued mid-1990s
343b. Imaged CF 0/117 0 N
343c. Unimaged CB 0/117 0 N
343d. Imaged CB 1/117 1 N
322a. Unimaged SC surface 2/117 1 N
322b. Imaged SC surface 0/117 0 N
1991 K23–33T–6B Keyline Research T–5282 impact carbonless paper, Lot X0510, CF imaged 0/224 0 N Test materials in use
1991 K23–33T–6F Keyline Research T–5283 impact carbonless paper, Lot X0510, CF unimaged 0/224 0 N Test materials in use
1991 K23–33T–6A Keyline Research T–5284 impact carbonless paper, Lot X1820, CF imaged 0/224 0 N Test materials in use
1991 K23–33T–6G Keyline Research T–5285 impact carbonless paper, Lot X1820, CF unimaged 0/224 0 N Test materials in use
1991 K23–33T–6C Keyline Research T–5280 carbonless paper, Lot E, EM0581, No. AI01540, CB imaged 0/224 0 N Test materials in use
1991 K23–33T–6E Keyline Research T–5281 carbonless paper, Lot E, EM058, No. A101540, CB unimaged 0/224 0 N Test materials in use
1993 93–1141–70 Hill Top Research, Inc. Imaged 368 0/15 0 N Test materials discontinued mid-1990s
Unimaged 368 0/15 0 N
Imaged 369 0/15 0 N
Unimaged 369 0/15 0 N
Imaged 370 0/15 0 N
Unimaged 370 0/15 0 N
Imaged 371 0/15 0 N
Unimaged 371 0/15 0 N
1993 93–1034–70 Hill Top Research, Inc. Imaged 368 0/107 0 N Test materials discontinued mid-1990s
Unimaged 368 0/107 0 N
Imaged 369 0/107 0 N
Unimaged 369 0/107 0 N
Imaged 370 0/107 0 N
Unimaged 370 0/107 0 N
Imaged 371 0/107 0 N
Unimaged 371 0/107 0 N
1994 93–1206–70 Hill Top Research, Inc. Imaged 368 0/94 0 N Test materials discontinued mid-1990s
Unimaged 368 0/94 0 N
Imaged 369 1/94 1 N
Unimaged 369 0/94 0 N
Imaged 370 0/94 0 N
Unimaged 370 0/94 0 N
Imaged 371 1/94 1 N
Unimaged 371 0/94 0 N
1995 95–1631–70 Hill Top Research, Inc. 396a. Unimaged CB 3/110 1 N Test materials discontinued mid-1990s
396b. Imaged CIF 5/110 1 N
396c. Unimaged CF 2/110 1 N
396d. Imaged CB 2/110 1 N
407a. Unimaged CB 4/110 1 N
407b. Imaged CF 2/110 1 N
407c. Unimaged CF 2/110 1 N
407d. Imaged CB 4/110 1 N
402a. Unimaged self-contained 5/110 1 N
402b. Imaged self-contained   1 N
1996 95–1632–70 Hill Top Research, Inc. 419a. Unimaged CB 0/118 0 N Test materials in use
419b. Imaged CF 2/118 1 N
422aq. Liquid 0/118 0 N
424a. Unimaged CB 0/118 0 N
424b. Imaged CF 0/118 0 N
424c. Unimaged CF 0/118 0 N
424d. Imaged CB 0/118 0 N
1998 98–101080–76 Hill Top Research, Inc. 215. CF unimaged 8/100   N Test materials in use
+ 7
1 1
215. Back of CF 11/100   N
+ 9
1 1
217. CB side 2/100 2 1[21] N
220. Non CB side 8/100   N
+ 2
+ 7
l 1
1999 99–101981–70 Hill Top Research, Inc. 215. CF side unimaged 5/115 + N Test materials in use
215. CF side imaged 16/115 + N
215. Backside of CF 6/115 + N
217. CB side unimaged 8/115 + N
217. CB side imaged 1/115 + N
220. Non-CB side 1/115 + N
226. CB side imaged 3/115 + N
227. CF side imaged 3/115 + N

Adapted from Graves and Tardiff [1999] supplemental submission of peer review comments.

