5 Dermal and Ocular Toxicity of Permethrin

DERMAL TOXICITY

To determine whether a compound is safe for application to human skin, a series of standard dermatological tests—namely, primary skin irritation, acute dermal irritation, 21-day dermal repeat application, photo-irritation, skin sensitization, and human 21-day repeat patch test—are usually conducted. The results of these toxicological evaluations are then summarized, and the compound is categorized according to its hazards.

Human Data

Little information exists on workers who manufacture permethrin. In a study of six Swedish forestry workers who handled seedlings immersed in a 2% aqueous solution of permethrin (Kolmodin-Hedman et al., 1982), airborne permethrin concentrations ranged from 0.01 to 0.09 mg/m3 No adverse effects of those exposures were noted. In another study of 87 Swedish nursery workers who were studied 1-2 months after the planting season, symptoms of itching and burning skin and respiratory and eye irritation were reported. Symptoms were twice as prevalent among workers exposed to a permethrin mixture of cis/trans isomers in a ratio of 25:75 than to a mixture of 40:60; skin and respiratory irritation



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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms 5 Dermal and Ocular Toxicity of Permethrin DERMAL TOXICITY To determine whether a compound is safe for application to human skin, a series of standard dermatological tests—namely, primary skin irritation, acute dermal irritation, 21-day dermal repeat application, photo-irritation, skin sensitization, and human 21-day repeat patch test—are usually conducted. The results of these toxicological evaluations are then summarized, and the compound is categorized according to its hazards. Human Data Little information exists on workers who manufacture permethrin. In a study of six Swedish forestry workers who handled seedlings immersed in a 2% aqueous solution of permethrin (Kolmodin-Hedman et al., 1982), airborne permethrin concentrations ranged from 0.01 to 0.09 mg/m3 No adverse effects of those exposures were noted. In another study of 87 Swedish nursery workers who were studied 1-2 months after the planting season, symptoms of itching and burning skin and respiratory and eye irritation were reported. Symptoms were twice as prevalent among workers exposed to a permethrin mixture of cis/trans isomers in a ratio of 25:75 than to a mixture of 40:60; skin and respiratory irritation

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms was reported by 63% of those exposed to a cis/trans ratio of 25:75 and by 33% of those exposed to a ratio of 40:60. In addition, increased nasal secretions were noted among 13% of those exposed to the 25:75 mixture. Staff involved with bagging, mixing, or spraying a 5% preparation of permethrin (cis/trans ratio, 25:75) in Nigeria were evaluated with a questionnaire and urinalysis (Rishikesh et al., 1978). Although substantial exposures and absorption occurred, as shown by urinary excretion studies, no adverse health effect could be attributed to permethrin exposures in this group. Among 17 civilian volunteers exposed to 1% permethrin (cis/trans ratio, 25:75) via skin patches for up to 9 days, two complained of mild erythema and skin irritation (Pegum and Doughty, 1978). A group of 10 male volunteer soldiers wore uniforms impregnated with an aqueous solution of 0.2% permethrin (cis/trans ratio, 25:75) (Farquhar et al., 1981). They were evaluated after 48 hr for their levels of permethrin exposure and for symptoms of toxicity. Their average exposure to permethrin was 3.8 mg/day, and none complained of skin irritation or other health problems. The production of skin paresthesia by various pyrethroids, including permethrin, has been examined in human volunteers (Flannigan and Tucker, 1985; Flannigan et al., 1985a,b). Permethrin (0.13 mg/cm 2) was applied on five occasions to 4 cm2 of an ear lobe; the other lobe had distilled water applied. Evaluation at 48 hr showed that all pyrethroids, including permethrin, produced altered skin sensation. Paresthesia typically developed within 30-60 min of application, was maximal within 8 hr, and slowly disappeared within 24 hr. The changes caused by permethrin were substantially less than those caused by pyrethroids that contained an α-cyano group. Snodgrass (1986) performed a Draize repeat insult patch test with 184 subjects who represented both sexes, ranged in age from 18 to 80, and were from all races. A 40% permethrin solution (technical-grade permethrin, 92.5%, and ethanol, 95%) was used. A dose of 0.2 mL was applied to the upper arm or back of each subject and placed beneath an occluded patch 3 times per week for 3 weeks. The patches were kept dry and left on between applications. Two weeks after the induction period, a challenge application was made on a previously untreated site and removed 72 hr later. Responses were recorded at 96 hr. None of

