A category approach to predicting the repeated-dose hepatotoxicity of allyl esters.

We tested a category approach to predict the hepatotoxic effects of repeated doses of allyl esters using a new database for repeated-dose toxicity. Based on information on hepatotoxic mechanism of allyl acetate, the category was defined as allyl esters that are hydrolyzed to allyl alcohol. Allyl alcohol is readily oxidized to acrolein in the liver, causing hepatotoxicity. Seventeen marketed allyl esters were obtained and grouped into category by identifying or predicting allyl alcohol formation. Allyl esters with a saturated straight alkyl carboxylic acid moiety (allyl acetate, hexanoate and heptanoate as tested species, and allyl butyrate, pentanoate, octanoate, nonanoate and decanoate as untested species) are likely similar in rate of ester hydrolysis, thereby defining subcategory 1. NOAEL and LOAEL for the hepatotoxic effects were estimated at 0.12 and 0.25 mmol/kg/d for the untested species, based on those of allyl acetate. The remaining nine allyl esters with other alkyl or aromatic carboxylic acid moieties were placed in subcategory 2: their hepatotoxicity levels were not predictable due to an unclear match between their degree of structural complexity and rate of hydrolysis. Our results demonstrate the usefulness of the category approach for predicting the hepatotoxicity of untested allyl esters with saturated straight alkyl chains.

Gender-related difference in the toxicity of 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole in rats: relationship to the plasma concentration, in vitro hepatic metabolism, and effects on hepatic metabolizing enzyme activity.

Previously, we showed that the toxic susceptibility of male rats to an ultraviolet absorber, 2-(2'-hydroxy- 3',5'-di-tert-butylphenyl)benzotriazole (HDBB), was nearly 25 times higher than that of females. The present study aimed to clarify the mechanism of gender-related differences in HDBB toxicity. Male and female rats were given HDBB by gavage at 0.5, 2.5, or 12.5 mg/kg/day for 28 days, and plasma HDBB levels were measured at various time points by using liquid chromatography-tandem mass spectrometry. HDBB was rapidly absorbed and eliminated from the plasma in both sexes, and no sexual variations were found in the plasma levels. In the plasma, HDBB metabolites were not detected at any dose by the liquid chromatography-photodiode array detector. In an in vitro metabolic study using hepatic microsomes from male and female rats, HDBB was slightly metabolized, but no sexual differences were found in the residual HDBB ratio after a 60-minute incubation with an NADPH-generation system. Following 28-day HDBB administration, sexually different changes were found in cytochrome P450-dependent microsomal mixed-function oxidase activities in the liver. In males, 7-ethoxyresorufin O-deethylase activity decreased and lauric acid 12-hydroxylase activity increased at all doses. Decreases in aminopyrine N-demethylase activity and testosterone 2alpha- and 16alpha-hydroxylase activity were also found at 2.5 mg/kg and above in males. In females, the only significant change was increased lauric acid 12-hydroxylase activity at 12.5 mg/kg. These findings indicate that HDBB would have hepatic peroxisome proliferative activity, and the difference in susceptibility of male and female rats to this effect might lead to marked gender-related differences in HDBB toxicity.

Reproductive and developmental toxicity screening study of 2,4-dinitrophenol in rats.

Rats were treated by gavage once daily with 2,4-dinitrophenol (DNP) at 0 (control), 3, 10, or 30 mg/kg bw. Males were dosed for 46 days, beginning 14 days before mating, and females were dosed for 40-47 days, from 14 days before mating to day 3 of lactation. No deaths were observed in males and females of any group. A significant decrease in body weight gain and significant increase in liver weight were found in males and females at 30 mg/kg bw/day. The number of live pups on postnatal days (PNDs) 0 and 4, live birth index, and body weight of live male and female pups on PNDs 0 and 1 were significantly lowered at 30 mg/kg bw/day. External and internal examinations of pups revealed no increased incidence of malformations in DNP-treated groups. On the basis of these findings, we concluded that DNP has general and reproductive/developmental toxicity, but not teratogenicity, under the present conditions. The NOAEL of DNP is considered to be 10 mg/kg bw/day in rats.

Renal Tubular Cyst Formation in Newborn Rats Treated with p-Cumylphenol.

