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Publications (8)13.92 Total impact

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    ABSTRACT: 4-Methoxy-2-nitroaniline (4M2NA) is widely used as an intermediate for the synthesis of dyes, pigments and other chemical compounds. Since 4M2NA has amino-group and nitro-group on the benzene ring, it was expected that it induced obvious hemolytic anemia. We conducted a combined repeated dose and reproductive/developmental toxicity screening test according to Organisation for Economic Co-operation and Development (OECD) Test Guideline No. 422 (OECD TG 422) to enrich the toxic information and ensure the safety of 4M2NA. 4M2NA was administered to Crl:CD(SD) male and female rats by gavage at 0, 12.5, 75 or 450 mg/kg/day for 42 to maximum of 54 days through pre-mating, mating, pregnancy and lactation periods. An extramedullary hematopoiesis and congestion in spleen, and higher reticulocyte ratio were noted in only females at 450 mg/kg/day without decreased anemic parameters in the hematological examination. Hypertrophy of centrilobular hepatocytes in both sexes was observed with increased relative liver weight at 450 mg/kg/day. Furthermore, the diffuse follicular cell hypertrophy of the thyroid was observed in females at 450 mg/kg/day. No abnormalities were detected in the reproductive indices of copulation, delivery or fetal viability. We concluded the no-observed-adverse-effect level (NOAEL) for repeated-dose toxicity was 75 mg/kg/day based on the trace evidences of hemolytic anemia, and the NOAEL for reproductive/developmental toxicity as 450 mg/kg/day based on no toxicological concerns for reproductive endpoints. The hemolytic anemia was much milder than expected. Thus, we discussed the reason of this much less hemolytic effect from the point of view of the structural characteristics of 4M2NA.
    Drug and Chemical Toxicology 11/2014; · 1.29 Impact Factor
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    ABSTRACT: An approach to predicting the bioconcentration factor (BCFPRE ) from the predicted uptake rate constant (k1Pre ) and the depuration rate constant measured in the dietary exposure bioaccumulation fish test (k2Dietary ) [BCFPRE = k1Pre /k2Dietary ] is proposed in the test guideline 305 of the Organisation for Economic Co-operation and Development Guidelines for Testing of Chemicals. In the present study, we collected BCF data of 197 test chemicals from Japan's Chemical Substances Control Law database, and to demonstrate how the BCFPRE compares to experimentally derived BCF under optimum conditions, 48 of 197 test chemicals including a many of studies that could be considered as problematic, were excluded from the analysis. We calculated k1Pre by 22 published prediction methods and shows that the correlation between experimental uptake rate constants (k1Aqueous ) and k1Pre for all prediction methods were very low and were statistically non-significant (p > 0.05). We also selected three prediction methods which gave relatively good values for the geometric mean of k1Pre /k1Aqueous and calculated values of BCFPRE for 12 test chemicals. Linear relationships (p < 0.05) were presented between logarithm of experimental and predicted BCF. The correlation coefficients of growth-corrected experimental and predicted BCF were tending to be higher than those of not growth corrected values. For some test chemicals, use of predicted BCF led to a bioaccumulation classification different from that according to existing regulatory criteria. Environ Toxicol Chem © 2014 SETAC.
    Environmental Toxicology and Chemistry 03/2014; · 2.62 Impact Factor
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    ABSTRACT: The OECD Guidelines for the Testing of Chemicals lists seven types of tests for determining the biodegradability of chemical compounds (301A-F and 310). In this study, we compared the biodegradation performance of test guideline (TG) 301C, which is applied in Japan's Chemical Substances Control Law, with the performance of the other six RBTs listed in the guidelines. TG 301C specifies use of activated sludge precultured with synthetic sewage containing glucose and peptone (301C sludge) as a test inoculum; however, in the other RBTs, activated sludge from wastewater treatment plants (WWTP sludge) is frequently employed. Analysis based on percentage biodegradation and pass levels revealed that the biodegradation intensity of TG 301C is relatively weak compared to the intensities of RBTs using WWTP sludge, and the following chemical compounds are probably not biodegraded under TG 301C conditions: phosphorus compounds; secondary, tertiary, and quaternary amines; and branched quaternary carbon compounds. The relatively weak biodegradation intensity of TG 301C may be related to the markedly different activities of the 301C and WWTP sludges. These findings will be valuable for evaluating RBT data in relation to Japan's Chemical Substances Control Law. Environ Toxicol Chem © 2013 SETAC.
    Environmental Toxicology and Chemistry 10/2013; · 2.62 Impact Factor
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    ABSTRACT: tert-Butylhydrazine monohydrochloride was daily administered by gavage to groups of Crl:CD (SD)IGS rats at doses of 0 (control), 0.8, 4, or 20 mg/kg/day. Twelve males per group were treated for a total of 42 days from 14 days before mating. Twelve females per group were treated from 14 days before mating to day 4 of lactation throughout the mating and gestation periods. Recovery groups of five males and five non-pregnant females per group were dosed for 42 days followed by a 14-day recovery period. No deaths were observed in any groups of either sex. There were no considerable changes in body weight, food intake, general appearance, functional observations or biochemical analysis. Values of the anemic parameters were decreased in the 20 mg/kg/day males and in all female dose groups. The relative weight of the liver, kidneys and spleen was significantly increased in 20 mg/kg/day females. Histopathological examination showed congestion and hemosiderin deposition in the spleen at 20 mg/kg/day in both sexes, but there were no changes in the liver or kidneys in either sex. Anemic parameters with hemosiderin deposition did not completely recover in the 20 mg/kg/day group in both sexes after the recovery period. As for reproduction, a significant reduction was only observed in the number of corpora lutea at 20 mg/kg/day. It was thus concluded that the LOAEL was 0.8 mg/kg/day based on the decreased values of the anemic parameters of repeated-dose toxicity, and that the NOAEL was 4 mg/kg/day based on the low number of corpora lutea of reproductive/developmental toxicity.
