Chemical Control Law Research Articles

Re-evaluation of the reduced heart weights in male rats in a 28-day oral repeated-dose toxicity study of tetramethylammonium hydroxide

We recently conducted a detailed hazard assessment of tetramethylammonium hydroxide (TMAH), a priority chemical substance under the Japan Chemical Substances Control Law. During this assessment, there was debate regarding the reduced heart weight observed in the treated male groups in the 28-day rat oral repeated-dose toxicity study. This finding was not observed in females in this study and in both sexes of oral toxicity studies for tetramethylammonium chloride (TMAC) or tetramethylammonium hydrogen phthalate (TMAHP). Unpublished individual data from the oral TMAH developmental and reproductive toxicity (DART) screening study were also obtained; no effect on heart weight was observed. In addition, background data on rat heart weight from six 28-day oral toxicity studies conducted in the same facility, year, strain, age, and breeder as the TMAH study were obtained from the Japan Existing Chemical Substances Database (JECDB). These investigations suggest that the statistically significant lower heart weight in the treated males in the 28-day toxicity study is likely caused by an incidental skewing of individuals with heavier heart weights toward control male groups and is not due to TMAH treatment. Thus, it is worthwhile to include as much relevant data as possible to confirm or refute unexpected findings in toxicity studies.

Statistical Post-Processing Method for Evaluating Bioaccumulation in Fish Due to Dietary Exposure in Japan.

In 2018, the dietary exposure bioaccumulation fish test of the Organization for Economic Co-operation and Development Test Guideline No. 305 was introduced into Japan's Chemical Substances Control Law. The Japanese government has adopted a single definitive testing criterion for the absence of high bioaccumulation: the growth-corrected kinetic dietary magnification factor (BMFKg) must be less than 0.007. The aim of this study was to decrease regulatory restrictions in order to increase newly developed chemical substances and their subsequent approval of their manufacture and import, i.e., the present study was motivated by concerns over the criterion being too restrictive, rather than scientific concerns, such as uncertainty in criterion. We used statistical post-processing to assess the possibility of expanding the criteria for not being highly bioaccumulative. Based on our results, we proposed the criterion that the test substance should be considered not highly bioaccumulative if the following two conditions are met: (1) The ratio of the maximum to the minimum measured 5% lipid-standardized biomagnification factor at the end of the uptake phase (BMF5%, n = 5) for the test substance and reference substance should be less than 3.0, and (2) For the measured BMF5% of the test substance (n = 5), the probability that the next (the sixth) BMF5% is below 0.0334 should exceed 95% based on statistical post-processing. It is worth noting that the BMF5% values should only be applied for non-ionizable lipid soluble compounds. Application of our suggested approach to Japan implies that the criterion for chemical substances that are not highly bioaccumulative in the dietary exposure bioaccumulation fish test would be increased from 0.007 to 0.0149.

Derivation of human health hazard assessment values of 1,2-dichloroethane under the Japan Chemical Substances Control Law

1,2-Dichloroethane, a priority assessment chemical substance under the Japan Chemical Substances Control Law (CSCL), required a detailed human health hazard assessment under Assessment II. We evaluated its general, reproductive, and developmental toxicities, genotoxicity, and carcinogenicity, based on the hazard information provided by domestic and international risk assessment organizations, and the hazard assessment values (HAVs) for oral and inhalation exposure were proposed. For oral exposure, a 78-week gavage carcinogenicity study (US NCI, 1978) with incidence data of hemangiosarcoma in male rats was selected as a significant toxicological endpoint and the lower confidence limit of benchmark dose (BMD) at 10% benchmark response (BMDL10) of 9.3 mg/kg/day was obtained as a point of departure (POD). A slope factor of 1.07 × 10−2 (mg/kg/day)−1 from which a carcinogenic 10−5 risk of 0.93 µg/kg/day was derived as an oral HAV. For inhalation exposure, a 104-week inhalation exposure carcinogenicity study (Nagano et al., 2006) with a BMDL10 of 11.5 ppm based on the incidence data of mammary gland tumors (adenocarcinoma + adenoma + fibroadenoma, combined) in female rats was obtained, and the human equivalent BMDL10 of 15.7 mg/m3 was calculated. Therefore, a unit risk of 6.40 × 10−6 (µg/m3)−1 from which a carcinogenic 10−5 risk of 1.6 µg/m3 (0.00039 ppm) was derived as an inhalation HAV.

Quantitative analyses of misclassification rates in the hazard classification of environmental chemicals: Evaluation of procedures for deriving predicted no-effect concentrations in the Chemical Substance Control Law in Japan.

