Two-Generation Reproduction Study and Immunotoxicity Screen in Rats Dosed with Phenol via the Drinking Water

Abstract

This study evaluated the potential reproductive toxicity of phenol in a rat two-generation reproduction study, which included additional study endpoints, such as sperm count and motility, developmental landmarks, histological evaluation of suspect target organs (liver, kidneys, spleen, and thymus), weanling reproductive organ weights, and an immunotoxicity screening plaque assay. Phenol was administered to 30 Sprague-Dawley rats/sex/group in the drinking water at concentrations of 0, 200, 1000, or 5000 ppm. Parental (P1) animals were treated for 10 weeks prior to mating, during mating, gestation, lactation, and until sacrifice. The F1 generation (P1 offspring) was treated using a similar regimen, while the F2 generation was not treated. After mating, 10 P1 males/group were evaluated using standard clinical pathology parameters and an immunotoxicity screening plaque assay. Significant reductions in water and food consumption were observed in the 5000-ppm group in both generations; corollary reductions in body weight/body weight gain were also observed. Mating performance and fertility in both generations were similar to controls, and no adverse effects on vaginal cytology or male reproductive function were observed. Vaginal opening and preputial separation were delayed in the 5000-ppm group, and were considered to be secondary to the reduction in F1 body weight. Litter survival of both generations was reduced in the 5000-ppm group. Absolute uterus and prostate weights were decreased in the F1 generation at all dose levels; however, no underlying pathology was observed and there was no functional deficit in reproductive performance. Therefore, these findings were not considered to be adverse. No evidence of immunotoxicity was noted in the 5000-ppm group. The effects noted at the high concentration were presumed to be associated with flavor aversion to phenol in the drinking water. Based on a comprehensive examination of all parameters, the no-observable-adverse-effect level (NOAEL) for reproductive toxicity of phenol administered in drinking water to rats is 1000 ppm. The corresponding daily intake of phenol for an adult rat at the NOAEL of 1000 ppm is equivalent to about 70 mg/kg/day for males and 93 mg/kg/day for females.

Histological and histometrical evidences for phenol immunotoxicity in mice

“…In line with these results, similarly, previous studies have demonstrated the immunological alterations on the splenic-forming cells and corresponding circulating antibody levels (Hsieh et al 1992) in the CD-1 mice. In contrast, no spleen toxicity was observed in the study of Ryan et al (2001) on the Sprague–Dawley rats. This dissimilarity may be associated with possible interspecies and inter strains differences between rats and mice for this endpoint.…”

Liquid Growth Hormone: Preservatives and Buffers

“…The potential reproductive toxicity of phenol was investigated in a two-generation reproductive study in rats [13]. In this study phenol was administered via the drinking water at doses of 0–5,000 parts per million for a period of 10 weeks before and during mating and gestation for two consecutive generations of rats.…”

Wildlife Toxicity Assessment for Phenol

“…For example, Ryan et al [16] administered phenol in the drinking water and observed reproductive effects (e.g., reduced survival of F 1 pups) at the highest dose level (379.5 mg/kg), a dose that was approximately six times greater than the dose that produced similar effects in a gavage study [14]. A contrast is evident in the toxic effects of phenol when administered as a bolus compared to similar doses administered throughout the day.…”