Human dermal application studies

There are no available carcinogenicity data in humans or animals using any route of exposure. Data from the CUT inhalation bioassay should provide valuable information on the carcinogenic potential of airborne nitrobenzene. There is currently no apparent need for studies using the oral or dermal route. However, as stated above, the results of the CUT bioassay may provide insight into the possible need for dermal application studies. 

Dermal Effects. No studies were located regarding the dermal effects in humans after dermal exposure to endrin. No damage to the skin at the site of application was observed in rabbits exposed to a single or repeated dermal application of dry endrin (Treon et al. 1955) however, the rabbits had convulsions. 

No studies were located regarding the metabolism of 3,3 -dichlorobenzidine in humans following dermal exposure. In a 24-hour urine sample of rats given a single dermal application of 3,3 -dichlorobenzidine (50 mg/kg/day), -diacetyl 3,3 -dichlorobenzidine (but not/V-acetyl 3,3 -dichlorobenzidine or the unchanged chemical) was detected (Tanaka 1981). Since the mutagenicity of diacetylated product is much less than either the monoacetylated or parent compoimd (Lazear et al. 1979 Reid et al. 1984 ... 

Limited excretion data are available in humans receiving 2-hexanone via inhalation, oral, and dermal exposure, in dogs via inhalation exposure, and in rats via oral exposure (DiVincenzo et al. 1977, 1978). However, human data on excretion of 2-hexanone via feces are not available, and the available information in dogs concerns excretion via exhaled breath only. In these and any other studies, information on all routes of excretion would help to evaluate the potential for 2-hexanone clearance in the exposed species. Excretion data in rats receiving 2-hexanone via inhalation and dermal application and in other species receiving 2-hexanone via all three routes would be useful for comparison with the human data and to assess the comparative risks of exposure by each route. In addition, information on excretion rates in each species via each route would be helpful in understanding how long 2-hexanone and its metabolites may persist in the body. 

The dermal adsorption of DEET in humans has been studied in the Netherlands by application of [14C] DEET as undiluted technical material or as 15% solutions in alcohol. Labeled material was recovered from the skin, and absorption of DEET was indicated by the appearance of label in urine after two hours of skin exposure. About 5—8% of the applied treatments was recovered as metabolites from urine, and excretion of metabolites in the urine came to an end four hours after exposure ended. DEET did not accumulate in the skin, and only a small (less than 0.08%) amount ended up in feces. Curiously, less has been absorbed through skin from 100% DEET application (3—8%, mean of 5.6%) than from 15% alcohol application (4—14%, mean of 8.4%). These results have been described as consistent with previous absorption/metabolism studies using guinea pigs, rats, and hairless dogs. Other publications on DEET toxicology have been cited (92). 

Toxicokinetic studies in humans have demonstrated that coumarin is rapidly absorbed from the gastrointestinal tract after oral administration and extensively metabolized by the liver in the first pass, with only 2-6% reaching the systemic circulation intact (Ritschel etal., 1977, 1979 Ritschel Hofimann, 1981).The elimination of coumarin from the systemic circulation is rapid, the half-lives following intravenous doses of 0.125, 0.2 and 0.25 mg/kg bw being 1.82, 1.46 and 1.49 h [109, 88 and 89 min], respectively (Ritschel et a/., 1976). Coumarin is also extensively absorbed after dermal application. In one study with human subjects, some 60% of a 2.0-mg dose applied for 6 h was absorbed (reviewed in Lake, 1999). The percutaneous absorption of coumarin has also been demonstrated in vitro with human skin (Beckley-Kartey et al, 1997 Yourick Bronaugh, 1997). 

A placebo-controlled, randomized clinical trial with monitoring of hypericin and pseudohypericin plasma concentrations was performed to evaluate the increase in dermal photosensitivity in humans after application of high doses of SJW extract (Table 2) (73). The study was divided into a single-dose and a multiple-dose part. In the single dose crossover study, each of the 13 volunteers received either placebo or 900, 1800, or 3600 mg of the SJW extract LI 160. Maximum total hypericin plasma concentrations were observed about four hours after dosage and were 0, 28, 61, and 159ng/mL, respectively. Pharmacokinetic parameters had a dose relationship that appeared to follow linear kinetics (73). 