  1. The report numbers refer to submissions to the NIOSH docket; they are not listed in the references. Except in Report 86–5436H, no test results for control materials are included in this table.
  2. Number of responders/total number of persons who completed the study.
  3. Highest recorded grade of skin reaction per study participant for a particular test material (based on multiple applications). Before 1980, Hill Top Research, Inc. employed a scoring scale that ranged from 0 to 7 (a score of 5 or greater=primary skin irritant; less than 5=nonirritating). Since 1980, Hill Top has used a scoring scale that ranges from 0 to 5 (a score of 3 or greater=primary skin irritant; less than 3=nonirritating). Inveresk Research International used a scoring system of 0 to 8, with a score of 5 or greater indicating irritancy. This laboratory scoring system is more analogous to the Hill Top pre-1980 system, even though it is a post-1980 study.
  4. Abbreviations: CB=coated back; CF=coated front; CFB=coated front and back; N=no; NA=not applicable; ND=no data provided; NR=no reaction; Y=yes.
  5. Y and N were determined by NIOSH according to the scoring system listed in footnote 3.
  6. Discontinued means that (1) the ingredient is no longer used to make CCP, or (2) the formulation as constituted is no longer used to make CCP, or (3) the CCP product is no longer sold in the United States.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 The study director described skin reactions as sensitization.
  8. Responders to sample E (grade 2 and grade 6 reactions) were dropped from the study (77–512–70).
  9. A responder to sample H (grade 1 reaction) was dropped (77–512–70 H).
  10. Responder to sample B (grade 1 reaction) was dropped (78–578–70).
  11. 11.0 11.1 Two reactors with grade 2 reactions and one reactor with grade 3 reaction to T3012PP dropped out of the study [81–0318–73(2)] and are not included in the denominators.
  12. 12.0 12.1 One grade 3 reactor to T3013PP was dropped from the study [81–0138–73(2)].
  13. Two dropped out with a score of 1; 1 dropped out with a score of 2.
  14. One dropped out with a score of 1; 2 dropped out with a score of 2.
  15. Three dropped out with a score of 1; 1 dropped out with a score of 3.
  16. One dropped out with a score of 1; 1 dropped out with a score of 3.
  17. Three dropped out with a score of 1; 1 dropped out with a score of 2.
  18. Two dropped out with a score of 1; 2 dropped out with a score of 2.
  19. 19.0 19.1 19.2 19.3 19.4 19.5 These results reflect the same person who expressed elevated scores throughout this study, regardless of the material tested. In addition, the scoring responses conflict with the study methodology since the responses increased, rather than decreased, across primary, secondary, and tertiary application sites. Therefore, the results for this person are suspect.
  20. As designated by performing laboratory, "+" denotes "slight, confluent or patchy erythema." This symbol indicates a score between 0 and 1 on a scale of 0 to 7 (see footnote 3 />) and is not used universally.
  21. The analytical laboratory that conducted this study concluded that this irritancy score was likely to be a recording error because of deviations from the study protocol.
One of the difficulties in interpreting the RIPT studies is that although there is a standard procedure for evaluating changes consistent with allergic contact dermatitis, no guidelines exist for determining what constitutes a significant irritant response in humans [Gupta 1999]. OSHA [29 CFR[1] 1910.1200, Appendix A] and the Consumer Product Safety Commission (CPSC) [16 CFR Part 1500.41] have guidelines for animal testing but not for human testing. Report 81—0138—73(2) from Hill Top Research, Inc., (Table 4-12) defines categories of responses for interpreting the findings in their test reports [Graves and Tardiff 1999]. The test report states the following:

If Category 1 responses (defined as negative or insignificant findings or significant findings unrelated to the test material) are projected to 98 percent or more of the total population, then the results are not significant for dermatotoxic potential. This means that two percent or less of the population could possibly have some type of mild reaction.

A mild significance is one where no Category III reactions (no vesicular, bullous, or spreading) exist and Category I (negative) reactions exist in 95 percent or more of total population. This means, that at most five percent of the population could have some type of mild, non—vesicular, non—bu1lous, non—spreading response.

A strong significance for dermatotoxic potential exists if there are any Category III responses (vesicular, bullous, strong spreading reactions) or if enough Category 11 responses (significant responses excluding vesicular, bullous, and spreading reactions) exist to decrease Category I to 85 percent or less of total population. This means that if any one person (approximately 1/200 or one-half percent of the test subjects) would have vesicular, bullous, or spreading reaction or 15 percent or more would have some type of significant reaction, then the test would be defined as having strong statistical significance for dermatotoxic potential. Eighty-five (85) percent of the population could have non-significant or negative reactions and the test would still be considered strongly significant.