In this study, we investigated the sequential changes in the development of renal tubular cysts in newborn rats treated with p-cumylphenol (PCP). Fifteen animals per sex were treated orally with 300 mg/kg/day of PCP for up to 18 days from postnatal day (PND) 4 and were sacrificed on PNDs 8, 12, 19 and 22 and after a 7 day recovery period. On PNDs 8 and 12, slight dilatation of the collecting ducts was frequently observed in the medulla and slight papillary necrosis was also noted in some cases. These dilated collecting ducts were lined with slightly hyperplastic epithelial cells. On PNDs 19 and 22, multiple large cystic changes arising from the collecting ducts in the outer medulla were seen. These cystically dilated ducts were also lined with hyperplastic epithelial cells. During the dosing period, the labeling index of proliferating cell nuclear antigen in the collecting duct epithelium was higher in the PCP-treated group than in the control group at all time points. After a 7 day recovery period, the cystic change still remained, although the cell density was decreased and the epithelial cells became flattened. On the other hand, basophilic tubules with peritubular lymphoid cell infiltration were multifocally observed in the cortex. In conclusion, PCP induced multiple renal cysts that developed in the collecting ducts of the outer medulla in neonatal rats, and it is suggested that epithelial cell proliferation may play some roles in the induction of cystic lesions.

Evaluation of developmental neurotoxicity of polysorbate 80 in rats.

The developmental neurotoxicity of polysorbate 80 (PS80) was evaluated in rats. Crl:CD(SD) rats were given drinking water containing PS80 at 0, 0.018, 0.13, 1.0, or 7.5% (0, 0.035, 0.245, 1.864, or 16.783ml/kgbw/day) on day 0 of pregnancy through day 21 after delivery. Pregnant rats were allowed to deliver spontaneously. Potential adverse effects of pre- and post-natal exposure on the development and function of the nervous system in offspring of rats given PS80 were examined. Maternal body weight was lowered at 7.5%. Number of pups born was lowered at 7.5%. There were no compound-related effects on locomotor activity of offspring on postnatal days (PNDs) 14-15, 17-18, 20-21 and 33-37. No compound-related changes were found in developmental landmarks, sexual maturation, or reflex responses. Although decreased rate of avoidance responses was noted on PNDs 23-27 in male and female offspring at 7.5%, no compound-related changes were found in performance in the conditioned avoidance response on PNDs 60-67. Histopathological examinations of the brain revealed no toxicological changes. Lowered body weight was observed in male and female offspring at 7.5%. The NOAEL in this study was considered to be 1.0% (1.864ml/mg/kgbw/day).

Two-generation reproductive toxicity study of the rubber accelerator N,N-dicyclohexyl-2-benzothiazolesulfenamide in rats.

Male and female Crl:CD(SD) rats were fed a diet containing rubber accelerator N,N-dicyclohexyl-2-benzothiazolesulfenamide (DCBS) at 0, 80, 600 or 4500ppm throughout the study beginning at the onset of a 10-week pre-mating period and continuing through the mating, gestation, and lactation periods for two generations. At 4500ppm, decreases in the body weight, body weight gain, and food consumption were found in F0 males and females. No changes in the estrous cyclicity, copulation index, fertility index, gestation index, delivery index, number of implantations, precoital interval, or gestation length were observed in any generation at any dose of DCBS. Delayed preputial separation at 4500ppm as well as delayed vaginal opening and higher body weight at the age of vaginal opening at 600 and 4500ppm were found in the F1 generation. A transient change in performance in a water-filled multiple T-maze was found at 600 and 4500ppm in F1 females. There were no compound-related changes in number of pups delivered, sex ratio of pups, viability of pups, anogenital distance, surface righting reflex, negative geotaxis reflex, mid-air righting reflex, pinna unfolding, incisor eruption, or eye opening in the F1 and F2 generations. The body weight of F1 and F2 male and female pups was lowered at 4500ppm. Reduced uterine weight of the weanlings was noted in the F1 generation at 4500ppm and in the F2 generation at 600 and 4500ppm. The data indicate that the NOAEL of DCBS for two-generation reproductive toxicity is 80ppm (5.2mg/kgbw per day) in rats.

Reproductive and developmental toxicity screening test of tetrahydrofurfuryl alcohol in rats.