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms the 184 test subjects showed evidence of allergic contact dermatitis. However, several subjects described a transient burning, stinging, or itching sensation. Clinical Trials Several clinical trials for the treatment of human ectoparasites have demonstrated the efficacy of permethrin in eradicating the organisms and its accompanying low toxicity to humans. The subcommittee reviewed a summary of clinical trials to date in which 1% permethrin cream rinse was used to treat body lice (650 subjects), head lice (3,041 subjects), and crab lice (56 subjects), and 5% permethrin dermal cream was used to treat scabies (2,068 subjects) and crab lice (28 subjects). Burroughs Wellcome, the manufacturer of permethrin, has published a summary of many of the studies (Andrews et al., 1992). Of the clinical trials to date, several provided details of possible health effects attributable to permethrin. All published studies made some mention of the presence or absence of side effects, and some provided a systematic account of their methods and findings; these studies are summarized in Table 5-1. Skin problems, ranging from mild itching to paresthesia and occasional erythematous or eczematous conditions, were reported in most of these trials; rates varied from none to 7% to an isolated rate of 70% among a group of 10 subjects treated intensively for scabies with 5% permethrin cream. In general, the reported skin effects of permethrin were uncommon and of a mild degree. Even the most pronounced skin effects were not disabling or a risk to the person's general health. The 1% permethrin cream rinse for head lice is available over the counter under the brand name NIX. This product has been more thoroughly tested than any pediculicide ever introduced. More than 21,000 patients have been followed under controlled conditions, including 18,000 monitored during postmarketing surveillance. The overall reported adverse events were approximately 2.5 per 1,000 patients, which is extremely low for any topical medication. These events include reports of pruritus, which is difficult to evaluate, because pediculosis (head lice) is a pruritic condition (Taplin and Meinking, 1993). The 5 % permethrin cream available only by a doctor's prescription

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms TABLE 5-1 Selected Clinical Trials of Permethrin with Detailed Possible Side Effects Condition Patients Treated, No. Dose Reactions Reference Head lice (Pediculus humanus var. capitis) 257 1% cream rinse for 10 min (25-50 mL applied) Evaluated at 30-60 min, 24 hr, days 7 and 14: skin problems in 37/257 (12.9%) Brandenburg et al., 1986 Head lice 659 1% cream rinse for 10 min (median 50 mL applied) Evaluated at days 7 and 14: skin problems in 8/659 (1.2%) Bowerman et al., 1987 Head lice 108 1% cream rinse for 10 min (25-50 mL applied) Evaluated at 30-60 min, 24 hr, days 7 and 14: skin problems in 17/231 (7%) DiNapoli et al., 1988 Human scabies 10 5% cream for 8 hr (mean weight applied, 25 g or 1.25 g of permethrin) Evaluated at 1 hr, 24 hr, days 7, 14, and 28: mild-to-moderate eczema in 7/10 (70%) van der Rhee et al., 1989 Human scabies 202 (scabies) 793 (contacts) 5% cream for 8-14 hr (mean weight applied, 25 g or 1.25 g of permethrin) Evaluated at 30 min, days 14 and 28: skin problems in 28/995 (2.8%) Yonkosky et al., 1990 Human scabies 234 5% cream for 8-14 hr (mean weight applied, 25 g or 1.25 g of permethrin) Evaluated at days 7 and 14: skin problems in 8/659(1.2%) Schultz et al., 1990