This definition, which henceforth will be referred to as the "Hilltop Guidelines," combines information about the likelihood of the response with information about the severity of the response to determine whether the overall response is significant. With this definition a test would be declared negative or insignificant even if mild reactions occurred in a small proportion (≤2%) of the test population. Moreover, as the ASTM standard argues, from a population experiencing 1.5 allergic reactions per 100 users, a sample of 200 could easily yield no cases just by chance [ASTM 1999].

Most of the RIPT reports submitted to NIOSH were judged to be negative by the investigators using criteria similar to those described above. However, in 8 of 217 test material combinations shown in Table 4-12, study directors indicated that skin sensitization occurred among human subjects. A few of the RIPT reports submitted in response to the 1987 Federal Register notice document responses to CCP or its components that were consistent with the induction of allergic contact dermatitis under the intensive exposures of the experimental protocols. These RIPT reports include Hill Top Research, Inc., Report 77-5 12-70, 77-896-71, 79-512-70, and 79-0085-73; and Shelanski Holding Company Report SH-72-4 (Table 4-12). Note, however, that reactions occurred in response to types of CCP that manufacturers claim are no longer in use. Cases of allergic contact dermatitis were not observed in any of the studies submitted in response to the 1997 Federal Register notice.

Two of the RIPT reports (e.g., Hill Top Research, Inc., Reports 98-101981-76 and 99-101981-70) suggest that some CCP test materials have a minor potential for skin irritation. Test results for these materials did not meet the testing laboratories' criteria for primary skin irritants, but they provided evidence of an irritant response. Because most studies did not include comparison groups exposed to plain paper, it is unclear whether this potential for skin irritation would have been much different from that of paper alone.

Tests Under Simulated Conditions of Use. Three industry-sponsored tests evaluating the irritation potential of CCP under simulated conditions of office use were submitted to the NIOSH docket in response to the 1987 and 1997 Federal Register notices.

Hill Top Research, Inc., conducted a double-blind placebo study in which subjects were provided with scissors and asked on 4 consecutive days to cut up samples of paper for 60 min under controlled temperature and humidity (Hilltop Research, Inc., Report 83–0965–70). Three types of CCP and a control ("white") paper were tested in random order by two groups of 10 and 9 subjects. After the 19 study subjects were exposed to one of the CCP samples (sample B), 10 (53%) reported irritation of the eyes, nose, or skin. When exposed to the second and third of the remaining CCP samples, 3 subjects (16%) and 2 subjects (10%), respectively, reported irritation symptoms. One subject (5%) reported irritation following exposure to the control paper. The authors concluded that their results demonstrated an unequal distribution of irritation symptoms among the samples tested and that the number of symptoms reported was particularly high with exposure to one of the CCP samples. The eyes were the most sensitive indicator, and some symptoms persisted for 24 hr. The authors recommended that studies of this type allow greater separation in time between samples to prevent carryover effects from preceding samples.

Hill Top Research, Inc., (Report 83–0123–70) conducted another double-blind study in which 20 subjects were recruited to handle a stack of 120 sheets of test paper. Every 30 sec, the subjects ran their hands over each side of another piece of paper until all the pieces had been handled at the end of 1 hr. The testing was done in a single room, with four different types of paper being handled each day. Subjects were examined for signs of irritation and were questioned regarding symptoms before exposure and 30 min, 60 min, and 24 hr after exposure. One subject dropped out. No irritation responses were reported or observed for the eyes, forearms, or face with any of the test papers. Seven subjects reported respiratory symptoms, but four of them demonstrated these effects with all four samples. These latter symptoms appear to have resulted from preexisting cold symptoms rather than from exposure to the paper samples. The results of this study are difficult to interpret in light of the coexisting cold symptoms and pretest symptoms present even for the control exposure.