Twelve male and female rats per group were given tetrahydrofurfuryl alcohol (THFA) by gavage at 0, 15, 50, 150 or 500 mg/kg/day. Males were dosed for 47 days, beginning 14 days before mating, and females were dosed for 42-52 days beginning 14 days before mating to day 4 of lactation throughout the mating and gestation period. Changes in locomotor activity, inhibition of body weight gain, and/or histopathological changes in the thymus, spleen, testes and/or epididymides were observed in males and females at 150 mg/kg and above. No effects of THFA were found on the copulation index, fertility index, or the number of corpora lutea and implantations in pregnant females. At 500 mg/kg, no pregnant females delivered any pups. At 150 mg/kg, gestation length was prolonged, and the total number of pups born and the number of live pups on postnatal days 0 and 4 was markedly decreased. No effects of THFA were found on the sex ratio and body weight of live pups, or the incidence of pups with malformations or variations. Based on these findings, the NOAELs for parental and reproductive/developmental toxicity of THFA were concluded to be 50mg/kg/day in rats.

Repeated-dose and reproductive toxicity of the ultraviolet absorber 2-(3',5'-di- tert-butyl-2'-hydroxyphenyl)-5-chlorobenzotriazole in rats.

2-(3',5'-Di-tert-butyl-2'-hydroxyphenyl)-5-chlorobenzotriazole (DBHCB) is widely used as an ultraviolet (UV) absorber. In this study, the repeated dose and reproductive toxicity of DBHCB was evaluated in rats. Crj:CD(SD)IGS rats were given DBHCB by gavage at 0, 2.5, 25, or 250 mg/kg/d. Male and female rats were dosed beginning 28 d before mating, and each female rat was mated with a male rat of the same dosage group. Males were dosed for a total of 56-57 d, and females were dosed for a total of 55-69 d up to Day 3 of lactation throughout the mating and pregnancy periods. Ten males from each group were killed on the next day of the last administration, and 10 females were killed on Days 4-6 after parturition. Five rats/sex treated at 0 and 250 mg/kg/d for 56 d were then kept without treatment for 14 d (recovery period). No deaths were found in any group. No effects of DBHCB on general condition, body weight, food consumption, or reproductive/developmental parameters were observed. Significant increases in serum albumin and an albumin/globulin ratio at 25 mg/kg/d and higher and alkaline phosphatase levels at 250 mg/kg/d were noted in males. The absolute and relative weights of the liver were significantly increased in males at 25 mg/kg/d and higher. Significantly increased serum albumin and absolute and relative liver weight were also found in males at 250 mg/kg/d after the recovery period. No changes in these parameters were observed in females of any DBHCB-treated groups. No significant changes in organ histopathology were found in males or females. These findings indicated a sex difference in the toxicity of DBHCB in rats.

Gender-related difference in the toxicity of ultraviolet absorber 2-(3',5'-di-tert-butyl-2'-hydroxyphenyl)-5-chlorobenzotriazole in rats.

2-(3',5'-Di-tert-butyl-2'-hydroxyphenyl)-5-chlorobenzotriazole (DBHCB) is widely used as an ultraviolet absorber. Previously, we showed that male rats had more than a 100 times higher susceptibility to the toxic effects of DBHCB than females. In order to investigate the role of sex steroids in the mediation of this gender-related difference, DBHCB (0 or 250 mg/kg/day) was given to male and female young intact and castrated rats by gavage for 28 days in the current study. In intact rats, relative liver weight increased to more than two times that of the control in males, while the rate of change was less than 10% in females. On histopathology, hypertrophy of hepatocytes was observed in males but not in females. In castrated rats, an approximately 40% increase in the relative liver weight was found only in males, and no histopathological changes in the liver were detected in either sex. The gender-related difference was also determined in preweaning rats administered DBHCB at 0, 250, or 500 mg/kg/day by gavage from postnatal days 4 to 21. Blood biochemical changes, including increases in the levels of AST, ALT, and ALP, 80-95% increase in the relative liver weight and histopathological changes in the liver, such as hypertrophy and single cell necrosis of hepatocytes, were observed at both doses in both sexes. In conclusion, the gender-related difference in the toxicity of DBHCB, which was observed in young rats, was markedly reduced by castration and abolished in preweaning rats.