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms under the brand name Elimite is used for the treatment of scabies. This product has an excellent record of safety. Most adverse reactions have been associated with localized burning, irritation, or tingling sensations, but these should be considered in light of the fact that the product is often applied to skin already damaged by the effects of the scabies mite. The preservative in Elimite is formaldehyde, which is expected to cause some cases of allergic contact dermatitis. In practice, the reported incidence of allergic skin reactions has been extremely low—about two patient reports for every 500,000 units distributed (Taplin and Meinking, 1993). To treat scabies, 60 g of 5% permethrin cream is applied to the entire human body (head to toe) for 12 hr. This treatment has no adverse effects in healthy individuals, although it might cause minor skin problems in persons with scabies. The margin of safety (MOS) is calculated as follows: 60 g of 5% permethrin cream applied to humans (70 kg) = 43 mg/kg of body weight. This level presumably includes a safety factor of at least 10. Therefore, NOAEL = 43 mg/kg/day × 10 = 430 mg/kg. The NOAEL of 430 mg/kg based on treatment of scabies with 5% permethrin cream and the daily intake of 3.4 × 10−3 (6.8 × 10−5/0.02) mg/kg per day from wearing permethrin-impregnated BDUs provide a MOS of approximately 126,000 as shown below: Since 60 g of 5 % permethrin cream provides a MOS of 6 million, 56 g of 1% permethrin cream rinse used for head lice would also provide a sufficient MOS. Animal Data Acute and Subchronic Effects Dermal Irritation Robinson (1989b) showed permethrin to be a

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms moderate skin irritant on the intact and abraded skin of rabbits (Category III). In an acute dermal toxicity test in rats, Robinson (1989a) found an LD50 greater than 200 mg/kg but also observed desquamation, edema, thickening, scab, or skin eruptions in 9 of 10 rats. These skin changes persisted in a few animals up to 10 days (Category III). In the rabbit study, Robinson (1989b) evaluated the skin irritation responses to several concentrations of permethrin. The author observed erythema and edema at a concentration of approximately 80 mg/cm2. The California Environmental Protection Agency (CEPA, 1992) concluded that the NOEL would be approximately 8 mg/cm2 (using an uncertainty factor of 10). The subcommittee believes that the CEPA's estimated NOEL of 8 mg/cm2 is appropriate. When a permethrin formulation was applied to the clipped dorsal surface (0.13 mg/cm2) of six New Zealand White rabbits (three of each sex) once a day for 16 days, a slight erythema appeared, which correlated with increased cutaneous blood flow. No significant histopathological changes were detected (Flannigan et al., 1985). Single applications of up to 0.5-mLa permethrin produced only mild, localized irritation (McCreesh, 1977). The treated area showed focal acanthosis and hyperkeratosis of the epidermis. Those pathological conditions are common skin reactions to nonspecific irritant chemicals. When 0.5 mL of undiluted technical permethrin (91.3 % purity) was applied to the clipped dorsal surface of Japanese White rabbits, there was no irritation (Okuno et al., 1976a). In occupational settings, dermal contact is one of the main routes of exposure to pesticides. To simulate human dermal contact, rabbits were clipped free of hair and dressed with cotton cloth impregnated with permethrin. After 21 days of exposure, the animals were necropsied. Tissues examined were skin, brain, eye, stomach, small intestine, large intestine, cecum, lung, heart, thyroid, liver, pancreas, adrenal gland, kidney, testes, urinary bladder, skeletal muscle, bone, bone marrow, and trachea. SGOT, SGPT, LDH, glucose, BUN, bilirubin, total protein, a   0.5 mL was equivalent to 0.3 mg/kg of body weight, assuming the permethrin was 100% pure and had a specific gravity of 1.214. The body weight of the rabbit was taken as 2 kg.