In 1998, Moore Business Forms, Inc., reported on tests for scoring irritation or sensitization as a result of challenge with Moore Clean Print® CB, CF, and CFB. This test was performed by Biosearch in 1983 (Table 4–12). The volunteers included 200 men and women aged 16 to 68. Of the 200 subjects, 33 had allergies to typical materials. Subjects were instructed to rub a sheet of the test paper (CFB) on their hands and wrists using a hand-washing motion. The procedure was performed over a 4-week period using 8 sheets of paper per day for 5 days per week. The subjects were examined weekly and were instructed to report any unusual interim occurrences. After day 20 of treatment, the subjects rested for 2 weeks and again performed the same procedure with 8 sheets of CCP. They were examined immediately after the challenge and 4 and 24 hr later. The commercial laboratory that performed the test reported that none of the 200 subjects had any signs of irritation or sensitization following any of the 20 initial or challenge exposures. Summary

In summary, the results of these laboratory studies in humans suggest that under some conditions of exposure to CCP or its components, workers may experience irritation of the upper respiratory tract or skin, and/or they may develop allergic contact dermatitis. It must be emphasized that most of these studies were negative, and the reactions observed in the positive studies were extremely rare. Furthermore, cases of allergic contact dermatitis were reported only in the earlier RIPT studies, which tested CCP types that are no longer in use; the more recent RIPT studies have detected only minor signs of skin irritation. If the Hill Top Research, Inc., guidelines are applied, then the mild irritation responses identified in some of the industry-sponsored RIPT studies would be considered Category I responses, which are defined as negative or insignificant findings, or significant findings unrelated to the test material. However, these same results do suggest that 2% or less of the population could have some type of mild reaction to CCP. Whether these mild irritation reactions would have been observed with ordinary bond paper is unclear, since these studies did not include bond paper as a control.

4.3 Animal Studies

4.3.1 Published Studies

Hasegawa et al. 1982a. Hasegawa et al. [1982a] reported that diisopropylnaphthalenes (Kureha Micro Capsule Oil [KMC-A]) and 1-phenyl-1-xylyl-ethanes (SAS) are two classes of solvents that are used in the manufacture of CCP. They were introduced in Japan as replacements for PCBs in 1971. KMC is used by the Federal Republic of Germany and by Japan at a rate of 10,000 tons per year [Sturaro et al. 1994]. Large amounts of both materials were found in the body fat and subcutaneous fat of male JCL-SD rats 2 hr after a single oral dose of 0.1 mg/kg. The amounts increased with time until 24 hr after the dose. In the liver, the amounts were nearly the same as those in the fat after 2 hr, but they rapidly disappeared thereafter. The concentrations in blood were similar to those of the heart, kidneys, and brain. Although the ratio of isomers in the KMC-A did not change, those of the SAS 296 differed by a ratio of 3:1 for 1-phenyl-1-metaxylyl to 1-phenyl-1-orthoxylylethane, respectively. This result was attributed to differences in hepatic metabolic rates. No accumulation was found in the organs, and little accumulation was found in the fat after daily administration for 1 month.

Hasegawa et al. 1982b. Hasegawa et al. [1982b] administered 0.1g/kg body weight of KMC-A and SAS 296 to JCL-SD rats every day for 1 month. Biochemical examination revealed (1) a slight decrease in body weight and a small increase in liver weight (0.3% to 0.6%) compared with the controls; (2) disturbance of lipid metabolism in the liver (statistically significant decreases in triglycerides, glycolipids, and phospholipids) and serum (statistically significant free fatty acid twofold to threefold increases, total and free cholesterol decreases); and (3) disturbance of glucose metabolism in the liver (statistically significant decrease in glycogen and increase in pyruvate) from administration of both substances. A significant increase in alkaline phosphatase activity in the serum occurred in the case of SAS 296 administration.

Löfroth 1982. Löfroth [1982] examined a number of office materials for their potential mutagenic activity and found that none of the CCPs contained detectable amounts of mutagenic components. However, the author commented that some impurities in triaryl methanes (used as color formers) have been reported to be mutagenic [Bonin et al. 1981].

Certin and Zissu I983. Certin and Zissu [1983] performed cutaneous irritation tests in rabbits. They compared extracts of 12 CCPs with 5 highly irritant reference oils, acetone (CB), or ethyl acetate or acetone (CF) extracts (4 hr of soxlet extraction of 50 g, or acetone extraction of 1 kg CB sheets in an ultrasonic tank for 1 hr). The CCP extracts were moderately or severely irritating using the Draize method (Table 4-1 3). Chemical analysis using GC/MS analysis identified the "oils" listed in Table 4-13.