Reproductive and developmental toxicity screening study of 4-aminophenol in rats.

Twelve male and female rats per group were given 4-aminophenol (PAP) by gavage at 0, 20, 100, or 500 mg/kg/day. Males were dosed for a total of 49 days, beginning 14 days before mating. Females were dosed for a total of 40-60 days, from 14 days before mating to Day 3 of lactation throughout the mating and gestation periods. Four males and 2 females died at 500 mg/kg/day, and all surviving males and females showed brown urine at 100 mg/kg/day and above. Body-weight gain was lower in males and females at 500 mg/kg/day, and food consumption was decreased in males at 500 mg/kg/day and in females at 100 and 500 mg/kg/day. Absolute and relative weights of the testes and epididymides were decreased at 500 mg/kg/day. Histopathological examinations revealed decreased spermatocyte and spermatid levels in the testis, debris of germ cell in the epididymis lumen, basophilic tubules in the kidney, and deposits of hemosiderin in the red pulp and extramedullary hematopoiesis in the spleen in males at 500 mg/kg/day. Longer gestation period, decreased delivery index, and lower body weight of pups on postnatal day (PND) 0 and increased number of stillborns at 500 mg/kg/day were also observed. At this dose, the viability of pups on PND 4 was decreased markedly. No adverse effects on reproduction or development were detected at 20 and 100 mg/kg/day. These findings indicate that PAP is general and reproductive/developmental toxic, but is unlikely to be teratogenic, in rats.

Developmental toxicity of dibutyltin dichloride in cynomolgus monkeys.

Dibutyltin dichloride (DBTCl) has been shown to be teratogenic in rats. The present study was conducted to determine the teratogenic potential of DBTCl given to pregnant monkeys during the entire period of organogenesis. Cynomolgus monkeys were dosed once daily by nasogastric intubation with DBTCl at 0, 2.5 or 3.8 mg/kg on days 20-50 of pregnancy, the whole period of organogenesis. The pregnancy outcome was determined on day 100 of pregnancy. In both DBTCl-treated groups, a significant increase in the incidence of pregnant females with soft stool and/or diarrhea, and with yellowish stool was observed. Maternal body weight gain at 3.8 mg/kg and food consumption at 2.5 and 3.8 mg/kg were decreased during the administration period. The survival rate of fetuses at terminal cesarean sectioning was decreased in the DBTCl-treated groups and significantly decreased at 2.5 mg/kg. There were no changes in the developmental parameters of surviving fetuses, including fetal body weight, crown-rump length, tail length, sex ratio, anogenital distance and placental weight, in the DBTCl-treated groups. No external, internal or skeletal malformations were found in the fetuses in any group. Although internal and skeletal variations were found, no difference in the incidence of fetal variation was noted between the control and DBTCl-treated groups. No effect on skeletal ossification was observed in fetuses in the DBTCl-treated groups. The data demonstrate that DBTCl is embryolethal but not teratogenic in cynomolgus monkeys.

[Progress on OECD Chemicals Programme (13)--SIAM 22 in Paris, 2006].

The 22nd Screening Information Data Set (SIDS) Initial Assessment Meeting (SIAM 22) was held at the Organisation for Economic Co-operation and Development (OECD) headquarters in Paris, France. The initial assessment documents of five substances (CAS numbers: 75-59-2, 80-51-3, 101-83-7, 103-24-2, 27813-02-1) sponsored by Japan were all agreed at the meeting. In this report, the documents of these substances are introduced.

Reproductive and developmental toxicity screening test of basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats.

Twelve male and female rats per group were exposed to the rubber accelerator 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 8, 20 or 50 mg/kg bw/day. Males were dosed for a total of 49 days beginning 14 days before mating. Females were dosed for a total of 40-49 days beginning 14 days before mating to day 3 of lactation throughout the mating and gestation period. At 50 mg/kg bw/day, deaths were observed in two males and three females. Lowered body weight gain and food consumption were noted in males at 50 mg/kg bw/day and females at 20 and 50 mg/kg bw/day. Mydriasis, decreased locomotor activity, bradypnea, prone position, tremor and/or salivation were observed in males and females at 20 and 50 mg/kg bw/day. No effects of DTG were found on the estrous cyclicity, precoital interval, copulation, fertility and gestational indices, numbers of corpora lutea and implantations, or gestation length. A significant decrease in the number, body weight and viability of offspring and increase in the incidence of fetuses with external malformations were found at 50 mg/kg bw/day. Oligodactyly, anal atresia and tail anomalies were observed. These data suggest that DTG may be teratogenic. The NOAELs of DTG for general and developmental toxicity in rats are 8 and 20 mg/kg bw/day, respectively.

