Systemic toxicity of di-2-ethylhexyl terephthalate (DEHT) in rodents following four weeks of intravenous exposure
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Keywords:
Histopathology
No-observed-adverse-effect level
Reproductive toxicity
Reproductive toxicity
Diethyl phthalate
Reproductive system
Anogenital distance
Developmental toxicity
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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of glyphosate (CAS No. 1071-83-6), an amino acid herbicide, based on results from various studies. Major adverse effects of glyphosate were observed on reduced gain of body weight, GI tract (diarrhea, increased cecum weight, bowel dilatation, thickening of intestinal mucosa), and liver (increased alkaline phosphatase (ALP), hepatocellular hypertrophy). Glyphosate had no neurotoxicity, carcinogenicity, reproductive toxicity, teratogenicity, and genotoxicity. As the whole, the lowest value among no-observed-adverse-effect levels (NOAELs) was 100 mg/kg bw/day obtained in the 90-days and one-year toxicity studies in dogs, and in the developmental toxicity studies of rabbits. FSCJ thus established an acceptable daily intake (ADI) for glyphosate at 1 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. The lowest NOAEL for adverse effects elicited by a single oral administration of glyphosate was 1,000 mg/kg bw observed in an acute toxicity studies in rats and mice. It is thus unnecessary to specify an acute reference dose (ARfD), due to the exceeding of the cut off level (500 mg/kg bw).
No-observed-adverse-effect level
Reproductive toxicity
Neurotoxicity
Reference dose
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This report aims to determine the permitted daily exposure (PDE) of flutamide, an androgen receptor blocker, as directed by guideline EMA/CHMP/CVPM/SWP/169430/2012 that came into effect on June 2015. A literature review was conducted to identify toxicity studies of flutamide. Hazards and sensitive endpoints were determined. Based on the no adverse effect levels (NOAELs) and lowest observed adverse effect levels (LOAELs) reported from both reproductive, developmental, and 28-day toxicity studies the PDE was calculated. Most of the toxicity studies converge toward a NOAEL of 1 mg/kg/d that translates to a PDE of 0.1 mg/d. However, taking into consideration the worst case scenarios for additional safety a PDE of 0.025 mg/d (25 μg/d) was calculated based on a reported NOAEL of 0.25 mg/kg/d. A PDE of 0.05 mg/d (50 μg/d) was also calculated from reproductive/developmental toxicity studies, which is in close agreement with the PDE from the 28-day toxicity studies. Considering the lowest PDE of 0.025 mg/d, residual flutamide at this dose is unlikely to pose any risk to humans. Nonmonotonic dose response (NMDR) effects of flutamide were not supported by literature. Oral route of administration was considered.
Flutamide
No-observed-adverse-effect level
Reproductive toxicity
Developmental toxicity
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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of oxathiapiprolin (CAS No. 1003318–67–9), a fungicide of piperidinyl thiazole isoxazoline-type, based on results from various studies. Major adverse effects of oxathiapiprolin observed are reduced gain of body weight and delayed preputial separation in rat offsprings in a two-generation reproductive toxicity study. No neurotoxicity, carcinogenicity, reproductive toxicity, teratogenicity or genotoxicity was observed. Oxathiapiprolin (parent compound only) was identified as a chemical for the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) obtained in all the studies was 346 mg/kg bw/day in a two-generation reproductive toxicity study in rats. FSCJ specified an acceptable daily intake (ADI) of 3.4 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. FSCJ considered it unnecessary to specify an acute reference dose (ARfD), since no adverse effects would be likely to be elicited by a single oral administration.
