Elevated susceptibility of newborn as compared with young rats to 2-tert-butylphenol and 2,4-di-tert-butylphenol toxicity.

In order to determine the susceptibility of newborn rats to 2-tert-butylphenol (2TBP) and 2,4-di-tert-butylphenol (DTBP) toxicity, studies were conducted with oral administration from postnatal days (PND) 4 to 21 and the findings were compared with results for young rats exposed from 5 or 6 weeks of age for 28 days. In the newborn rats, specific effects on physical and sexual development and reflex ontogeny were not observed. While there were no clear differences in toxicological profiles between newborn and young rats, the no-observed-adverse-effect levels (NOAELs) differed markedly. For 2TBP, clinical signs such as ataxic gait, decrease in locomotor activity and effects on liver, such as increase in organ weight, were observed and the NOAELs were concluded to be 20 and 100 mg/kg/day in newborn and young rats, respectively. Based on hepatic and renal toxicity (histopathological changes and increase in organ weight with blood biochemical changes), the respective NOAELs for DTBP were concluded to be 5 and 20 mg/kg/day. Therefore, the susceptibility of newborn rats to 2TBP and DTBP was found to be 4-5 times higher than that of young rats.

Susceptibility of newborn rats to hepatotoxicity of 1,3-dibromopropane and 1,1,2,2-tetrabromoethane, compared with young rats.

Newborn rat studies were conducted with oral administration of 1,3-dibromopropane (DBP) and 1,1,2,2-tetrabromoethane (TBE) from postnatal Days 4 to 21 to allow comparison of NOAELs and unequivocally toxic levels with those from 28-day young rat studies starting at 5-6 weeks of age. The unequivocally toxic level was estimated by our specified criteria, requiring simultaneous change of organ weights, histopathology, some biochemical parameters and body weights, because in this study only hypertrophy of hepatocytes was observed as a major histopathological change. DBP caused centrilobular hypertrophy of hepatocytes with alteration in biochemical parameters, as well as lowering of body weights, regardless of sex, in both newborn and young rats. NOAELs and unequivocally toxic levels were considered to be 50 and 150 mg/kg/day in newborn rats and 10 and 250 mg/kg/day in young rats, respectively. In the newborn rat study of TBE, some hepatic effects observed at the top dose of 50 mg/kg were not considered adverse because of the lack of histopathological changes. Significant lowering of body weight was noted at 200 mg/kg in the dose-finding study but histopathological data were not available. In the young rat study, there was no definite toxicity at 6 mg/kg and hypertrophic changes in liver and thyroids without body weight change occurred at 200 mg/kg. There were no clear sex differences in both the newborn and young rat studies. NOAELs were considered to be 50 and 6 mg/kg/day in newborn and young rats, respectively, but unequivocally toxic levels for both rats could not be estimated. Abnormalities of external and sexual development and reflex ontogeny in the newborn were not observed with either chemical. Based on these results, it can be concluded that the target organ of DBP and TBE is the liver in both newborn and young rats, and that while the doses at which toxic signs began to appear are higher in newborn rats, those causing clear toxicity may be paradoxically lower in the newborn case.

Unexpected nephrotoxicity induced by tetrabromobisphenol A in newborn rats.

The repeated dose toxicity of tetrabromobisphenol A (TBBPA), a flame retardant, was examined in male and female newborn rats given TBBPA orally at 0, 40, 200, or 600 mg/kg per day for 18 days from 4 days of age until weaning at 21 days of age. Half the rats in each dose group were sacrificed for a full gross necropsy and a histopathology on the organs and the tissues at 22 days of age and the remaining rats were reared without any treatment from post-weaning until 84 days of age to examine the recovery and the delayed occurrence of toxic effects. Treatment with 200 or 600 mg/kg TBBPA-induced nephrotoxicity characterized by the formation of polycystic lesions, and some deaths occurred in the 600 mg/kg group. There was no gender difference of nephrotoxicity and there were no other critical toxicities. At 85 days of age, nephrotoxic lesions were still present in the 200 and 600 mg/kg groups, but no abnormalities indicating delayed occurrence of toxic effects were found in the treated groups. In order to investigate the specificity of the nephrotoxicity induced by TBBPA in newborn rats, TBBPA was given to male and female young rats (5 weeks old) by oral administration at 0, 2000, or 6000 mg/kg per day for 18 days. The kidneys showed no histopathological changes even at the high dose. These results clearly indicate that the nephrotoxicity of TBBPA is specific for newborn rats although the toxic dose level was relatively high. To gain insight into the possible effects on human infants, the mechanism of this unexpected nephrotoxicity of TBBPA in newborn rats should be examined.