Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity (2001) / Chapter Skim
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Appendix A: Application of the Recommended Evaluative Process to Specific Chemicals
Appendix A: Application of the Recommended Evaluative Process to Specific Chemicals
Pages 115-167
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\ Appendixes
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A complete assessment by the Navy would require an evaluation of each component under the full range of environmental conditions in which human exposures occur. A number of toxicity studies, including reproductive and developmental toxicity studies, have been conducted on HFC-134a.
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Reproductive Toxicology, 11~: 123-160; end An Assessment of Lithium Using the IEHR Evaluative process For Assessing Human Developmental and Reproductive Toxicity ofAgents. Reproductive Toxicology, 9~2~:175210.
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for the chemicals analyzed. Two recent studies measured exposure of Air Force personnel to jet fuels, including IBM.
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bThe Occupational Safety and Health Administration PEL for benzene is during aircraft fuel tank entry and repair at 12 Air Force bases. They report that the highest S-hr time-weighted average fuel exposure found was 1,304 mg/m3, and the highest 15-min short-term exposure was 10, 295 mg/m3.
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Experimental Animal Studies Respiratory effects, such as bronchoconstriction, were observed in rabbits and guinea pigs exposed by inhalation to kerosene (Casaco et al. 1982; Garcia et al.
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1981~. Hepatic effects were observed in rats exposed by Savage to single doses of IP-5 at 24-60 ml /kg (Bogo et al.
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The study authors concluded that personality changes and emotional dysfunctions are effects of long-term exposures to jet fuels. The usefulness of this study for determining the general toxicity of exposure to IP-S in the context of Naval operations is unclear for the following reasons: (~)
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1994~. Rats exposed to an average concentration of 950 mg/m3 of IP-8 for 28 d exhibited pathological changes, including disruption of epithelial and endothelial structures, convoluted airways, and alveoli filled with red blood cells and fluid (Pfaff et al.
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1995~. In addition to the a-2u-giobulin protein droplet nephropathy observed in male rats, there was a dose-related decrease in body weight, a dose-related increase in gastritis and perianal dermatitis, and an increase in liver enzymes that was not related to the dose of Jim.
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treated with IP-5 showed decreases in relative lymph node and thymus weight and decreases in thymocyte count, bone marrow nucleated cell count, thyme cortical lymphocytes, and the cellularity of the thyme lobules.
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to study absorption and disposition of JP-~. The percutaneous absorption and cutaneous disposition of topically applied neat Tet-A and JP-S jet fuels were assessed by monitoring the absorptive flux of the marker components ~4C naphthalene and 3H dodecane simultaneously.
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Experimental Animal Studies Developmental Toxicity Cooper and Mattie (1996) reported the results of a study of the developmental toxicity of IP-8 in Sprague-Dawley rats dosed orally at 0, 500, 1,000, 1,500, 2,000 mg/kg/d on days 6-15 of pregnancy.
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No other studies have assessed the developmental toxicity of JP-S (or other kerosene-based fuels) in experimental animals.
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1997) reported measurements of human exposures and the values for the components of jet fuels analyzed that were far below the TWA threshold limit values (see Tabe]
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Whether the developmental toxicity is directly related to the maternal toxicity or is independent of the effects on the mothers is not known. Data on comparative pharmacokinetics are sparse; there are no data to support a conclusion that adverse reproductive or developmental toxic effects in rats or mice are not predictive of some adverse effect in humans.
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No reproductive toxicity studies have been done in experimental animals. One adequate study demonstrated developmental toxicity in rats treated orally at 1,500-2,000 mg/kg/d (Cooper and Mattie 1996)
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Occupational exposure standards are based on knowledge of the toxicity of components of JP-~. Those few exposure values that are published suggest that human exposures were below ACGTH TWA threshold limit values for those chemicals.
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, the UET~ for developmental toxicity for a short term exposure is ~ mg/kg/~. Reproductive Toxicity There are no human or animal data from which to develop a quantitative evaluation or calculate UET~s for male or female reproductive toxicity endpoints.
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They primarily serve as replacements for CFCs in refrigiSubcommittee member Paul Foster was previously employed at a company that conducted reproductive and developmental toxicity studies on HFC-134a. Because Dr.
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Briefly, male rats exposed at concentrations of 10,000 ppm and 50,000 ppm had a significant increase in the incidence of Leydig cell hyperplasia compared with controls. The study is described below.
