Acute, Subchronic, and Developmental Toxicity and Genotoxicity of 1,1,1-Trifluoroethane (HFC-143a)

Brock, William J.; Trochimowicz, Henry J.; Farr, Craig H.; Millischer, R; Rusch, George M.

doi:10.1006/faat.1996.0092

Cited by 22 publications

(12 citation statements)

References 12 publications

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“…Atrophic changes (e.g., apoptosis, atrophic epithelium and decreased secretion) may be seen in the seminal vesicles and prostate as a qualitative finding, but organ weights are generally a more sensitive and quantitative endpoint. Histological testicular changes have been reported in rats restrained in inhalation tubes, but this may be due to heating of the testes rather than to restraint stress per se (Brock et al 1996; Dodd et al 1999; Rothenberg et al 2000). In mice, but not rats, dietary restriction can result in mild degeneration and/or partial depletion of germ cells from the testis (Chapin, Gulati, Barnes et al 1993; Chapin, Gulati, Fail et al 1993).…”

Section: Reproductive System and Stressmentioning

confidence: 99%

“…Testicular lesions are commonly noted in control rats in nose-only inhalation studies when compared with oral gavage studies (Lee et al 1993). In addition, testicular degeneration exhibits a dose-related trend in increased incidence and/or severity following nose-only inhalation exposure of rats to trifluoroiodomethane or trifluoroethane (Brock et al 1996; Dodd et al 1997). After equivalent dosing by whole body inhalation exposure, testicular changes were absent (Brock et al 1996; Dodd et al 1999).…”

Section: Reproductive System and Stressmentioning

confidence: 99%

“…In addition, testicular degeneration exhibits a dose-related trend in increased incidence and/or severity following nose-only inhalation exposure of rats to trifluoroiodomethane or trifluoroethane (Brock et al 1996; Dodd et al 1997). After equivalent dosing by whole body inhalation exposure, testicular changes were absent (Brock et al 1996; Dodd et al 1999). The effects observed in the nose-only exposure setting were attributed to stress and immobilization caused by restraint (Lee et al 1993) and thermal stress due to restraint (Brock et al 1996; Dodd et al 1999).…”

Section: Reproductive System and Stressmentioning

confidence: 99%

“…After equivalent dosing by whole body inhalation exposure, testicular changes were absent (Brock et al 1996; Dodd et al 1999). The effects observed in the nose-only exposure setting were attributed to stress and immobilization caused by restraint (Lee et al 1993) and thermal stress due to restraint (Brock et al 1996; Dodd et al 1999). These immobilization and thermal stress effects on reproductive parameters, including changes in organ weights, histology, sperm parameters, or fertility are eliminated when rats are first acclimated to the tubes and tube restraint is performed in a cooled environment (Rothenberg et al 2000).…”

Section: Reproductive System and Stressmentioning

confidence: 99%

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Interpreting Stress Responses during Routine Toxicity Studies

et al. 2013

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Stress often occurs during toxicity studies. The perception of sensory stimuli as stressful primarily results in catecholamine release and activation of the hypothalamic-pituitary-adrenal (HPA) axis to increase serum glucocorticoid concentrations. Downstream effects of these neuroendocrine signals may include decreased total body weights or body weight gain; food consumption and activity; altered organ weights (e.g., thymus, spleen, adrenal); lymphocyte depletion in thymus and spleen; altered circulating leukocyte counts (e.g., increased neutrophils with decreased lymphocytes and eosinophils); and altered reproductive functions. Typically, only some of these findings occur in a given study. Stress responses should be interpreted as secondary (indirect) rather than primary (direct) test article-related findings. Determining whether effects are the result of stress requires a weight-of-evidence approach. The evaluation and interpretation of routinely collected data (standard in-life, clinical pathology, and anatomic pathology endpoints) are appropriate and generally sufficient to assess whether or not changes are secondary to stress. The impact of possible stress-induced effects on data interpretation can partially be mitigated by toxicity study designs that use appropriate control groups (e.g., cohorts treated with vehicle and subjected to the same procedures as those dosed with test article), housing that minimizes isolation and offers environmental enrichment, and experimental procedures that minimize stress and sampling and analytical bias.This article is a comprehensive overview of the biological aspects of the stress response, beginning with a Summary (Section 1) and an Introduction (Section 2) that describes the historical and conventional methods used to characterize acute and chronic stress responses. These sections are followed by reviews of the primary systems and parameters that regulate and/or are influenced by stress, with an emphasis on parameters evaluated in toxicity studies:

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Section: Reproductive System and Stressmentioning

confidence: 99%

Section: Reproductive System and Stressmentioning

confidence: 99%

Section: Reproductive System and Stressmentioning

confidence: 99%

Section: Reproductive System and Stressmentioning

confidence: 99%

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Interpreting Stress Responses during Routine Toxicity Studies

et al. 2013

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“…In cardiac sensitization studies, dogs were exposed by a snout-only system as described previously (Brock et al 1996). Metering the test material from the cylinder through an in-lineow controller produced the test atmosphere of the HFC isomer in air.…”

Section: Atmosphere Generation and Analysismentioning

confidence: 99%

Inhalation Toxicity and Genotoxicity of Hydrofluorocarbon (HFC)-236fa and HFC-236ea

et al. 2000

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The acute, subchronic, and developmental and genetic toxicity of hydro uorocarbon (HFC)-236fa and HFC-236ea were evaluated to assist in establishing proper handling guidance. In acute inhalation studies, rats were exposed whole body for 4 hours to various concentrations of each isomer. Based on the lack of mortality, the approximate lethal concentration for HFC-236ea for male rats was > 85,000 ppm. For HFC-236fa, the LC 50 for males and females (combined) was > 457,000 ppm. Narcotic-like effects, e.g., prostration, incoordination, and reduced motor activity, were observed only during exposure to either isomer, but were not evident after termination of exposure. In cardiac sensitization studies, HFC236ea induced cardiac sensitization at¸35,000 ppm, with fatal responses occurring at 50,000 ppm and greater. For HFC-236fa, a cardiac sensitization response was observed at 150,000 ppm and greater but not at 100,000 ppm. A fatal cardiac sensitization response was observed in one dog exposed to 150,000 ppm HFC236fa. In 90-day subchronic inhalation studies, male and female rats were exposed whole body to HFC-236ea at concentrations of 0, 5000, 20,000, or 50,000 ppm for 6 hours/day, 5 days/week. Similarly, male and female rats were exposed whole body to HFC-236fa at concentrations of 0, 5000, 20,000, or 50,000 ppm for 6 hours/day, 5 days/week. During exposure, narcotic-like effect (reduced acoustic startle response) was observed at 50,000 ppm with both isomers, although there appeared to be an adaptive response to this effect as the study progressed. With HFC-236ea, dilatation of the seminiferous tubules, without effects on germ or Sertoli cells, was observed only in rats at 50,000 ppm. No other effects on in-life measures or on clinical or anatomic pathology, including histopathology, were observed for either isomer. In rat developmental toxicity studies, no evidence of embryotoxicity or teratogenicity was observed with either isomer exposed up to 50,000 ppm during gestational days 7 to 16. Also, no developmental toxicity was observed in rabbits exposed to HFC-236fa at concentrations of up to 50,000 ppm during gestational days 7 to 19. Neither of the HFC-236 isomers was mutagenic in the Ames reverse mutation assay or clastogenic in the chromosomal aberration assay with human lymphocytes. No increase in chromosomal aberrations was observed in in vivo micronucleus studies with either isomer.

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