Dermal system study

A series of acute- and intermediate-duration inhalation, oral, and dermal exposure studies in animals provide information on death, systemic effects, neurological effects, and immunotoxicity following exposure to polyalphaolefm hydraulic fluids. 

Two studies on intermediate-duration exposure to mineral oil hydraulic fluids are available a single oral exposure rat study to MIL-H-5606 (Mattie et al. 1993), and an inhalation-exposure study in rats to Houghto-Safe 5047F (Kinkead et el. 1991). Because no other intermediate-duration studies were located, no inhalation or oral intermediate MRLs were derived. Inhalation, oral, and dermal systemic toxicity studies examining a number of end points would be useful in identifying the targets of toxicity of mineral oil hydraulic fluids. 

Polyalphaolefin Hydraulic Fluids. Because no chronic-duration human or animal inhalation, oral, or dermal exposure studies using polyalphaolefin hydraulic fluids were located, chronic-duration inhalation or oral MRLs could not be derived. Systemic toxicity studies in which animals were exposed via inhalation, oral, and dermal routes would be useful in identifying the end points of toxicity for humans living at or near hazardous waste sites and exposed for chronic durations. Further carcinogenicity studies on individual organophosphate ester components of hydraulic fluids maybe useful. 

C. Systemic Toxicity. On rare occasions, the dermal irritation study is begun only to have the animals die very rapidly after test material is applied. 

The paucity of systemic toxicity data for this chemical appears to be related to primary interest in testing for carcinogenicity. Treatment- related neoplasms developed in rats and mice that were treated with 1,2-diphenylhydrazine in a diet. An inconclusive chronic dermal carcinogenicity study of... 

Neurotoxicity. No clinical signs of central nervous system toxicity or histological alterations of nervous system organs and tissues were observed in rats or mice in the NCI (1978) chronic oral bioassay. Tests for neurotoxicity in animals may be appropriate if there is clinical evidence of neurological dysfunction in general oral or dermal toxicity studies of I 2-diphenylhydrazine. 

Immunotoxicity. There are a number of reports that parenteral exposure of animals to carbon tetrachloride can affect the immune system (Kaminski et al. 1989 Kaminski et al. 1990 Tajima et al. 1985). The effects of carbon tetrachloride on the immune system have been investigated following oral (Smialowicz et al. 1991), but not after inhalation or dermal, exposure. Studies of the immunotoxic potential of carbon tetrachloride by these routes would be valuable, especially in view of the scattered bits of suggestive data (McGuire 1932 Taylor 1925) indicating carbon tetrachloride may cause a hypersensitization reaction following dermal exposure. As noted by Luster et al. 

White Phosphorus Smoke. There is limited information on the potential of white phosphorus smoke to induce cardiovascular effects in humans. No human exposure studies examining the cardiovascular system were located. No gross or histological alterations were observed in the hearts of rats exposed to white phosphorus smoke at concentrations as high as 1,742 mg orthophosphoric acid equivalents/m315 minutes/day, 5 days/week, for 13 weeks (Brown et al. 1981). No dermal exposure studies examining the cardiovascular system were located. 

Studies on animals dermally (nonbum) exposed to white phosphorus are limited to an acute exposure study which monitored for dermal and ocular effects. Several dermal burn studies were identified which provided data on death and a limited number of acute systemic effects. Neurological effects were also observed in an acute animal dermal bum study. 

White Phosphorus Smoke. There is a limited amount of available information on human toxicity of white phosphoms smoke. These acute-duration human exposure studies monitored for systemic effects following inhalation exposure. Death, systemic effects, and developmental effects have been observed in animals exposed to airborne white phosphoms smoke for acute and intermediate durations. Reproductive and neurological end points have also been monitored following intermediate-duration inhalation exposure. No dermal exposure studies were located. 

Test System The adult rat, rabbit, or guinea pig have been considered useful for repeated dermal toxicity studies. Other species may be used if justified. The body weight for different species should range as follows rats 200 to 300 g rabbits 2 to 3 kg guinea pig 350 to 450 gm. 