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reported no deaths or treatment-related effects on cI~n~cal signs, body weight, food and water consumption, or postmortem findings in rats and m~ce exposed via inhalation at a concentration of S10,000 ppm with oxygen supplementation for ~ hr.
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In the same study, rats exposed at concentrations of 47,000 ppm had significantly reduced respiratory rates. Dogs exposed via inhalation to HFC-134a at concentrations of 40,000 and 80,000 ppm for 1 hr did not show treatmentrelated clinical signs.
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Carcinogenicity Studies Rats were exposed, whole body, to HFC-134a via inhalation at concentrations of 2,500,10,000, and 50,000 ppm for 6 hr/d,55/wk for up to 104 wk (Hext and Parr-Dobrzanski 1993; Collins et al.1995~. At 50,000 ppm there was an increase in testicular weight, T~eydig cell hyperplasia, and Leydig cell tumors.
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(1997) , in a thorough evaluation of Leydig cell hyperplasia and adenomas, indicated that the incidence in humans is uncertain and that, as a default when the mode of induction is unknown, agents that induced both hyperplasia and adenomas should be considered relevant and of concern for progression to carcinogenesis in humans.
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Absorption of fluorocarbons and bromofluorocarbons via inhalation in experimental animals is rapid; the maximal blood concentrations of the substances develop within 5 min and equilibrium is achieved within the next 15 min of exposure (Azar et al. 1973; Trochimowicz et al.1974; Mullin et al.1979~.
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Toxic effects observed in animals following oral and inhalation exposure to HFC-134a indicate it is absorbed by the lungs and gastrointestinal tract (Salmon et al.1980~. Studies conducted in rats exposed to high concentrations of HFC-134a, either orally or via inhalation, indicate it is rapidly excreted, mostly as the unchanged parent compound (Salmon et al.1980)
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Physical and reflex development were evaluated in F1 and F2 offspring, as were locomotor coordination, activity, and learning, memory, and reversal. A slight but statistically significant decrease in body weight gain was seen in P males exposed to 10,000 and 50,000 ppm after 2 wk exposure; cumula
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The increase in progesterone was consistent with increased Leydig cell function at this exposure level. Developmental Toxicity Studies Four developmental toxicity studies testing HFC-134a have been conducted in rats and rabbits (Table A-5.
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There was no effect on the number of implants, litter size, or litter weight. At 50,000 ppm, fetal weight was slightly but significantly decreased and there was an increased incidence of skeletal variations, primarily reduced ossification of cervical vertebrae, sternebrae, and digits.
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The NOAEL was considered to be 10,000 ppm, based on maternal toxicity, and the NOAEL for developmental toxicity was 240,000 ppm. In a pert- and postnatal study design, Alexander et al.
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There is no evidence of genetic toxicity for HFC-134a. The primary effect reported is the induction of Leydig cell hyperplasia and adenomas in male rats exposed at 50,000 ppm for 6 in/d, 5 d/wk over a 2-yr period (Collins et al.
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No data were found from studies of developmental toxicity of HFC-134a in humans. The experimental animal data are sufficient to conclude that HFC-134a does not cause prenatal developmental toxicity when pregnant animals were exposed (whole body)
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Default Assumptions The data on Leydig cell hyperplasia and adenoma are assumed to be relevant to humans. Likewise, the lack of developmental toxicity is also assumed to be relevant to humans.
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300 For chronic exposure, the subcommittee chose the NOAEL of 10,000 ppm for a 6-hr/d, 2-yr exposure based on a significant increase in the incidence of Leydig cell hyperplasia in treated rats (Collins et al. 1995; Hext and Parr-Dobrzanski 1993~.
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A total uncertainty factor of 300 was applied to the NOAEL: 3 for interspecies extrapolation, 10 to protect sensitive individuals, and 10 for database deficiencies due to the lack of both a two-generation study and a developmental neurotoxicity study. The latter concern was raised by the Alexander et al.
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The animal data are sufficient to support a conclusion that exposures to HFC-134a does not cause prenatal developmental toxicity when pregnant animals are exposed for 6 fur/d during major organogenesis to concentrations of HFC-134a below those associated with narcosis (less than 30,000 ppm)
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Laboratory studies in rats identified a NODES of 10,000 ppm based on a significant increase in the incidence of Leydig cell hyperplasia. Applying an aggregate uncertainty factor of 300 (3 for interspecies extrapolation, 10 for intraindividual differences, and 10 for an incomplete database)
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