The toxicity of p-aminophenol in the Sprague-Dawley rat: effects on growth, reproduction and foetal development.

p-Aminophenol (p-AP) was fed in the diet to groups of 40 male and 45 female Sprague-Dawley rats at levels of 0.07, 0.2 or 0.7% for up to 6 months. Methaemoglobin levels were determined after 6 wk. During wk 12, urine was collected from ten rats/sex/group for evaluation of mutagenicity in the Ames test. Clinical chemistry, haematology and histopathology studies were performed in subgroups after 13 and 27 wk. In addition, after 13 wk, 25 females/group were mated to untreated males in a teratology study. After 20 wk, 20 males/group were removed from the test diets and mated to untreated virgin females in a dominant lethal mutagenicity study. These males remained untreated until they were killed at 27 wk. Rats that had been maintained on the test diets throughout the study were also killed at wk 27. The high dose level of 0.7% p-AP resulted in a significant (10-15%) reduction in body-weight gain in both sexes. There was no increase in the level of methaemoglobin and, other than slight reductions in total erythrocytes and haemoglobin in female rats at 13 wk, there were no toxicologically important differences between groups in haematology or clinical chemistry values at any time during the 27 wk of treatment. Dose-related nephrosis was seen in both sexes after 13 and 27 wk and in the high-dose males that were removed from the test diet for a 7-wk recovery period. The compound was not teratogenic, but an increase in developmental variations associated with maternal toxicity was noted at the mid- and high-dose levels. In the dominant lethal study, an increase in the total number of resorptions (but not litters with resorptions) was observed in the high-dose group in the first of two matings but this observation was not confirmed in a follow-up study. Mutagenic activity was not detected in the urine of rats fed p-AP.

Evaluation of the teratological and dominant lethal potential of N,N-bis-(2-hydroxyethyl)-p-phenylenediamine sulphate in a 6-month feeding study in rats.

N,N-Bis-(2-hydroxyethyl)-p-phenylenediamine sulphate (N,N-Bis) was administered to 40 male and 45 female Sprague-Dawley rats per group by admixture with their diets at levels of 0.03, 0.1 and 0.3% for periods up to 6 months. Methaemoglobin levels were determined at wk 6. After 90 days ten animals/sex/group were killed for studies of possible target organs, haematology and blood chemistry. After 90 days, 25 females in each group were mated to untreated males in a teratology study. At wk 20, 20 males in each group were transferred from the test diets containing N,N-Bis to the control diet and were mated to untreated females in a dominant lethal study. The remaining animals were killed after 6 months for terminal studies (gross examination of organs, haematology and blood chemistry). The males used in the dominant lethal study were also killed at month 6, to serve as a comparison recovery group (gross examination of organs). Feeding of N,N-Bis at levels up to 0.3% in the diet caused a significant reduction in the body weight of male rats. The only signs of gross pathology after either 3 or 6 months of N,N-Bis feeding were darkened thyroids. This effect was noted in the high-dose group at both time intervals and, to a lesser extent, in the mid-dose group at month 6, and it was also seen in most of the high-dose recovery males and in a small number of mid-dose recovery males. No pathological effects were detected microscopically after the feeding of N,N-Bis for 90 days. N,N-Bis was not teratogenic, nor did it induce a dominant lethal effect in this study when administered to rats at levels including those causing borderline toxicity.

A subchronic, teratologic, and dominant lethal study of 2-methylresorcinol in rats. I. Subchronic toxicity.