Systemic Effects. No studies were located regarding systemic effects in humans after exposure to 2,3-, 2,5-, 2,6-, 3,4-, or 3,5-DNP or in animals after inhalation exposure to any of the DNP isomers. Studies of systemic effects of DNPs in animals after dermal exposure were limited to two dermal irritation studies on 2,4-DNP. 

Inhalation data were sufficient to derive an intermediate MRL based on chemical changes suggesting physical damage in the brain of gerbils (Rosengren et al. 1985). Data were not sufficient to derive an intermediate oral MRL. Intermediate-duration oral and dermal exposure studies that attempt to determine NOAEL and LOAEL values for systemic and other neurological effects would be valuable, because populations near hazardous waste sites might be exposed to... 

Limited data are available on effects in humans, consisting of an occupational study of workers exposed to mixtures of plasticizers and dermal sensitization studies conducted to evaluate the effects of di- -butyl phthalate in cosmetic products. Data from animal studies are more extensive. As a result of early findings on testicular effects of di- -butyl phthalate, most studies have tended to concentrate mainly on developmental and reproductive effects. A few studies provide data on systemic effects, but since these appear to be minor, research in this area has not been extensive. No data are available on the chronic effects of di- -butyl phthalate, or on its carcinogenic potential. 

Both of these approaches allow for assessment of systemic absorption by not conducting complete mass balance studies (e.g., expired air to catch absorbed compound metabolized to COj or HjO expired end products). In vivo dermal absorption studies not taking into account other routes of excretion must be interpreted with caution. One extension of this mass balance excretory analysis is to assess dermal absorption by only monitoring the primary excretory route for the compound studied. Dermal bioavailability has been assessed in exhaled breath using real-time ion trap mass spectrometry to track the uptake and ehmination of compounds (e.g., trichloroethylene) from dermal exposure in humans and rats (Poet et al., 2000). A physiologically based pharmacokinetic model can be used to estimate the total bioavailability of compoimds. The same approach was extended to determine the dermal uptake of volatile chemicals imder non-steady-state conditions using real-time breath analysis in rats, monkeys, and humans (Thrall et al., 2000). 

Skin is a heterogeneous, multiple-layer organ. In a typieal dermal absorption study, three biologieal levels are of main eoncem stratum comeum, epidermis, and whole skin (Sehaefer and Redelmeier, 1996). When the skin is exposed to a ehemieal mixture, the skin and the medium of the chemical mixture form an absorption system. For the three skin layers, three absorption systems could be generated for a given chemical mixture, which will provide abundant information on the three biological levels. 

PDMS membranes have been widely used as a skin imitation membrane for dermal absorption studies (Moss et al., 2002). A membrane-coated fiber technique has bear developed in our center for quantitative analysis of the absorption kinetics and rapid determination of the partition coefficients of chemicals between the PDMS membrane and chemical mixtures (Xia et al., 2003). In the following sections, the system coefficient approach is demonstrated by measuring the partition coefficients of chemicals in the P/W systems. 

Hydraziae is toxic and readily absorbed by oral, dermal, or inhalation routes of exposure. Contact with hydraziae irritates the skin, eyes, and respiratory tract. Liquid splashed iato the eyes may cause permanent damage to the cornea. At high doses it can cause convulsions, but even low doses may result ia ceatral aervous system depressioa. Death from acute exposure results from coavulsioas, respiratory arrest, and cardiovascular coUapse. Repeated exposure may affect the lungs, Hver, and kidneys. Of the hydraziae derivatives studied, 1,1-dimethylhydrazine (UDMH) appears to be the least hepatotoxic monomethyl-hydrazine (MMH) seems to be more toxic to the kidneys. Evidence is limited as to the effect of hydraziae oa reproductioa and/or development however, animal studies demonstrate that only doses that produce toxicity ia pregaant rats result ia embryotoxicity (164). 

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