The quality of chemical management depends more or less on practical procedures used to assess chemicals. This study quantitatively assessed the efficacy of a derivation procedure for calculating no-effect concentrations for screening assessment of environmental hazards under the Chemical Substance Control Law in Japan. We first evaluated the derivation procedure by applying a series of test ecotoxicity datasets to the procedure and calculating the resulting misclassification rates of the hazardous class of chemicals. In this study, a chemical was deemed to have been misclassified if its classification differed from its classification based on the full dataset (chronic toxicity data for three trophic levels), which was defined as the correct assignment. We also calculated the effects of additional uncertainty factors to decrease the variance (i.e., to improve the consistency) of the misclassification rates among cases with different data availability in the derivation procedure. The results showed that the derivation procedure resulted in very high rates of misclassification when only particular sets of ecotoxicity data were available (e.g., only chronic toxicity data of algae were available). Our analyses also showed that the use of additional uncertainty factors improved the consistency of the misclassification rates within the derivation procedure. Our study presents a broadly applicable calculation framework for quantifying error rates in assessment procedures and serves as a case study for future development and reforms of chemical assessment processes and policies, while additional analyses using more extensive ecotoxicity data with various modes of actions are needed in the future.

Establishing a ready biodegradability test system using OxiTop® to evaluate chemical fate in a realistic environment.

The purpose of this study is to propose the use of OxiTop® for measuring biochemical oxygen demand (BOD) under the Japanese Chemical Substances Control Law in order to properly evaluate chemical fate in a real environment. In our previous study, the biodegradation of test chemicals was accelerated by both adsorbing the chemical to silica gel with chloroform and increasing the medium volume from 300 to 3900 mL in the OECD 301F test using a coulometer. However, the biodegradability of these chemicals could not be evaluated based on BOD due to chloroform residue in the silica gel, or the medium volume could not be increased further due to the oven size of the coulometer. In this study, we established an evaluation system using OxiTop® based on BOD by increasing the medium volume to 9000 mL. Based on triplicate testing, increasing the medium volume accelerated biodegradation and decreased variation in BOD.

Derivation of human health hazard assessment values for toluene under the Japanese Chemical Substances Control Law

Derivation of human health hazard assessment values for toluene under the Japanese Chemical Substances Control Law

CSCL and Industrial Chemical Management Framework in Japan

Despite Japan’s presence in the global economy, its industrial chemical regulations were less accessible than other economies’ chemical regulation frameworks, such as the United States’ Toxic Substances Control Act (TSCA) and Europe’s Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH), due to the limited information in English. Since the Japanese government considered chemical regulations as domestic issues, it did not prioritize disseminating information to overseas stakeholders. This Case Study outlines Japan’s industrial chemical regulation framework and highlights the Chemical Substance Control Law (CSCL) by elaborating on its development history and amendments. The author was involved in CSCL implementation for more than 14 years.

Read-across approaches: current applications and regulatory acceptance in Korea, Japan, and China

ABSTRACT The aim of this paper was to investigate the current status of read-across approaches in the Republic of Korea, Japan, and China in terms of applications and regulatory acceptance. In the Republic of Korea, over the last 6 years, approximately 8% of safety data records used for chemical registrations were based upon read-across, and a guideline published on the use of read-across results in 2017. In Japan, read-across is generally accepted for screening hazard classification of toxicological endpoints according to the Chemical Substances Control Law (CSCL). In China, read-across data, along with data from other animal alternatives are accepted as a data source for chemical registrations, but could be only considered when testing is not technically feasible. At present, read-across is not widely used for chemical registrations and regulatory acceptance of read-across may differ among countries in Asia. With consideration of the advantages and limitations of read-across, it is expected that read-across may soon gradually be employed in Asian countries. Thus, regulatory agencies need to prepare for this progression.

Initial hazard assessment of ethyl(dimethyl)(tetradecyl)ammonium ethyl sulfate: Genotoxicity tests and combined repeated-dose and reproductive/developmental toxicity screening in rats

Ethyl(dimethyl)(tetradecyl)ammonium ethyl sulfate, used in laundry detergents, shampoos, and body soaps, is classified by the Japanese Chemical Substances Control Law as a priority assessment chemical substance for environmental effects. However, its toxicity data for human health are insufficient. This study evaluated this chemical under the Safety Examination of Existing Chemicals and Safety Programmes of the Ministry of Health, Labour and Welfare (MHLW). The MHLW conducted bacterial reverse mutation (Ames test), in vitro chromosomal aberration, and combined repeated-dose and reproductive/developmental toxicity screening tests. We performed a screening assessment of ethyl(dimethyl)(tetradecyl)ammonium ethyl sulfate for human health. The chemical showed a negative reaction in the Ames test and a positive reaction in the in vitro chromosomal aberration test with metabolic activation in rats. The combined repeated-dose and reproductive/developmental toxicity screening test showed significantly decreased food consumption at 50 mg/kg body weight/day, but no reproductive and developmental toxicity was observed. The no-observed-effect level of 15 mg/kg/day was obtained as a screening value. Therefore, this chemical was classified as hazard class 3, with a derived-no-effect level of 0.025 mg/kg/day. The results of this study will be useful for risk assessment of groups of structurally similar alkyl quaternary ammonium surfactants.