    The Journal of Toxicological Sciences 01/2013; 38(2):177-192. · 1.38 Impact Factor
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    ABSTRACT: The substance 3-amino-5-mercapto-1,2,4-triazole (AMT, CAS No. 16691-43-3) was daily administered by gavage to Crl:CD (SD)IGS rats at doses of 0 (control), 10, 50, and 250 mg/kg bw/day. Males (12/group) were treated for a total of 42 days beginning 14 days before mating. Females (12/group) were treated beginning 14 days before mating to day 4 of lactation throughout the mating and gestation periods. No deaths occurred in males but three females died on day 23 of gestation at 250 mg/kg/day. Only temporary decreases in body weight and food intake were found in both sexes at 250 mg/kg/day. There were no considerable changes in general appearance, the functional battery tests, biochemical analysis or urinalysis. Anemia was observed in both sexes at 250 mg/kg/day. The relative weight of thyroid glands was significantly increased in both sexes at 250 mg/kg/day and hypertrophy of thyroid follicular cells was observed in 50 and 250 mg/kg/day males and 250 mg/kg/day females. As this effect on thyroid glands was considered to be the major toxicity, the possible mechanism was discussed comparing with the toxicity of structural similar analogs. Other histopathological changes in males were hypertrophy of centrilobular hepatocytes at 250 mg/kg/day, and anterior pituitary glands at 50 mg/kg/day and more. Vacuolization in renal tubular epithelium of females was observed at 50 and 250 mg/kg/day. For reproduction, the gestation period was prolonged and the delivery index was decreased at 250 mg/kg/day. The number of pups born and the birth index were also reduced. It was thus concluded that the NOAEL for repeated-dose toxicity was 10 mg/kg/day based on the thyrotoxicity and renal toxicity, and that the NOAEL for reproductive/developmental toxicity was 50 mg/kg/day based on the reduced number of offspring, etc.
    The Journal of Toxicological Sciences 01/2013; 38(5):759-73. · 1.38 Impact Factor
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    ABSTRACT: Existing standard bioconcentration tests (e.g., the Organization for Economic Cooperation and Development [OECD] test guideline [TG] 305) require large numbers of test animals and resources. The minimized aqueous exposure test is a new approach based on the standard bioconcentration test but allows estimation of bioconcentration factor (BCF) by minimized sampling of the test fish. We collected BCF data (298 curves from 155 chemicals, using common carp as test species) from Japan's Chemical Substances Control Law database and resampled the data to simulate the calculation of BCF that would be obtained if studies had been designed to obtain kinetic BCF derived from minimized aqueous exposure test (BCF(km) ). The correlation was high (r(2) = 0.967) between BCF derived from standard bioconcentration tests (BCF(full) ) and BCF(km) . The average value of the BCF(full) to BCF(km) ratio (BCF(full) :BCF(km) ) was 1.04 and ranged from 0.54 to 1.93, the 5th and 95th percentiles being 0.74 and 1.45, respectively. Our results based on the 5th and 95th percentiles of the BCF(full) :BCF(km) ratio suggest that BCF(full) 2,000 corresponds to BCF(km) 1,400 to 2,700, whereas BCF(full) 5,000 corresponds to BCF(km) 3,400 to 6,800. We also emphasize that the standard bioconcentration test should be performed when the resulting BCF(km) are in the region of regulatory concern. Environ. Toxicol. Chem. © 2012 SETAC.
    Environmental Toxicology and Chemistry 11/2012; · 2.62 Impact Factor
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    ABSTRACT: Existing regulatory criteria for bioaccumulation assessment of chemicals are mainly based on a bioconcentration factors (BCF) not a biomagnification factors (BMF). We performed dietary exposure tests for nine poorly water-soluble chemicals and developed a linear regression between the 5 % lipid normalized BCF (BCF(L)) and the lipid-corrected BMF (BMF(L)). The BMF(L) of substances with BCF(L) = 5,000 was 0.31 (95 % CI 0.11-0.87), whereas the BCF(L) of substances with BMF(L) = 1 was 13,000 (95 % CI 5,600-30,000). Five substances can be considered very bioaccumulative (vB) according to the BCF end point (BCF > 5,000), but only two substances were recognized to biomagnify according to the BMF end point (BMF ≥ 1). Although our results are highly suggestive of a relationship between BCF and BMF, additional BMF and trophic magnification factor data for chemicals are required to support this relationship, and new techniques (e.g., fugacity approach) may help in resolving the apparent contradiction in hazard categorization.
    Archives of Environmental Contamination and Toxicology 04/2012; 63(2):241-8. · 2.01 Impact Factor
  • Journal of Japan Society on Water Environment 01/2009; 32(4):213-218.