Thirteen papers contained a phenolic resin in the CF layer and traces of free phenols, bis-phenol A, and phenylphenol. For all of the CF analyses, compounds similar to abietic acid were found. Certin and Zissu [1983] reported that 8 of the 12 extracts were moderately irritating (irritation index from 2.7 to 4.7), and the remaining 4 extracts were severely irritating (irritation index from 5.6 to 7.3). Histopathology results from animals exposed to moderately irritating products exhibited epidermal acanthoses alternating with superficial epidermal necrosis, which led to thin, scaly crust that was sometimes continuous over the entire extent of the lesion. The severely irritating products caused more pronounced morphological findings. These were characterized by necrosis of the epidermis and superficial dermis, with inflammatory exocytosis and homogeneous degeneration of the connective tissue of the mid-derrnis. The authors concluded that it was probably the oily constituents of the papers that produced the observed irritation of the skin and mucosa of office workers. However, they also noted that the animal test results are probably more grave than those experienced by humans, since human exposures were limited to several hundred micrograms on the fingers at the end of a day of handling. The authors

Table 4-13. Frequency of occurrence and animal irritation category for chemicals identified in 12 French CCPS
Chemical Number of times identified by GC/MS analysis Irritation category
Hydrogenated terphenyls 16 Severe
Diisopropylnaphthalenes 11 Severe
Phenylxylylethanes[2] 10 Moderate to severe
Alkylbenzenes 6 Severe
Methybutyl naphthalenes 1 Not tested
Benzylxylenes 1 Not tested
Chlorinated pacaffins 1 Not tested
Chlorinated biphenyls 1[3] Not tested
Dibutylphthalate 1 Not tested
Kerosene [4] Severe

Source: Certin and Zissu [l983].

  1. Code 0f Federal Regulations. See CFR in references.
  2. This constituent was noted to have a very pungent odor.
  3. 1972
  4. Not enumerated.
remarked that nasal or ocular irritation is probably explained by contact with soiled fingers. They did not think that it was likely that the oils produced respiratory irritation because of the low volatility of their constituents; however, they did not discuss paper fibers as a potential vehicle for the irritants.

Cameron et al. 1986. Cameron et al. [1986] studied the percutaneous absorption of triarylmethane and phenoxazine-type color former components of CCPs. The percutaneous absorption of carbon-14-labeled color former components of CCP was investigated in the rat as a model for assessing possible absorption of these components by human users of such papers. Formulations of a proprietary color former/solvent mixture were applied to the shaved backs of hooded rats. The mixture contained carbon-14-labeled 6-(dimethyl-amino)-3,3-bis(4-(dimethyl-amino) phenyl)-1(3H)isobenzofuranone (CVL), a triarylamine color former, or 10-benzoyl-N,N,N',N'-tetraethyl-3,7-diamino-10H-phenoxazine (BLASB), a phenoxazine color former. Some of the rats had been surgically prepared with bile duct and urinary bladder cannulae. Urine and bile samples were collected hourly for 24 hr and assayed for carbon-14 activity. The animals were then sacrificed, and carbon-14 activity was measured in the skin, skin dressing, and body. Selected animals were sacrificed 2, 6, 24, or 96 hr after application, and carbon-14 activity in the excreta, skin and dressings, and body was determined. Microhistoautoradiography was performed on the skins of some animals. Nearly all the CVL- or BLASB-derived carbon-14 activity was retained in or on the skin. Only 2.6% to 3.4% of the CVL and 1.0% to 2.1% of the BLASB doses were absorbed. During the 12 to 24 hr after application, 0.02% of the CVL and 0.11% of the BLASB doses were eliminated in the urine and bile. The authors conclude that CVL and BLASB are slowly absorbed into the systemic circulation following topical application to rat skin. The authors concluded that these results (if extrapolated to humans) suggest that percutaneous absorption of these compounds should not be significant during normal handling of CCP.

'Wolkoff et al. 1988.' Wolkoff et al. [1988] reported airway-irritating effects in mice exposed to CCP using sensory irritation techniques [Alarie 1973]. Four mice were exposed for 10 min to emissions from CCP and emissions from crushed and compressed virgin copy papers. One CCP suspected of causing complaints decreased the respiratory rate significantly more than did a second CCP used without adverse effects. This result suggests irritation. Because the CB layer of the first CCP produced only negligible irritation, the authors concluded that neither the solvent nor the color formers caused the irritation. The authors suggested that the irritation was due to one or more of the following: the evolution of formaldehyde or other unidentified irritants in the paper, the evolution of irritant solvents from the paper and their transfer to the hands of the users, and the transfer of irritant particulate matter from the paper to the hands. The authors concluded that it would be beneficial to minimize the free formaldehyde content of the paper, eliminate volatile irritants from the CCP, and minimize the transfer of irritant particulates or solvents to the skin.

