Limitations, dermal absorption studies

Hexachloroethane has been found in the plasma of workers wearing protective clothing and respiratory protection suggesting that hexachloroethane can be absorbed following inhalation and/or dermal exposure. Based on the minimal effects seen on target tissues (liver and kidney) in animal studies, absorption from the lungs seems to be limited. Dermal absorption was also estimated to be low based on calculated dermal penetration rates. 

Hexachloroethane caused reversible corneal injury in rabbits following ocular contact, but contact with the skin for 24 hours resulted in no dermal effects (Weeks et al. 1979). The physical properties of hexachloroethane suggest that absorption across human skin would be limited (Fiserova-Bergerova et al. 1990). Therefore, unless dermal absorption studies indicate that this prediction is incorrect, there is no need for additional studies of acute dermal toxicity. 

Absorption, Distribution, Metabolism, and Excretion. Studies in laboratory animals indicate that di- -butyl phthalate given orally is readily absorbed, mainly as the metabolite mono- -butyl phthalate, and subsequently, is rapidly excreted. Limited data exist regarding inhalation and dermal absorption. Studies on the absorption and metabolism of di- -butyl phthalate by the inhalation and dermal routes are needed to evaluate human health risk by these routes of exposure. 

There are a number of practical limitations that must be considered in conducting dermal absorption studies. 

A study with a dog exposed to an occluded dermal dose of TOCP labeled with radioactive phosphorus provides limited evidence that organophosphate esters in hydraulic fluids may be widely distributed after dermal absorption (Hodge and Sterner 1943). Similar widespread distribution of radioactivity among tissues was observed in male cats after dermal exposure to [uniformly labeled 14C-phenyl]TOCP (Nomeir and Abou-Donia 1986). Tissues and fluids with the highest concentrations of radioactivity in these studies included the bile, gall bladder, urinary bladder, liver, kidney, and fat, thus suggesting that TOCP and metabolites are somewhat preferentially distributed to these tissues. 

Limited information was located regarding dermal absorption of inorganic lead in animals. An early study reported that lead acetate was absorbed from the clipped skin of rats, as determined by an increase in the concentration of lead in the kidneys relative to controls (Laug and Kunze 1948). It was further shown in that study that mechanical injury to the skin significantly increased the penetration of lead and that the penetration of lead from lead arsenate was significantly less than from lead acetate. 

No studies were located regarding the toxicokinetics of di-/ -octylphthalate in humans or animals following inhalation or dermal exposure. Information on the toxicokinetics of 6i-n-octylphthalate in humans following oral exposure is not available. There are studies that provide indirect evidence for the oral absorption of di- -octylphthalate in animals (Albro and Moore 1974 Oishi 1990 Poon et al. 1995) however, quantitative information is lacking on the rate and extent of absorption following oral exposure to di- -octylphthalate. Information on the distribution of di-w-octylphthalate is limited to oral studies in rats by Oishi (1990), which reported the identification of mono- -octy lphthalate in blood and testes within 1-24 hours (plasma peak at 3 hours, testes peak at 6 hours) after dosing, and by Poon et al. (1995), which reported di- -octylphthalate... 

Polybrominated Diphenyl Ethers. No information was located regarding dermal absorption of PBDEs in humans. The only information regarding dermal absorption in animals is that from a study of absorption in an in vitro preparation (Hughes et al. 2001). In that study, " C-dccaBDE dissolved in tetrahydrofuran was applied to dorsal skin (three dose levels) excised from adult hairless female mice and fractions of receptor fluid were collected over a 24-hour period. Transfer of radioactivity to the receptor fluid was minimal, only 0.07 to 0.34% of the applied radioactivity. Two to 20% of the radioactivity was found in the skin, and the lowest dose applied had the highest percentage of the dose in the skin. Washing the skin with solvent 24 hours after application removed 77-92% of the applied dose. In this study, decaDBE did not easily penetrate the skin, but inferences to dermal absorption in humans based on these limited results may not be appropriate. 

Information on toxic effects of acute-duration exposure to PBBs by routes other than oral are limited to data on hepatic, renal, dermal, and ocular effects of inhalation and dermal exposure in rats or rabbits (Millischer et al. 1980 Needham et al. 1982 Norris et al. 1975a Waritz et al. 1977), but these data may not be reliable due to study limitations and possible delayed lethality. Quantitative data for inhalation and dermal absorption of PBBs are lacking. Studies of inhalation and dermal absorption following exposure to soil containing PBBs (i.e., bioavailability studies) would be useful for assessing risk at a hazardous waste... 

Absorption, Distribution, Metabolism, and Excretion. The database for inhalation and dermal absorption of silver compounds in humans consists primarily of qualitative evidence from occupational case studies. Limited quantitative information exists on the oral absorption of silver compounds in humans. Research into the quantitative absorption of various silver compounds following relevant exposure routes would be useful to better predict the potential for toxic responses to particular silver compounds in humans. 

Comparative Toxicokinetics. A limited number of studies exist regarding the comparative toxicokinetics of orally administered silver compounds in rats, dogs, monkeys, and humans. A more complete comparison of the absorption and elimination of silver in humans and rats may be warranted given that much of the toxicokinetic data comes from rats. It would also be useful to acquire data on the comparative toxicokinetics of various silver compounds in several species of experimental animals and in humans following inhalation and dermal exposure in order to model the kinetics of silver deposition across different exposure scenarios and within sensitive populations. 

As is apparent from Figure 3-6, there are minimal data on health effects following dermal absorption. In addition, there were only two studies on toxicokinetics that used the dermal exposure route. Although there are several animal studies that evaluated the health effects of DEHP through the respiratory route, these studies are also limited in scope. In each case, exposures were at very low levels and without effect. Although the exposure concentrations were relevant to human exposures through inhalation, the lack of observed effects makes it difficult to evaluate whether there are specific risks that apply to respiratory exposures. 

No data are available in animals from standard studies of acute toxicity using the inhalation or dermal routes of exposure. Therefore, an MRL value for acute inhalation exposures cannot be derived. DEHP concentrations in the atmosphere are limited by the low vapor pressure of this compound. Dermal absorption of neat DEHP is demonstrated as minimal (Deisinger et al. 1991 Melnick et al. 1987). 

In addition to the membrane types mentioned above, reconstituted human epidermis has been put forward to be used in skin absorption studies. Because of the limited and irregular availability of human skin for in vitro testing purposes and the inter-individual differences between donors, a standardized reconstituted epidermis with proper barrier properties would be of great value. Until now, however, the permeability of reconstituted epidermis has been shown to be far greater than that of normal human epidermis (Doucet et al., 1998). Therefore, reconstituted epidermis models are, at this stage of development, not suitable for the estimation of dermal absorption potential. 

Thus, despite the value of human volunteer studies, the technical and ethical constraints for studying dermal absorption of pesticides in human volunteers prevail. As a consequence, only limited data on the dermal absorption of chemicals are available from human volunteer studies. This is in contrast to pharmaceutical products, where the use of human volunteers is considered to be the only relevant approach to generate data of precise relevance to man. 

In order to assess risk to individuals following dermal exposure to a pesticide, dermal absorption data are often required to convert dermal deposition data to estimates of systemic exposure. These estimates of systemic exposure are then compared with the No Observed Adverse Effect Levels (NOAELs) from oral toxicity studies or limit values (for instance. Acceptable Operator Exposure Levels (AOELs)) derived from these oral data (Bos et at., 1998 Rennen et al 1999). As noted in the introduction, oral studies are generally used because the toxicology database is typically focused on the oral route of exposure. 

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