Thomas A. Re

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.

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.

Antiperspirant activity of H1-histamine blockers as determined by a modified rat foot pad assay.

A method for inducing sweating in the rat via heat stress and without the use of general anesthetics is presented. Five commonly used H1-blocking antihistamines were evaluated in this model for their antiperspirant efficacy. The antihistamines evaluated and their ED50 values (µg base/pad) were as follows: phenindamine, 3.02; diphenhydramine, 3.25; chlorpheniramine, 3.12; tripelennamine, 4.91; and pyrilamine, 13.03. Atropine sulfate, injected into the foot pads, was also found to inhibit the sweat response. The response to atropine varied directly with dose. The ED50 was estimated to be 0.4 ng base/foot pad. No systemic effects or contralateral involvement were seen. The rat foot pad contains eccrine sweat glands that are innervated by sympathetic cholinergic fibers. This relationship is analogous to that in the eccrine sweat glands of man. The rat data suggest that antihistamines, possibly via an anticholinergic effect, may be useful as potential antiperspirants in man.

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.