2-methylresorcinol (2-MR) was administered to groups of 40 male and 35 female Sprague-Dawley rats by admixture with diets at levels of 0.1, 0.4, and 1.5% for periods up to 6 months. Methemoglobin levels were determined after 6 weeks. After 90 days 10 animals/sex/group were killed for clinical pathological and histopathologic determinations. The 25 remaining females and 20 males per group were utilized in teratology and dominant lethal studies presented in Part II (T.A. Re, R.F. Loehr, S.C. Rodriguez, D. E. Rodwell, C.M. Burnett, 1986, Fundam. Appl. Toxicol. 7, 293-298). Ten additional males were killed after 6 months of exposure for additional clinical pathologic determinations and gross pathologic observations. The 20 males/group used in the dominant lethal study (Part II) were also killed after 6 months to serve as a comparison recovery group (gross examination of organs). Feeding 2-MR at a level of 1.5% in the diet was associated with a significant reduction in body weight gains. Females fed at a level of 0.4% also weighed significantly less than the control. No pathological effects were noted after either 90 or 180 days of feeding.

A subchronic, teratologic, and dominant lethal study of 2-methylresorcinol in rats. II. Teratologic and dominant lethal study.

2-Methylresorcinol (2-MR) was administered to groups of 40 male and 35 female Sprague-Dawley rats by admixture with the diets at levels of 0.1, 0.4, and 1.5% (see Part I; T.H. Re, R.F. Loehr, S.C. Rodriguez, C.E. Gilmore, and C.M. Burnett, 1986, Fundam. Appl. Toxicol. 7, 287-292). Following 90 days of exposure, 25 randomly selected females in each group were mated to untreated males in a teratology study in which exposure to 2-MR continued throughout the gestation period. After 20 weeks of exposure to 2-MR, 20 males per group were removed from the test diets containing 2-MR and were mated to untreated females in a dominant lethal study. Feeding 2-MR at levels of 0.4 and 1.5% in the diet was associated with a significant reduction in body weight gain. 2-MR was not teratogenic nor did it induce a dominant lethal effect under the conditions of this study.

Results of teratogenicity testing of m-aminophenol in Sprague-Dawley rats.

meta-Aminophenol (m-AP) was administered in the diet to female Sprague-Dawley rats for a period of at least 90 days at levels of 0.1, 0.25, and 1.0%. In the 0.25% group a significant reduction in body weight was noted, in comparison with control values, and in the 1.0% group a significant reduction in both body weight and food consumption was noted. Ten of the rats in each group were necropsied. Deposition of iron positive pigment in the spleen, liver, and kidney combined with decreased red blood cell count and hemoglobin and increased mean corpuscular volume indicated a hemolytic effect. There were also morphologic changes in the thyroid which were consistent with hyperactivity. The remaining 25 rats in each group were removed from m-AP treatment and immediately mated to untreated males of the same strain. After the mating period the dams again were given m-AP for the duration of gestation. All dams were killed on Day 20 of gestation; one-third of the fetuses were examined for visceral malformations and two-thirds for skeletal malformations and variations. An additional significant reduction in body weight gain was noted during gestation in the 1.0% group as compared to the control group. There were no other adverse dose-related findings demonstrated in the reproduction performance of the dams or in the survival or development of their offspring. Therefore, although maternal toxicity was demonstrated at the highest dose level, there was no evidence of teratogenic or embryofetal toxicity at any dose level tested.

The absence of teratogenic hazard potential of p-phenylenediamine in Sprague-Dawley rats.

Para-phenylenediamine (PPD) was administered by gavage to pregnant Sprague-Dawley Rats at dose levels of 5, 10, 15, 20, and 30 mg/kg/day on days 6 through 15 of gestation (day 0 = day sperm was found in the vagina). A sham control group and a pair fed control group were studied at the same time. Pregnant animals were killed on day 20 of gestation and 1/3 of the fetuses were examined for visceral malformations and 2/3 for skeletal malformations and variations. Significant reductions in food consumption and weight gain were noted in the 30 mg/kg and pair fed control groups. Two pregnant rats given PPD at 30 mg/kg/day died but there were no deaths in any other dose groups. Fetal evaluations showed no biologically or statistically significant increase in malformations or developmental variations in any group. Therefore, although maternal toxicity was demonstrated at the two highest dose levels, there was no evidence of teratogenic or other embryotoxic effects.