Prenatal developmental toxicity study of the basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats.

Pregnant rats were given 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 10, 20 or 40 mg/kg bw/day on days 6-19 of pregnancy and the pregnancy outcome was determined on day 20 of pregnancy. At 40 mg/kg bw/day, deaths were observed in four out of 24 females. The incidences of females showing mydriasis at 20 and 40 mg/kg bw/day and showing decreased locomotor activity at 40 mg/kg bw/day were significantly increased. Alopecia, bradypnea, prone position and tremor were also observed at mg/kg bw/day. The maternal body weight gain at 20 and 40 mg/kg bw/day and food consumption at 40 mg/kg bw/day were significantly reduced. A significantly decreased weight of the gravid uterus, increased incidence of postimplantation loss, decreased number of live fetuses, and lowered weights of fetuses and placentae were found at 40 mg/kg bw/day. The incidences of the total number of fetuses with external malformations at 40 mg/kg bw/day and with skeletal malformations at 20 and 40 mg/kg bw/day were significantly increased. Significantly higher incidences of fetuses with brachydactyly and short tail and defects of caudal vertebrae, phalanges and metacarpals were observed at 40 mg/kg bw/day. Delayed ossification was also noted at 40 mg/kg bw/day. The data indicate that DTG is teratogenic at maternal toxic doses and the NOAELs of DTG for maternal and developmental toxicity are 10 mg/kg bw/day in rats.

Susceptibility of newborn rats to 3-ethylphenol and 4-ethylphenol compared with that of young rats.

Newborn rat studies were conducted with oral administration of 3-ethylphenol (3EP) and 4-ethylphenol (4EP) on postnatal days (PND) 4-21 to allow comparison of no observed adverse effect level (NOAEL) and unequivocally toxic level (UETL) with those from 28-day studies of young rats starting at 5-6 weeks of age. In the newborn rat studies, slightly lowered body weight was observed after 3EP treatment, and deaths, hypoactivity, Straub tail, deep respiration and delayed righting reflex were clearly observed after 4EP treatment. In the young rat studies, salivation, staggering gait, changes in the liver including high values of liver weight and alanine aminotransferase or total cholesterol and the lesions in the forestomach were clearly observed after 3EP and 4EP treatments. NOAELs of 3EP and 4EP in the newborn rat studies appeared to be almost 3 times lower than those in the young rat studies. As a clear toxicity of 3EP was not observed in newborn rats, UETLs were not established for 3EP. Regarding 4EP, UETL of young rats was 4-5 times higher than that of newborn rats. In conclusion, newborn rats were 3-5 times more susceptible to 3EP and 4EP than young rats.

Semi-quantitative immunohistochemical analysis of male rat-specific alpha2u-globulin accumulation for chemical toxicity evaluation.

We purified male rat urinary alpha(2u)-globulin, prepared the antibody in rabbits, and improved an immunohistochemical detection method using this antibody for male rat-specific alpha(2u)-globulin accumulation appearing as hyaline droplets in the kidneys. Our prepared antibody reacted specifically with alpha(2u)-globulin in both immunohistochemical and Western blotting analyses, furthermore, and the graded immuno-reactivities on the slide were well associated with computational image analyzing results. Using this method, we retrospectively analyzed the renal sections from the toxicity studies of 12 nephrotoxic chemicals, which had already been conducted under the Japanese Existing Chemicals Survey Program. We demonstrated that the hyaline droplets induced by treatment with 10 chemicals (1,4-dibromobenzene, dicyclopentadiene, 3,4-dimethylaniline, 1,4-dicyanobenzene, tetrahydrothiophene-1,1-dioxide, 1,3-dicyanobenzene, acenaphthene, 3,4-dichloro-1-butene, 3a,4,7,7a-tetrahydro-1H-indene and 3,5,5-trimethylhexan-1-ol) were directly associated with alpha(2u)-globulin accumulation. This immunohistochemical method is convenient for applying, even retrospectively, paraffin sections from general toxicity studies and could be useful for qualifying male rat-specific hyaline droplets consisting of alpha(2u)-globulin and renal risk in humans.