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms Na+, and K+ were determined. No abnormalities in any of the values were observed (McCreesh, 1977). Dermal Sensitization In a study by Parkinson et al. (1976), guinea pigs were dermally administered permethrin as a 10% solution in dimethylformamide for 3 consecutive days. This was followed 4 days later by challenge doses of 0.1%, 1%, and 10% solutions of permethrin in dimethylformamide. Only very slight erythema was observed. Permethrin was therefore considered to be either nonsensitizing or only mildly so. In studies conducted by the U.S. Army Environmental Hygiene Agency (AEHA), guinea pigs (10 per group) were initially injected intradermally with 0.1-mL permethrin solution, and 14 days later were challenged with an intradermal injection (0.1 mL) of either a 0.1% solution of permethrin or dinitrochlorobenzene (DNCB). Five other animals per group received intradermally a challenge dose of 0.1% permethrin or DNCB without a prior sensitizing dose. The positive control substance (DNCB) elicited sensitization reactions in all guinea pigs when examined 24 and 48 hr after the challenge dose, whereas permethrin did not cause any sensitization reactions (Metker et al., 1977; Metker, 1978). Permethrin (cis/trans ratio, 25:75) in corn oil (1% wt/vol) or Freund 's complete adjuvant (1% wt/vol) did not produce dermal irritation or sensitization in groups of 10 male guinea pigs when applied as a 25% dispersion in petrolatum. The positive control, DNCB (5% wt/vol), in petrolatum produced marked sensitization (Chesher and Malone, 1974b). Employing the guinea pig maximization test, Leah (1989a) reported permethrin to be a moderate skin sensitizer. In this study, technical-grade permethrin was applied both intradermally (six 0.05-0.1 mL injections of 10% solution in corn oil with and without Freund's complete adjuvant) on day 0 and topically (undiluted) on day 7 of the induction phase. The animals were challenged on day 21 with a 30% solution in corn oil and with the undiluted test material, which were applied topically. Slight to moderate erythema was observed in 6 of 20 animals. However, the subcommittee believes that in the absence of supporting data from studies conducted by using current knowledge, the results of Leah (1989a) might have yielded a false positive response.

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms Photochemical Irritation Irradiation of permethrin-pretreated guinea pigs with UV light (365 nm) for 30 min at a distance of 10-15 cm did not cause a photochemical irritation reaction (McCreesh, 1977). Single applications of 0.05 mL of 25% (wt/vol) permethrin (in 95% ethanol) or 10% (wt/vol) oil of bergamot solution (in 95% ethanol) (positive control) were applied to the intact skin of six rabbits. Five minutes later, some of the rabbits were exposed to UV light (365 nm) at a distance of 10-15 cm for 30 min (the intensity of UV light was not specified). Skin treated with the positive control solution and irradiated exhibited a greater irritation reaction than did nonirradiated skin. Permethrin did not cause any irritation reaction under the test conditions with or without irradiation (Metker et al., 1977). OCULAR TOXICITY The ocular irritation of permethrin has been tested by several investigators in rabbits. Okuno et al. (1976) instilled 0.1 mL of undiluted technical permethrin (91.3% pure) into the eyes of Japanese White rabbits. The eyes were washed with distilled water 5 min or 24 hr after the application of permethrin. No eye irritation was observed in the rabbits. Parkinson et al. (1976) applied undiluted permethrin to the eyes of female rabbits. Application of permethrin only caused minimal pain, redness, or chemosis of the conjunctiva; there was a slight discharge. Chesher and Malone (1974a) applied 0.1 mL (dissolved in corn oil and containing a 25:75 ratio of cis/trans isomers) of 40% permethrin into the ocular sac of New Zealand White rabbits. No ocular effects were seen. Leah (1989b) instilled 0.1 mL of permethrin in the conjunctival sac of rabbits and observed conjunctival erythema, chemosis and discharge. However, no corneal or iridial effects were seen. Shapiro (1989b) instilled 0.1 mL of the tick-repellent formulation in the conjunctival sac of rabbits and observed mild conjunctival erythema, chemosis, and discharge.

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms CONCLUSIONS Ocular Toxicity The results of the ocular toxicity studies also show that permethrin in BDUs should not be a problem at the intended-use concentrations. Dermal Toxicity Review of the available information on dermal toxicity of permethrin indicates that permethrin might be a skin sensitizer at high doses in guinea pigs, although the Draize repeat insult patch test in 184 human subjects did not cause any dermal sensitization. However, several subjects described a transient burning, stinging, or itching sensation. The results of the photochemical irritation studies described above showed that permethrin does not cause phototoxicity (photochemical irritation). The weight of evidence indicates that exposure to permethrin from wearing permethrin-impregnated BDUs at the recommended concentrations is unlikely to cause skin sensitization or other skin effects in humans. Recommendation The Army needs to be aware that a few persons might be hypersensitive to permethrin-treated BDUs and thus develop skin sensitization. The Army should monitor for hypersensitivity when they begin to use permethrin-treated BDUs on a regular basis.

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