Developmental Effects. No studies were located that examined the developmental effects of 2-nitrophenol in humans or animals or 4-nitrophenol in humans. In a 3-generation study, dermal application of 4-nitrophenol to rats, in doses of 50-250 mg/kg for 120 days that included the gestation... 

Reproductive Effects. It is not known whether 2-nitrophenol or 4-nitrophenol could cause reproductive effects in humans. Rats exposed to 30 mg 4-nitrophenol/m for 4 weeks (Hazleton 1983) or administered 140 mg 4-nitrophenol/kg/day for 13 weeks (Hazleton 1989) had no treatment-related effects on the weight or histopathology of the reproductive organs, but reproductive performance was not assessed. In a 2-generation study in rats, dermal application of 4-nitrophenol in doses of 50-250 mg/kg for 120 days did not alter reproductive performance. The relevance of this information to human health is not known. Data regarding the reproductive effects of 2-nitrophenol were not available. 

Because human pharmacokinetic data are often minimal, absorption data from studies of experimental animals-by any relevant route of exposure-might assist those who must apply animal toxicity data to risk assessment. Results of a dermal developmental toxicity study that shows no adverse developmental effects are potentially misleading if uptake through the skin is not documented. Such a study would be insufficient for risk assessment, especially if it were interpreted as a negative study (one that showed no adverse effect). In studies where developmental toxicity is detected, regardless of the route of exposure, skin absorption data can be used to establish the internal dose in the pregnant animal for risk extrapolation to human dermal exposure. For a discussion pertinent both to the development and to the application of pharmacokinetic data, risk assessors can consult the conclusions of the Workshop on the Acceptability and Interpretation of Dermal Developmental Toxicity Studies (Kimmel and Francis 1990). 

In vivo experiments on 4 human volunteers, to whom 0.0026 mg/cm2 of 14C-benzene was applied to forearm skin, indicated that approximately 0.05% of the applied dose was absorbed (Franz 1984). Absorption was rapid, with more than 80% of the total excretion of the absorbed dose occurring in the first 8 hours after application. Calculations were based on urinary excretion data and no correction was made for the amount of benzene that evaporated from the applied site before absorption occurred. In addition, the percentage of absorbed dose excreted in urine that was used in the calculation was based only on data from rhesus monkeys and may not be accurate for humans. In another study, 35-43 cm2 of the forearm was exposed to approximately 0.06 g/cm2 of liquid benzene for 1.25-2 hours (Hanke et al. 1961). The absorption was estimated from the amount of phenol eliminated in the urine. The absorption rate of liquid benzene by the skin (under the conditions of complete saturation) was calculated to be low, approximately 0.4 mg/cm2/hour. The absorption due to vapors in the same experiment was negligible. The results indicate that dermal absorption of liquid benzene is of concern, while dermal absorption from vapor exposure may not be of concern because of the low concentration of benzene in vapor form at the point of contact with the skin. No signs of acute intoxication due to liquid benzene dermally absorbed were noted. These results confirm that benzene can be absorbed through skin. However, non-benzene-derived phenol in the urine was not accounted for. 

Exposure to other RCAs causes similar dermal effects. CN is a more potent irritant than CS. In a human study involving dermal application, CN (0.5 mg) powder caused irritation and erythema when on the skin for 60 min (Holland and White, 1972). It took 20 mg CS to cause similar effects for the same duration of exposure. Exposure to 5% capsaicin pepper spray causes immediate and severe erythema and edema in the skin (Herman et al, 1998). Similarly, pepper ball pellets fired at individuals will cause erythema, pain, and edema at the site of impaet. The initial point of contact may become infected, scar, or heal with hyperpigmentation (Hay et al, 2006). 

ATSDR (1998b) concluded from a review of several studies of mice dermally exposed to jet fuels (including JP-5 and Jet A) that chronic dermal application of jet fuels can act as a skin carcinogen, but noted that further investigation is needed to more fully elucidate the impact of dermal exposure of jet fuels on humans. ... 

A number of studies of the carcinogenicity of dermal application of crude oil to animals have been reviewed by IARC (1989c), which concluded that there is limited evidence for the carcinogenicity of crude oil to experimental animals. A cohort study of U.S. petroleum-producing and pipeline workers, and case control studies that included exposure during crude oil exploration and production, were evaluated by IARC (1989c), which concluded that there is inadequate evidence for the carcinogenicity of crude oil in humans. 

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