Anderson 1992. Anderson [1992] used standard method ASTM E 981 [ASTM 1984] an adaptation of the Alarie [1973] method (which evaluates respiratory irritation) in mice to assess the offgassing of CCP and determine its effects on sensory irritation (upper airway) and pulmonary irritation (deep lung). Using groups of mice, the author concluded CCP to be a demonstrable irritant for both upper and lower airways, causing a greater than 50% change in respiratory rate. The type or composition of the CCP was not given except that it was commercially purchased. No other details were provided.

4.3.2 NIOSH Docket Submissions

Most information submitted to the NIOSH docket concerned animal testing of CCP or its components in extensive, widely accepted toxicology test procedures. The coded submissions did not allow specific identification of chemicals or formulations. Each of the approximately 1,500 animal studies submitted to the docket was reviewed independently by a NIOSH toxicologist. Most materials had been tested in a series of protocols such as inhalation LC50, cutaneous and/or oral LD50, skin and/or eye irritation, and skin sensitization. Some materials had been tested for mutagenesis, reproductive toxicity, or upper airway irritation. Not all materials were tested using every protocol. Most test results were negative; but positive results that were reported during the NIOSH review summarized as follows:

  • The Mead Corporation sent summaries of eight reports to the NIOSH 1987 docket. The material tested was code 151 (chemical identification code), and all tests were negative except for a 1980 study of acute dermal toxicity in rabbits that estimated the acute dermal LD50 to be greater than 2 g/kg body weight. However, slight to well-defined erythema was noted in all animals on days 1, 3, and 7; it continued in most of the animals through day 14.
  • Hazelton Laboratories in Madison, Wisconsin, and Vienna, Virginia, submitted a series of 22 reports to the NIOSH 1987 docket. Irritation was produced by some of the samples, but sensitization did not occur. Inhalation experiments were negative, but exposure concentrations were very low in most cases.
  • Biosearch evaluated CCP constituents from Moore Business Forms, Inc., and submitted the results to the NIOSH 1987 docket for acute oral toxicity, primary eye irritation, primary skin irritation, and 5-day repeated dermal irritation. All products tested were considered nontoxic, with LD50s greater than 5 g/kg. None of the materials were classified by the Food and Drug Administration’s regulatory definition as primary eye irritants, primary skin irritants, or dermal sensitizers. Several of the materials acted as mild or moderate skin and eye irritants.
  • A series of toxicological test reports on a variety of CCP constituents were submitted to the NIOSH docket and reviewed. These test reports (Documents 002 through 148) were originally prepared for the Monsanto Company in St. Louis, Missouri. The tests had been conducted between 1956 and 1980. Test material ranged from "white paper" to "yellow liquid" or "white powder." The toxicological tests included acute oral and dermal toxicity and dermal and eye irritation. They also included a few 90-day feeding studies, mutagenesis assays, and inhalation studies as well as two aquatic studies with trout fry and midge larvae. Most substances were nontoxic or exhibited mild toxicity. Some caused mild or moderate irritation to the skin or eyes. However, in most cases, the low scores on the dermal or ocular irritation assays resulted in their classification as nonirritants. A few of the tests (2/69 primary irritation assays and 3/69 primary eye irritation assays) were graded as positive. From the other tests, NIOSH could infer that the product would cause mild irritation in humans. However, it must be recognized that such testing of pure compounds may produce more exaggerated results than testing the final CCP product, since less of the toxic component is available to consumers in the finished product. In the brief comments noted below, substances identified as mild irritants were not classified as primary irritants, even though some irritation occurred in more than one animal. Many of the compounds caused diarrhea. These observations are probably not relevant to humans—especially when animals were gavaged with a large volume of a slurry of white paper. Also of questionable relevance was the liver damage caused by compound 043. This effect occurred when animals were exposed to 10,000 ppm for 90 days.
  • In a NIOSH docket submission numbered Document 050–EMI, a crystalline white powder was suspected to be relatively toxic. Peer reviewers from the industry noted that at full strength, this substance was corrosive to the skin, severely irritating to the eyes, and acutely toxic by oral ingestion [Graves and Tardiff 1999]. However, comments from the same peer reviewers noted that this component was never used in CCP production or offered for sale commercially. When the component was tested as part of a trial CCP, the paper was negative for acute and dermal toxicity and eye and skin irritation.
  • Also of concern were a few studies in which compounds (033, 034, 036, 038–TR–33 to TR–38) were tested by inhalation or dermal application. Although these compounds did not produce any deaths or pathological findings, exposures resulted in modified behavior. Animals became hyperactive, salivated, became ataxic, and lost their righting reflex. NIOSH concluded that low exposures to these compounds could produce comparable effects in humans. Peer reviewers from the industry noted that these tests involved pure compounds, and that tests of the finished CCP products containing these compounds were negative [Graves and Tardiff 1999]. The chemical or component identification was unknown to NIOSH because of trade secret claims by the industry. Thus connecting the test results from pure compounds to finished products was not possible. None of the mutagenicity studies were positive, but not all substances were tested for mutagenicity.
  • Another NIOSH docket submission from Monsanto is a series of 44 toxicity reports conducted by various testing laboratories on papers and dyes that were tested during the years 1978 to 1986. Each report consists of one to six toxicity tests that include oral and dermal toxicity, skin and eye irritation assessment, mutagenicity testing, and skin sensitization testing in animals. Santosol 150 dye solution was tested more than any other product. Tests included a 90-day feeding study, developmental toxicity testing, and a series of studies in fish and midges. Unlike the other products tested in the Monsanto series, an LD50 and a maximum tolerated dose were determined for Santosol 150. In general, this dye solution exhibited low toxicity. None of the products tested in the Monsanto series (including Santosol 150) were mutagenic, but not all products were tested for mutagenicity. None of the products were skin sensitizers in animals or humans, but not all products were tested for skin sensitization. Most compounds were not acutely toxic by the oral or dermal route. This conclusion was based on the fact that they were not lethal at 5 g/kg (oral route) or 2 g/kg (dermal route). However, many of the products induced modified behavior (including lethargy, ataxia, and even paralysis) from which the animals recovered. At necropsy, some animals exhibited mottled kidneys or livers. Diarrhea was a common symptom. For example, rat sgavaged with a slurry of white paper exhibited white diarrhea for 1 to 2 days. The relevance of such exposures and effects is questionable.

