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.

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of Listeria monocytogenes (LM) in ready-to-eat (RTE) foods contaminated with LM. Data used for the assessment were those of food intake, the susceptible people population, estimated incidence of human listeriosis, and LM contamination in RTE foods in Japan. Contamination levels of LM in RTE foods and exponential dose-response model described in the evaluation report of Joint FAO/WHO Expert Meetings on Microbiological Risk Assessment (JEMRA) were also used for the assessment. The result of the assessment shows that if the contamination level of LM in RTE foods is below 10,000 CFU/g at consumption, the number of invasive listeriosis cases would be lower than those (200 cases) calculated from data of surveillance conducted by the Ministry of Health, Labour and Welfare. Therefore, the development of invasive listeriosis in Japan is likely caused by consumption of foods contaminated with LM at a level higher than 10,000 CFU/g. Furthermore, the result indicates that if some foods are contaminated with such an extremely high level of LM as 1,000,000 CFU/g at consumption, the number of patients would increase with the increase in the proportion of such heavily contaminated foods even when contamination levels in foods are relatively low as a whole. Therefore, to reduce the incidence of listeriosis, it is necessary to decrease the frequency of occurrence of foods contaminated heavily with LM by specifying a storage period for RTE foods. Manufacturers and processors of RTE foods should implement end product testing on LM, good hygienic practices, and environmental monitoring for LM in their plants.

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of a parasiticide moxidectin (CAS No. 113507-06-5). Negative results were obtained in all of the genotoxicity studies. In addition, no carcinogenicity was identified in combined chronic toxicity/carcinogenicity studies in mice and rats. The results from a reproductive and developmental toxicity study of moxidectin in rats implied its toxicity to human infants due to exposure through breast milk. However, different from rats, P-glycoprotein is expressed in human fetuses from the middle pregnancy period and is present throughout adulthood after birth. Additionally cytochrome P450 3A form, which is an isoform involved in metabolism of moxidectin, is identified in human fetuses from the late pregnancy period as well as after birth. Therefore, FSCJ concluded that the effects of moxidectin on human infants due to exposure through breast milk are not as great as those on rats. A developmental toxicity study in CF-1 mice reported a significant increase in the malformation percentages of cleft palate and others in the offspring, but the no-observed-adverse-effect level (NOAEL) was 1.5 mg/kg body weight/day. Neurotoxic signs such as tremor and hypersensitivity reactions to contact were observed in toxicity studies of moxidectin, but lacked histopathological findings. Further, the recovery from such signs was observed in rats and dogs when the dose was reduced. Considering the differences in the toxicities including neurotoxicity between the structurally similar moxidectin and ivermectin, FSCJ concluded that neurotoxicity of moxidectin is short-lasting and reversible. The effect identified at the lowest dose in the toxicity studies of moxidectin was dose-dependent reductions in body weights and food consumption observed in a 90-day subacute toxicity study in dogs, and NOAEL was 0.3 mg/kg body weight/day. Applying the safety factor of 100 to NOAEL, FSCJ specified the acceptable daily intake (ADI) of moxidectin to be 0.003 mg/kg body weight/day.

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of advantame (CAS number: 714229-20-6), a food additive used as a sweetener, based on results from various studies. FSCJ concluded that advantame and its degraded-products are of no concern in terms of their genotoxicity. In a prenatal developmental toxicity study in rabbits, dams administered advantame exhibited digestive disorders accompanied by deterioration of general conditions at doses of 1,000 mg/kg body weight/day or higher. FSCJ considered this effect attributable to the administration of advantame, and regarded 500 mg/kg body weight/day (a dose lower than that causing the above-mentioned effect) as the lowest no-observed-adverse-effect level (NOAEL) of advantame. In addition, advantame showed no carcinogenicity. Taking the observed toxicological effects and the estimated intake of advantame (3.57 mg/person/day (0.0714 mg/kg body weight/day)) after its approval in Japan into account, FSCJ considered that it is necessary to specify an acceptable daily intake (ADI) for advantame. FSCJ specified the ADI of 5.0 mg/kg body weight/day, based on the NOAEL in the prenatal developmental toxicity study in rabbits (500 mg/kg body weight/day) and applying a safety factor of 100.