[Progress on OECD chemicals programme (11)--SIAM 19 in Berlin, 2004].

The 19th Screening Information Data Set (SIDS) Initial Assessment Meeting (SIAM 19) was held in Berlin, Germany, hosted by the Germen Federal Agency for the Environment. The initial assessment documents of four substances (CAS numbers: 92-70-6, 126-33-0,131-17-9, 7580-85-0) and one category (High Molecular Weight Phthalate Esters) at SIAM 19 were submitted by the Japanese Government with or without the International Council of Chemical Associations (ICCA) and all of them were agreed at the meeting. In this report, the documents of these substances are introduced.

In silico assessment of chemical mutagenesis in comparison with results of Salmonella microsome assay on 909 chemicals.

Genotoxicity is one of the important endpoints for risk assessment of environmental chemicals. Many short-term assays to evaluate genotoxicity have been developed and some of them are being used routinely. Although these assays can generally be completed within a short period, their throughput is not sufficient to assess the huge number of chemicals, which exist in our living environment without information on their safety. We have evaluated three commercially available in silico systems, i.e., DEREK, MultiCASE, and ADMEWorks, to assess chemical genotoxicity. We applied these systems to the 703 chemicals that had been evaluated by the Salmonella/microsome assay from CGX database published by Kirkland et al. We also applied these systems to the 206 existing chemicals in Japan that were recently evaluated using the Salmonella/microsome assay under GLP compliance (ECJ database). Sensitivity (the proportion of the positive in Salmonella/microsome assay correctly identified by the in silico system), specificity (the proportion of the negative in Salmonella/microsome assay correctly identified) and concordance (the proportion of correct identifications of the positive and the negative in Salmonella/microsome assay) were increased when we combined the three in silico systems to make a final decision in mutagenicity, and accordingly we concluded that in silico evaluation could be optimized by combining the evaluations from different systems. We also investigated whether there was any correlation between the Salmonella/microsome assay result and the molecular weight of the chemicals: high molecular weight (>3000) chemicals tended to give negative results. We propose a decision tree to assess chemical genotoxicity using a combination of the three in silico systems after pre-selection according to their molecular weight.

Comparative susceptibility of newborn and young rats to six industrial chemicals.

To elucidate the comparative susceptibility of newborn rats to chemicals, newborn and young animals were administered six industrial chemicals by gavage from postnatal days (PND) 4 to 21, and for 28 days starting at 5-6 weeks of age respectively, under the same experimental conditions as far as possible. As two new toxicity endpoints specific to this comparative analysis, presumed no-observed-adverse-effect-levels (pNOAELs) were estimated based on results of both main and dose-finding studies, and presumed unequivocally toxic levels (pUETLs) were also decided. pNOAELs for newborn and young rats were 40 and 200 for 2-chlorophenol, 100 and 100 for 4-chlorophenol, 30 and 100 for p-(alpha,alpha-dimethylbenzyl) phenol, 100 and 40 for (hydroxyphenyl)methyl phenol, 60 and 12 for trityl chloride, and 100 and 300 mg/kg/day for 1,3,5-trihydroxybenezene, respectively. To determine pUETLs, dose ranges were adopted in several cases because of the limited results of experimental doses. Values for newborn and young rats were thus estimated as 200-250 and 1000 for 2-chlorophenol, 300 and 500 for 4-chlorophenol, 300 and 700-800 for p-(alpha,alpha-dimethylbenzyl) phenol, 140-160 and 1000 for (hydroxyphenyl)methyl phenol, 400-500 and 300 for trityl chloride, and 500 and 1000 mg/kg/day for 1,3,5-trihydroxybenzene, respectively. In most cases, newborn rats were 2-5 times more susceptible than young rats in terms of both the pNOAEL and the pUETL. An exception was that young rats were clearly more susceptible than their newborn counterparts for trityl chloride.

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.