Reproductive toxicity
No-observed-adverse-effect level
Reference dose
Acceptable daily intake
Preputial gland
Neurotoxicity
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To assess the effects of acrylonitrile (AN) exposure on reproduction, Sprague-Dawley rats (25/sex/group) were exposed to vapor atmospheres of AN via whole-body inhalation at concentrations of 0, 5, 15, 45 (two offspring generations) and 90 ppm (one offspring generation), 6 h daily, 1 litter/generation, through F2 weanlings on postnatal day 28. After approximately 3 weeks of direct exposure following weaning, exposure of the F1 animals at 90 ppm was terminated due to excessive systemic toxicity in the males. There were no exposure-related mortalities in adult animals, no functional effects on reproduction or effects on reproductive organs, and no evidence of cumulative toxicity or of enhanced toxicity in pregnant and lactating dams or in developing animals. Adult systemic toxicity was limited to body weight and/or food consumption deficits in both sexes and generations (greater in males) at 45 and 90 ppm and increased liver weights in the 90 ppm F0 males and females and 45 ppm F1 males. Neonatal toxicity was expressed by F1 offspring weight decrements at 90 ppm. Clinical signs of local irritation during and immediately following exposure were observed at 90 ppm. Microscopic lesions of the rostral nasal epithelium, representing local site-of-contact irritation, were observed in some animals at 5 to 45 ppm. The no-observed-adverse-effect level (NOAEL) for reproductive toxicity over two generations and neonatal toxicity of AN administered to rats via whole-body inhalation was 45 ppm. The NOAEL for reproduction was 90 ppm for the first generation. The NOAEL for parental systemic toxicity was 15 ppm.
Reproductive toxicity
No-observed-adverse-effect level
Litter
Inhalation exposure
Developmental toxicity
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Trifluoroiodomethane (CF 3 I) is a colorless and odorless gas used primarily as a fire suppressant. CF 3 I has low acute inhalation toxicity. The no-observed adverse effect level (NOAEL) of CF 3 I for cardiac sensitization in dogs was 2000 ppm. The potential effects of 4-week inhalation exposure in both rats and mice have been examined. In rats, the NOAEL was 10,000 ppm, and in mice, the NOAEL was 10,000 ppm. In a subchronic inhalation study in rats, the lowest observed adverse effect level (LOAEL) was 20,000 ppm for thyroid-related effects; the study NOAEL (for non-thyroid-related effects) was 20,000 ppm. In a reproductive/developmental inhalation toxicity study in rats, 20,000 ppm CF 3 I produced minimal general toxicity and no indication of reproductive or developmental toxicity. The LOAEL for parental toxicity (based on thyroid hormone effects) was 2000 ppm; excluding thyroid effects, the parental NOAEL was 7000 ppm CF 3 I. The observed effects on the thyroid in rats were considered of less relevance to human risk assessment than the other observed systemic effects because of known species-specific differences in sensitivity to thyroid hormone perturbations. There are no chronic toxicity or carcinogenicity studies available. CF 3 I had mixed results in various in vitro and in vivo genotoxicity assays. The NOAEL of 7000 ppm from the reproductive/developmental inhalation study was used as the point of departure (POD) for workplace environmental exposure level (WEEL) value development. This POD was adjusted to account for interindividual variability, duration of exposure, and database limitations. The resulting 8-h time-weighted average WEEL value of 500 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to CF 3 I. A 15-min short-term exposure limit of 1500 ppm was also established to protect workers from potential cardiac effects produced by acute, high-dose inhalation of CF 3 I.
No-observed-adverse-effect level
Reproductive toxicity
Inhalation exposure
Reference dose
Developmental toxicity
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Phthalate esters (PEs) are widely used as plasticizers in various kinds of plastic products. Some PEs have been known to induce developmental and reproductive toxicity (DART) as well as hepatotoxicity in laboratory animals. In some cases of DART, the strength of toxicity of PEs depends on the side chain lengths, while the relationship between hepatotoxicity and side chain length is unknown. Therefore, in this study, we compared DART and hepatotoxicity in rats, focusing on 6 PEs with different side chains. We collected toxicity data of 6 PEs, namely, n-butyl benzyl phthalate (BBP), di-n-butyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP), di-isodecyl phthalate (DIDP), di-isononyl phthalate (DINP), and di-n-octyl phthalate (DNOP), from open data source, then, we constructed the toxicity database to comprehensively and efficiently compare the toxicity effects. When we compared DART using the toxicity database, we found that BBP, DBP, and DEHP with short side chains showed strong toxicities against the reproductive organs of male offspring, and the No-Observed-Adverse-Effect Levels (NOAELs) of BBP, DBP, and DEHP were lower than DIDP, DINP, and DNOP with long side chains. Comparing hepatotoxicities, the lowest NOAEL was shown 14 mg/kg/day for DEHP, based on liver weight gain with histopathological changes. However, as BBP and DBP showed higher NOAEL than the other 3 PEs (DIDP, DINP, and DNOP), we conclude that hepatotoxicity does not depend on the length of side chain. Concerning side chain length of PEs, we effectively utilized our constructed database and found that DART and hepatotoxicity in rats showed different modes of toxicities.
