New parameter that supports speculation on the possible mechanism of hypothyroidism induced by chemical substances in repeated-dose toxicity studies.

Hypothyroidism induced by xenobiotic treatment was analyzed for possible underlying mechanism(s) on the basis of different responses of the thyroid gland and the liver, using a newly-created database of repeated-dose toxicity of 500 chemicals. Two mechanisms are proposed: direct inhibition of thyroid hormone biosynthesis in the thyroid gland, and stimulated degradation of thyroid hormone by induction of hepatic drug-metabolizing enzymes. In the database there were 10 chemicals inducing hypertrophy/hyperplasia of follicular cells in the thyroid gland and having data on thyroid glands.

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.

No toxicological effects on acute and repeated oral gavage doses of single-wall or multi-wall carbon nanotube in rats.

Three female Crl:CD(SD) rats/group were dosed with single wall carbon nanotube (SWCNT) or multi wall carbon nanotube (MWCNT) four times by gavage at a total of 50 mg/kg bw or 200 mg/kg bw (four equally divided doses at one-hour intervals). Acute oral doses of SWCNT and MWCNT caused neither death nor toxicological effects, and thus the oral LD50 values for SWCNT and MWCNT were considered to be greater than 50 mg/kg bw and 200 mg/kg bw, in rats respectively. Five or ten Crl:CD(SD) rats/sex were dosed with SWCNT once daily by gavage at a dose of 0 (control), 0.

Validation of the (Q)SAR combination approach for mutagenicity prediction of flavor chemicals.

Most exposure levels of flavor in food are considered to be extremely low. If at all, genotoxic properties should be taken into account in safety evaluations. We have recently established a (quantitative) structure-activity relationship, (Q)SAR, combination system, which is composed of three individual models of mutagenicity prediction for industrial chemicals.

Influence of coefficient of variation in determining significant difference of quantitative values obtained from 28-day repeated-dose toxicity studies in rats.

In order to understand the influence of coefficient of variation (CV) in determining significant difference of quantitative values of 28-day repeated-dose toxicity studies, we examined 59 parameters of 153 studies conducted in accordance with Chemical Substance Control Law in 12 test facilities. Sex difference was observed in 12 parameters and 10 parameters showed large CV in females. The minimum CV was 0.

Relation between statistics and treatment-related changes obtained from toxicity studies in rats: if detected a significant difference in low or middle dose for quantitative values, this change is considered as incidental change?

The purpose of a toxicity test is to determine the no-observed-effect level (NOEL) of test substance through biological and pharmacological techniques. If the low dose not does show statistically significant and biologically relevant changes in the data evaluated in a study, the usual practice is to consider this dose as the NOEL. To overcome this, 6 types of techniques that seemed to be appropriate are presented in this paper by investigating the results of several domestic and foreign theses on toxicology.

Disappearance of gender-related difference in the toxicity of benzotriazole ultraviolet absorber in juvenile rats.

2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB) is an ultraviolet absorber used in plastic resin products, such as building materials and automobile components. In oral repeated dose toxicity studies using 5- or 6-week-old rats, this chemical induced hepatic histopathological changes, such as hypertrophy accompanied with eosinophilic granular changes and focal necrosis of hepatocytes, and male rats showed nearly 25 times higher susceptibility to the toxic effects than females. Castration at approximately 4 weeks of age markedly reduced the sex-related variation in HDBB toxicity, but some difference, less than five times, remained between male and female castrated rats.

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.

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.

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.

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.

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.

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.

Lack of gender-related difference in the toxicity of 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole in preweaning rats.

In our previous toxicity studies using young rats, we showed that an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), principally affected the liver, and male rats had nearly 25 times higher susceptibility to the toxic effects than females. In the present study, the toxicity of HDBB was investigated in preweaning rats. HDBB was administered by gavage to male and female CD(SD) rats from postnatal days 4 to 21 at a dose of 0, 0.

Evaluation of statistical tools used in short-term repeated dose administration toxicity studies with rodents.

In order to know the different statistical tools used to analyze the data obtained from twenty-eight-day repeated dose oral toxicity studies with rodents and the impact of these statistical tools on interpretation of data obtained from the studies, study reports of 122 numbers of twenty-eight-day repeated dose oral toxicity studies conducted in rats were examined. It was found that both complex and easy routes of decision trees were followed for the analysis of the quantitative data. These tools include Scheffe's test, non-parametric type Dunnett's and Scheffe's tests with very low power.

[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 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.

Gonadal influence on the toxicity of 2-(2'-hydroxy-3',5'-di-tert-butylphenyl) benzotriazole in rats.

Previously, we showed that susceptibility of male rats to the toxicity of an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), was nearly 25 times higher than that of females. In the current study, we investigated the role of sex steroids in the mediation of the gender-related difference using castrated rats. Male and female castrated CD(SD) rats were given HDBB by gavage at 0, 0.

A 52-week repeated dose toxicity study of ultraviolet absorber 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole in rats.

A 52-week repeated dose toxicity study of an ultraviolet absorber, 2-(2'-hydroxy-3',5' -di-tert-butylphenyl)benzotriazole (HDBB), was conducted according to OECD TG 452 under GLP. CD(SD)IGS rats were given HDBB by gavage at 0, 0.1, 0.

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.

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.

A 28-day repeated dose toxicity study of ultraviolet absorber 2-(2'-hydroxy-3',5'-di-tert-butylphenyl) benzotriazole in rats.

To examine the possible repeated-dose toxicity of an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), CD(SD)IGS rats were administered HDBB by gavage at a dose of 0 (vehicle: corn oil), 0.5, 2.5, 12.

Screening study for repeated dose and reproductive/developmental toxicity of rubber accelerator, N,N-dicyclohexyl-2-benzothiazolesulfenamide, in rats.

A screening study for a vulcanization accelerator N,N-dicyclohexyl-2-benzothiazole-sulfenamide (DCBS) was performed in rats. Rats were given DCBS by gavage daily at 0, 6, 25, 100, or 400 mg/kg. Males were dosed for a total of 44 days beginning 14 days before mating.

[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.

Early pregnancy failure induced by dibutyltin dichloride in mice.

In this study, we examined the adverse effects of dibutyltin on initiation and maintenance of pregnancy after maternal administration during early pregnancy in mice. Following successful mating, female ICR mice were given dibutyltin dichloride (DBTCl) at 0, 7.6, 15.