Investigation of OECD 301F ready biodegradability test to evaluate chemical fate in a realistic environment.

The OECD 301F ready biodegradability test has been approved for use under the Japanese Chemical Substances Control Law since 2018. This test uses activated sludge obtained from a sewage treatment plant instead of the standard activated sludge used for the 301C test. In addition, the test is allowed to add an inert support or emulsifying agent, and/or to change the volume of the test medium. In this study, we first confirmed that the standard sludge had lower biodegradation activities than the sludge taken from a sewage treatment plant. Second, we showed that biodegradation percentages were increased by adding suitable amounts of silica gel or Tween 80. Third, we found that the biodegradations were accelerated by only increasing the medium volume under the conditions that concentrations of chemical, silica gel, and sludge were held constant. These findings are expected to contribute to the appropriate evaluation of chemical fate in a realistic environment.

An all-in-one tool for multipurpose ecological risk assessment and management (MeRAM) of chemical substances in aquatic environment

A quality-assured ecological risk assessment (ERA) requires enormous resources (time and labor) in collection/assessment of hazard data, as well as considerable expertise to interpret the risk. The ERA of chemicals is thereby considered difficult or impossible for those with little assessment experience and cumbersome or complicated for practitioners. To meet the concerns regarding ERA and accelerate the risk assessment and management of chemicals, we developed an all-in-one free tool for multi-purpose ecological risk assessment management (MeRAM) of chemical substances in aquatic environment called the AIST-MeRAM Ver. 2.0.0 (Copyright No: H28PRO-2007). It allows users from beginners to experts to conduct ERA without any preparation because all the necessary ecotoxicity test data and methodologies are available in the system. Approximately 270,000 ecotoxicity test data points for 3900 chemical substances together with the scientific methodologies from traditional simple hazard quotient (HQ) to more ecologically relevant complicated assessments such as species sensitivity distribution (SSD) and population-level assessment are embedded in the AIST-MeRAM. In addition, users can easily understand the Japanese regulatory RA and management of chemical substances due to a special function based on the Japanese Chemical Substance Control Law (CSCL). Here, we demonstrate a tiered ERA using the embedded sample data to evaluate and ensure the functions of AIST-MERAM. We show that the AIST-MeRAM can provide a comprehensive and accurate ERA, suggesting that it is a powerful IT solution for cumbersome ERA.

Initial hazard assessment of 1,4-dichlorobutane: Genotoxicity tests, 28-day repeated-dose toxicity test, and reproductive/developmental toxicity screening test in rats

1,4-Dichlorobutane (1,4-DCB) is used as raw materials for drugs, pesticides, fragrances, and chemical fibers, and being used as a solvent. Its toxicity data was insufficient for screening assessment under the Japanese Chemical Substances Control Law. We conducted toxicity tests and hazard classification for screening assessment 1,4-DCB showed negative in the Ames test, positive in the in vitro chromosomal aberrations test with metabolic activation, and negative in the in vivo mouse bone-marrow micronucleus test. The 28-day repeated-dose toxicity study, where male and female rats were administered 1,4-DCB by gavage at 0, 12, 60, and 300 mg/kg/day, showed significant effects on the liver and pancreas from 12 mg/kg/day and kidney at 300 mg/kg/day. Based on periportal hepatocellular hypertrophy and decreased zymogen granules in pancreas, the lowest observed adverse effect level (LOAEL) of 12 mg/kg/day was obtained. The reproductive/developmental toxicity screening study, in which male and female rats were administered 1,4-DCB by gavage at dose of 0, 2.4, 12, and 60 mg/kg/day for 42–46 days, showed that the delivery index was decreased at 60 mg/kg/day without maternal toxicity. Based on the general toxicity, we classified this chemical as hazard class 2, with a D-value (Derived No Effect Level) of 0.002 mg/kg/day.