    One product (96 Solvent CB Paper Internal Phase) was tested for developmental toxicity; it produced fetal malformations at a concentration that was toxic to the mother.

    None of the products were corrosive, and very few were classified as primary irritants. However, some of the products caused mild eye irritation and transitory erythema and edema of the skin.

    Several paper products were tested for formaldehyde content, which ranged from 0.014 to <0.001 µg/g in the products tested. Levels of detection for the methods were not noted. Overall, the materials tested exhibited low or negligible toxicity. Some could act as mild irritants.
  • The Mead Corporation submitted toxicology tests performed between March 3, 1987, and July 18, 1996. Tardiff [1997] reviewed the complete testing program of the Mead Corporation’s evaluation of CCP and of the ingredients used to manufacture Mead’s CCP. (These same materials were also submitted to and reviewed by NIOSH.) The Tardiff review encompasses 191 substances consisting of individual chemicals, mixtures used in the production of CCP, and various batches of CCP. The individual chemicals and mixtures included various inks, dyes, powders, coatings, adhesives, and other materials. Their identities were not known because of trade secret considerations by the company. Ingredients were selected for testing to supplement information provided by the suppliers of the raw materials and to test chemicals considered for formulations that were sufficiently reactive to have the potential for producing synergistic reactions with other ingredients of CCP. The following is a list of assays that were selectively performed (based on scientific judgment) with the test substances:

    —Eye irritation test in the rabbit

    —Primary skin irritation test in the guinea pig

    —Skin sensitization test in the guinea pig

    —Acute oral toxicity test in the rat

    —Acute dermal toxicity test in the rabbit

    —Acute inhalation toxicity test in the rat

    —Genotoxicity tests (Ames mutagenicity assay and chromosomal aberration test)

    The toxicity studies summarized in Tardiff [1997] were evaluated using data interpretation methods and guidelines accepted by the CPSC. Since that commission does not require the genotoxicity testing mentioned above, Tardiff [1997] used conventional professional practice found acceptable by the U.S. Environmental Protection Agency and supported by the National Academy of Sciences. To confirm the quality of the toxicologic tests summarized in the report, each study was verified as having been conducted in accordance with the testing requirements of the CPSC or the Organization for Economic Cooperation and Development. Each of the protocols included stipulations for adhering to good laboratory practices.

