Two-Generation Reproductive Toxicity Study of Inhaled Acrylonitrile Vapors in Crl:CD(SD) Rats

Abstract

To assess the effects of acrylonitrile (AN) exposure on reproduction, Sprague-Dawley rats (25/sex/group) were exposed to vapor atmospheres of AN via whole-body inhalation at concentrations of 0, 5, 15, 45 (two offspring generations) and 90 ppm (one offspring generation), 6 h daily, 1 litter/generation, through F2 weanlings on postnatal day 28. After approximately 3 weeks of direct exposure following weaning, exposure of the F1 animals at 90 ppm was terminated due to excessive systemic toxicity in the males. There were no exposure-related mortalities in adult animals, no functional effects on reproduction or effects on reproductive organs, and no evidence of cumulative toxicity or of enhanced toxicity in pregnant and lactating dams or in developing animals. Adult systemic toxicity was limited to body weight and/or food consumption deficits in both sexes and generations (greater in males) at 45 and 90 ppm and increased liver weights in the 90 ppm F0 males and females and 45 ppm F1 males. Neonatal toxicity was expressed by F1 offspring weight decrements at 90 ppm. Clinical signs of local irritation during and immediately following exposure were observed at 90 ppm. Microscopic lesions of the rostral nasal epithelium, representing local site-of-contact irritation, were observed in some animals at 5 to 45 ppm. The no-observed-adverse-effect level (NOAEL) for reproductive toxicity over two generations and neonatal toxicity of AN administered to rats via whole-body inhalation was 45 ppm. The NOAEL for reproduction was 90 ppm for the first generation. The NOAEL for parental systemic toxicity was 15 ppm.

Derivation of Noncancer Reference Values for Acrylonitrile

“…All available dose‐response models were applied to the subchronic nasal lesion incidence data for F1 rats (Nemec et al ., 2008), with the probit model providing the best fit based upon visual inspection, AIC value (58.3), and p ‐value (0.999) for goodness of fit. The probit model is described by the following equation: …”

“… UFa: Because the RGDR methods were used to account for pharmacokinetic differences between rats and humans, a factor of 3 is considered to be appropriate for UFa to account for remaining pharmacodynamic differences. UFh: Because the critical effect (nasal lesions) is not expected to depend upon systemic factors that may vary from one individual to another, a value of 3 was considered to be sufficient to address variation in factors affecting nasal tissue dosimetry. UFs: Because the Nemec et al . (2008) study included a subchronic exposure duration of 70 days, a value of 1 is considered to be appropriate for deriving a subchronic RfC based on this study.…”

“…UFs: Because the Nemec et al . (2008) study included a subchronic exposure duration of 70 days, a value of 1 is considered to be appropriate for deriving a subchronic RfC based on this study.…”

“…This value of 20 ppm can be considered as the LOAEL. Subchronic exposures to AN are also associated with nasal lesions in rats, following exposures to 5 to 45 ppm (Nemec et al ., 2008). The lesions showed a clear exposure‐related response in incidence and severity, and included respiratory/transitional epithelial hyperplasia, subacute inflammation, squamous metaplasia, and/or degeneration of the olfactory epithelium, and the study identifies LOAEL values of 45 ppm in F0 animals and 5 ppm in F1 animals.…”

“…2.4.1.2. Subchronic study A two‐generation reproduction toxicity study was conducted for AN in Sprague‐Dawley rats (Nemec et al ., 2008). For both generations, groups of 20 animals (10 per sex) were exposed to 0, 5, 15, and 45 ppm AN for six hours/day, seven days/week, for 70 days.…”