Overview of the Chemical Substances Control Law and of Test Methods for Chemical Safety

Overview of the Chemical Substances Control Law and of Test Methods for Chemical Safety

위험물질 사고대응에 관한 법규정 개선방안에 관한 연구

Since the rapid industrialization in the 1980s and 1990s, relative facilities dealing with hazardous materials are prone to the risk of accidents due to the aging process, therefore, active and preemptive responses for increased potential risks are required. However, there are limitations to plausible responses since the Act on Hazardous Material Accident Response is inadequate, and the Law on Hazardous Material Accidents, such as the Chemical Substance Control Law, focuses on the prevention of hazardous material accidents. Therefore, in this study, we propose an improvement plan through cross-examining of contents of Japanese basic firefighting law, dangerous materials safety management law, etc. Improvement of laws and regulations that can respond rationally and efficiently in the event of a hazardous material accident has been provided while minimizing the conflict between government departments through the provision of

Initial hazard assessment of benzyl salicylate: In vitro genotoxicity test and combined repeated-dose and reproductive/developmental toxicity screening test in rats

Benzyl salicylate is used as a fragrance ingredient and an ultraviolet light absorber, but its toxicity is unknown. Therefore, toxicity tests and hazard classification were conducted for screening assessment under the Japanese Chemical Substances Control Law. Benzyl salicylate was found to be non-genotoxic in vitro based on the chromosomal aberration test using Chinese hamster lung cells. However, the combined repeated-dose and reproductive/developmental screening toxicity test, in which male and female rats were administered benzyl salicylate by gavage at 0, 30, 100, or 300 mg/kg/day for 42 and 41–46 days, respectively, from 14 days before mating until postnatal Day 4, showed that repeated doses had major effects on the thymus, liver, epididymis, and femur at 100 and/or 300 mg/kg/day. Furthermore, although benzyl salicylate had no effect on the estrus cycle, fertility, corpus lutea, or implantation rate, embryonic resorption, offspring mortality, and neural tube defects were observed at 300 mg/kg/day, and the offspring had lower body weights at 30 and 100 mg/kg/day, suggesting teratogenicity similar to other salicylates. Based on the developmental toxicity, this chemical was classified as hazard class 2, with a lowest observed adverse effect level (LOAEL) of 30 mg/kg/day and a D-value of 0.003 mg/kg/day.

<b>Study on Hexabromocyclododecane and Benzotriazole UV Stabilizers in the Water Environment in Japan, via the Joint Environmental Research for National </b><b>Institute for Environmental Studies with Regional Institutes,“The Survey of the Emission Sources and Destiny of Chemicals </b><b>under Chemical Substances Control Law” </b>

<b>Study on Hexabromocyclododecane and Benzotriazole UV Stabilizers in the Water Environment in Japan, via the Joint Environmental Research for National </b><b>Institute for Environmental Studies with Regional Institutes,“The Survey of the Emission Sources and Destiny of Chemicals </b><b>under Chemical Substances Control Law” </b>

TSCA Affects on Algae, Other Novel Biosources, and Bioprocesses

Introduction The Toxic Substances Control Act (TSCA) is the federal gap-filling chemical control law regulating chemical substances used in applications other than food, drugs, cosmetics, and pesti...

CATALOGIC 301C model – validation and improvement

In Europe, REACH legislation encourages the use of alternative in silico methods such as (Q)SAR models. According to the recent progress of Chemical Substances Control Law (CSCL) in Japan, (Q)SAR predictions are also utilized as supporting evidence for the assessment of bioaccumulation potential of chemicals along with read across. Currently, the effective use of read across and QSARs is examined for other hazards, including biodegradability. This paper describes the results of external validation and improvement of CATALOGIC 301C model based on more than 1000 tested new chemical substances of the publication schedule under CSCL. CATALOGIC 301C model meets all REACH requirements to be used for biodegradability assessment. The model formalism built on scientific understanding for the microbial degradation of chemicals has a well-defined and transparent applicability domain. The model predictions are adequate for the evaluation of the ready degradability of chemicals.

Washington’s revolving door

David Vitter, a former Republican senator from Louisiana, was a key sponsor of legislation enacted last year to reform the nation’s commercial chemical control law, the Toxic Substances Control Act (TSCA). In February, Vitter joined a consulting firm that lobbies on behalf of businesses, including the chemical industry group the American Chemistry Council (ACC). Nancy Beck, an ACC senior director, has criticized EPA’s chemical risk assessment program and called for including industry experts in EPA peer reviews. ACC supported modernization of TSCA with the aim of boosting consumer confidence in the safety of chemicals. Beck is expected in May to become a key official in the Office of Chemical Safety & Pollution Protection, the EPA office tasked with implementing the revised law. Liz Bowman, former ACC director of issue and advocacy communications, in March joined EPA’s public affairs office.

化学物質の審査及び製造等の規制に関する法律（化審法）について

化学物質の審査及び製造等の規制に関する法律（化審法）について