    The following results were reported. Oral toxicity in rats was tested with 84 chemicals and mixtures. Each possessed an LD50 of >5 g/kg. According to CPSC criteria, these materials are negative and unlikely to pose an acute hazard to humans by ingestion. Ocular irritation tests in rabbits were conducted with 83 chemicals or mixtures; 55 produced no ocular irritation. According to Tardiff [1997], the 28 materials that tested positive consisted of powders, liquids, and pastes. They produced a range of treatment-related effects, including iridal and/or corneal involvement and slight to moderate conjunctival irritation (which cleared within 24 to 72 hr of the test material administration). According to the author, these substances are unlikely to lead to positive results in humans exposed to CCP because the test results indicated only mild and transitory effects with liquids, and end users would not be exposed to the liquids.

    Primary skin irritation tests in the guinea pigs were conducted with 86 chemicals or mixtures. Each produced a skin irritation score of less than 5. Tardiff [1997] states that based on CPSC criteria and the primary irritation scoring data, these materials are negative and are unlikely to cause primary skin irritation in humans exposed to CCP. Acute dermal toxicity tests in rabbits were conducted with 18 chemicals or mixtures. Each possessed an LD50 >2 g/kg. On the basis of CPSC criteria, these materials are negative for acute dermal toxicity. Skin sensitization tests in guinea pigs were performed with 95 chemicals or mixtures. Eighty-seven were negative. Of the eight positive tests, treatment-related results ranged from very faint to faint erythema reactions that cleared within 24 hr of the test material administration. Six materials were tested as liquids—which does not represent normal usage of CCP. Therefore, Tardiff [1997] concludes that these reactions would not occur in humans. The other two positive substances were tested as powders. Because the exposure is expected to be limited to "minute" quantities produced as CCP is cut, shredded, or torn, the doses encountered were considered insufficient by the authors to cause sensitization.

    Acute inhalation toxicity testing in rats was conducted with 44 chemical substances or mixtures. Forty-three were negative according to CPSC criteria. The only positive result came from a liquid mixture with an LC50 between 2 and 200 mg/L. Treatment-related effects included failure to gain expected body weight, respiratory distress, increased secretory responses, other changes in hair coat, and death. Since exposure conditions with normal use of CCP would not be in liquid form, Graves and Tardiff [1999] concluded that the test material was unlikely to be an acute hazard to humans by inhalation.

    All 22 chemicals or mixtures tested for genotoxicity were negative for point mutations and did not increase chromosomal aberrations. These toxicity tests demonstrate that the tested CCP constituents are not mutagenic.

4.3.3 Summary

After examining the toxicological animal studies submitted to the NIOSH docket, NIOSH concludes that with a few exceptions, CCP constituents are not acutely toxic by the oral, dermal, or inhalation route. A number of CCP constituents were shown to be mild irritants to the skin and eyes of experimental animals. One study [Anderson 1992] stated that CCP from an unspecified source acted as both a sensory and pulmonary irritant in mice.

In summary, more than 300 substances and various combinations of materials were included in the animal studies. Of 238 tested for skin irritation, 8 were positive. In addition, some materials caused mild, transient irritation (25.2%; 60/238) but did not satisfy FDA's regulatory definition of an irritant. In 129 dermal lethality tests, mild skin irritation was noted (17.8%; 23/129); however, the regulatory definition is not based on this type of test. No pattern was observed to identify the CCP component responsible for the mild skin irritation reported in humans. A total of 271 substances were tested in the allergic contact dermatitis animal model, and 13 were positive. This result suggests that CCP infrequently causes allergic contact dermatitis in animals. Whether materials with positive toxicological outcomes were actually marketed is unclear; but the general rationale for toxicity testing is to prevent the marketing of materials that may harm users.

Most of the toxicological data submitted to the NIOSH docket were coded by the manufacturers for proprietary reasons. Thus it was not possible to identify replicate tests or the nature of the test materials or their means of preparation (dry, aqueous, neet, etc.). However, the animal toxicology results indicate only mild and transitory effects with liquids, and end users would not be exposed to the liquids.