Reproductive toxicity
Developmental toxicity
No-observed-adverse-effect level
Liver toxicity
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No-observed-adverse-effect level
Reproductive toxicity
Dose
Developmental toxicity
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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of bis(2-ethylhexyl)phthalate (DEHP) (CAS No.117-81-7) as a substance related to revision of the standards and criteria for apparatuses, containers and packages. The primary adverse effects of DEHP were observed on reproductive and developmental toxicity and carcinogenicity in the tested animals. Maternal exposure to DEHP during gestational and lactational periods resulted in adverse effects on the reproductive tract in male offspring. For carcinogenicity, DEHP has been reported to induce hepatic tumors in mice and rats, but the carcinogenicity in humans is unclear after oral exposure. With regard to the genotoxicity of DEHP, most of data in vitro and in vivo were negative. DEHP and its metabolites were thus likely to interact indirectly with DNA. Thus, FSCJ regarded it as possible to establish the tolerable daily intake (TDI) of DEHP. The lowest no-observed-adverse-effect level (NOAEL) of all the tests is 3 mg/kg body weight/day, which was obtained in gavage administration study in rats during the period from gestation day 7 to postnatal day 16. FSCJ established a TDI of DEHP of 0.03 mg/kg body weight/day, applying uncertainty factor of 100, which consists of 10 for species difference and 10 for individual difference, to the lowest NOAEL of 3mg/kg body weight/day.
Reproductive toxicity
Tolerable daily intake
No-observed-adverse-effect level
Anogenital distance
Reference dose
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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of flubendiamide (CAS No. 272451-65-7), an iodophthalimide insecticide for the setting of an acceptable daily intake (ADI) in 2006. FSCJ now has assessed this insecticide for the setting of an acute reference dose (ARfD). Data including fate in animals (rats and mice) and residues in crops (burdock roots, pumpkins and others) were newly submitted. Major adverse effects of flubendiamide include hepatocellular hypertrophy, fatty changes in hepatocytes, follicular epithelial cell hypertrophy in thyroid and ocular enlarged eye in rats. No neurotoxicity, carcinogenicity, reproductive toxicity, teratogenicity, neurodevelopmental toxicity and genotoxicity were observed. The lowest no-observed-adverse-effect level (NOAEL) in the toxicological studies was 1.70 mg/kg body weight/day in a two-year carcinogenicity study in rats. FSCJ confirmed an ADI of 0.017 mg/kg bw/day after applying a safety factor of 100 to the NOAEL. Adverse effects elicited by a single oral administration of flubendiamide would be abnormalities in eyes such as ocular hypertrophy and iris adhesion in offspring, which were obtained in a two-generation reproductive toxicity study, a one-generation reproductive toxicity study and a neurodevelopmental toxicity study in rats. FSCJ judged that these studies may be applicable to set the ARfD for lactating women in relation to the exposure of flubendiamide to offspring after the birth through breast milk. By taking into account the overall evaluations of the two-generation reproductive toxicity study, one-generation reproductive toxicity study and neurodevelopmental toxicity study in rats, FSCJ judged NOAEL of 15.0 mg/kg bw/day as for an overall NOAEL, and consequently specified an ARfD of 0.15 mg/kg bw/day for lactating women by applying a safety factor of 100 to the NOAEL.
Reproductive toxicity
No-observed-adverse-effect level
Neurotoxicity
Developmental toxicity
Tolerable daily intake
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