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of ‘polyvinylpyrrolidone’ (CAS number: 9003-39-8), a food additive used for producing foods in capsules and/or tablet form, based on data from various studies. The food additive ‘polyvinylpyrrolidone’ (hereinafter referred to as ‘this additive’) contains polyvinylpyrrolidone (hereinafter referred to as ‘PVP’) as well as the residual monomer, 1-vinyl-2-pyrrolidone (hereinafter referred to as ‘NVP’) and hydrazine as impurities. FSCJ considered that PVP taken orally is barely absorbed from the digestive tract and is directly excreted into feces, based on toxicokinetic studies done on experimental animals. According to case reports available, oral intake of pharmaceutical products containing PVP seldom but evidently cause allergic reactions in humans. Allergenicity of PVP thus cannot be ruled out, but these reports on allergenicity lacked any information on doses; FSCJ therefore does not neglect the possibility that PVP potentially acts as a sensitizer in a limited population through unidentified mechanisms. Therefore, FSCJ deemed that most of the allergic reactions observed after oral intake of PVP might be attributable to sensitization caused by topical or other application of povidone-iodine. It deemed that the probability of sensitizing through oral intake of PVP alone is extremely low. FSCJ concluded that NVP is of no concern for genotoxicity, acute toxicity and repeated dose toxicity on human health. Therefore FSCJ considered that the carcinogenicity of NVP manifested due to a mechanism other than a genotoxic one. FSCJ concluded that it is difficult to assess the carcinogenicity based on the amount of intake of NVP included in this additive. Regarding the safety of hydrazine, carcinogenicity and genotoxicity have been reported. FSCJ thus concluded that the no-observed-adverse-effect level (NOAEL) cannot be established. Based on the quantitative carcinogenic risk assessments of hydrazine performed in the United States and Europe, and based on the amount of hydrazine contained (500 ppb at the highest estimate), FSCJ estimated the carcinogenic risk level of humans exposed to this additive at an estimated daily intake (480 mg/person/day) in Japan. Consequently the risk level was estimated to be 9.0×10⁻⁷ (about 1.1 millionths). This estimated risk level is smaller than one-in-a-million, which is generally considered negligible as a genotoxic carcinogenic risk level. The risk is thus considered extremely low. FSCJ concluded that consumption of hydrazine contained in this additive does not pose safety concerns for the consumers. Based on the above findings, this additive is considered to be of no concern for food safety as long as used appropriately as a food additive, and FSCJ concluded that it is unnecessary to specify the acceptable daily intake (ADI). The risk management agency thus must take appropriate measures to prevent development of allergy upon use of this additive. Regarding hydrazine, the risk management agency must continue to commit itself to reduce the risk to a technically feasible level.

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of ethoxyquin (CAS No. 91-53-2), an antioxidant and a plant growth regulator. The data from all the in vitro reverse mutation tests were negative, while positive results were obtained in chromosomal aberration tests using Chinese hamster ovary cells and human peripheral blood lymphocytes and also in the mouse lymphoma TK test. As for in vivo studies, ethoxyquin gave a weak positive response in the liver micronucleus test in juvenile rats, but negative responses in the mouse bone marrow micronucleus test and the unscheduled DNA synthesis test using rat liver. Although ethoxyquin and/or its metabolite(s) induce chromosomal aberration, the influence on the chromosomal aberration is likely to be associated with ethoxyquin’s action on the functional protein component rather than the direct DNA damage in the body. Results from the 30-month combined chronic toxicity/carcinogenicity study suggest that ethoxyquin has a carcinogenic potential in the urinary bladder in female rats. Therefore, it is unlikely that ethoxyquin in normal uses exerts the carcinogenicity through a genotoxic mechanism. Based on various data, FSCJ designated ethoxyquin and its dimer to the residue definition in agricultural products. Residual ethoxyquin dimer has been found as an ethoxyquin metabolite at a substantial level in cultured fishes such as salmons. Toxicity of the dimer has been studied only in one 90-day subacute toxicity test where the toxicity was not observed at the dose of 12.5 mg/kg body weight/day. Ethoxiquin used for the most of toxicity studies seems to contain ethoxiquin dimer as an impurity. Taking the results from such toxicity studies into consideration, it is unlikely that toxicity of the dimer is stronger than that of the parent compound. Among the no-observed-adverse-effect levels (NOAELs) obtained in various studies, the lowest NOAEL was 2 mg/kg body weight/day obtained in the 90-day subacute toxicity study in dogs. FSCJ, however, judged that it was more appropriate to adopt the lowest-observed-adverse-effect level (LOAEL) of 2.5 mg/kg body weight/day obtained in the two-generation reproduction toxicity study in dogs which was performed more recently and administered for a longer period of time, as a basis for acceptable daily intake (ADI). Accordingly, FSCJ specified the ADI for ethoxyquin as 0.0083 mg/kg body weight/day, based on this LOAEL and applying a safety factor of 300.

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of an isoxazoline herbicide fenoxasulfone (CAS No. 639826-16-7). Major adverse effects observed are: degeneration in the peripheral nerves of dogs, renal papillary necrosis, chronic progressive nephrosis and others in the kidney, and increased organ weights, centrilobular hypertrophy of hepatocytes and others in the liver. No carcinogenicity, effects on reproductive ability, developmental toxicity or genotoxicity was observed. Nerve fiber degeneration and other effects in the peripheral nerves were observed in a 90-day subacute toxicity study and a one-year chronic toxicity study in dogs, indicating neurotoxicity of fenoxasulfone. Based on the results from various studies, FSCJ specified the residue definition for this dietary risk assessment in agricultural products and seafood to be fenoxasulfone (parent compound only). The lowest no-observed-adverse-effect level (NOAEL) in toxicological studies was 17.6 mg/kg body weight/day in an 18-month carcinogenicity study in mice. Applying the safety factor of 100 to this NOAEL, FSCJ specified the acceptable daily intake (ADI) to be 0.17 mg/kg body weight/day.

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