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The potential adverse effects of resorcinol, delivered via drinking water at 0, 120, 360, 1000, and 3000 mg/L (palatability limit), were assessed in a regulatory guideline compliant two-generation reproduction study in Crl:CD(SD) rats. Expanded end points of thyroid gland (TG) function were added because of clinical case reports indicating human TG toxicity. Average daily resorcinol intake (mg/kg) at the 3000 mg/L concentration was 233 in F0 and F1 males, whereas in females it was 304 (premating/gestation) and 660 (lactation). No resorcinol ingestion-related clinical signs of toxicity were observed. Furthermore, neither gross morphologic anomalies nor effects on reproductive function or thyroid hormone levels were detectable. Body weight reductions occurred in 3000 mg/L F0 and F1 animals and were more pronounced in males. However, there was no evidence of either cumulative toxicity in the second generation or of enhanced sensitivity to resorcinol in pregnant/lactating females. Water intake was lower in 3000 mg/L rats of both generations and intermittently, to a lesser extent, at 1000 mg/L; however, concurrent feed intake and utilization were unaffected. Decreased TG follicular colloid content (conventional histopathology; confirmed by quantitative stereomicroscopy) in the 3000 mg/L F0 males was attributed to resorcinol but not considered adverse. The 3000 mg/L intake level appeared to have caused an adaptive thyroid response to a new homeostatic level with no adverse physiological consequences in either males (the more susceptible gender) or females. There were no differences in TG histology in F0 rats of either sex at 1000 mg/L. Thus, resorcinol intake at maximum palatability via a route and mode relevant to potential human exposures via contaminated drinking water at presently unknown environmental concentrations caused no detectable adverse effects on any reproduction or TG end points. The 3000 mg/L resorcinol exposure level was the no-observed-adverse-effect level (NOAEL) for parental systemic and offspring toxicity, while 1000 mg/L was the no-observed-effect level (NOEL).

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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.