Fundamental Toxicological Sciences

2023 - Vol. 10 No. 3

2023 - Vol. 10

Original Article
A trial to predict skin irritancy of cosmetic products using cytotoxicity tests Vol.10, No.3, p.113-123
Minori Mezaki , Chika Manabe , Junichiro Nagumo , Tomohisa Yoshimura , Tohru Nagahama , Hiroshi Itagaki , Akiko Takaoka
Released: May 12, 2023
Abstract Full Text PDF[1M]

Alternatives to animal testing are being used to assess the safety of raw ingredients during the process of developing cosmetics. However, since cosmetic products are composed of a variety of raw ingredients, the safety of the product itself should also be tested. In this study we attempted to evaluate the skin irritation potential of skin lotions by modifying existing alternative test methods. To evaluate the skin irritation potential of commercial skin lotions in the form of an objective indicator, we calculated their Irritation Score (IS) based on the results of searches using keywords related to skin irritation in review statements posted on Japanese cosmetics and beauty websites. We then modified the reconstructed human epidermis (RhE) test method to evaluate irritation by commercial skin lotions. The results showed that exposure to skin lotions with higher ISs tended to result in lower cell viability, and that exposure to many of the lotions with lower ISs resulted in higher cell viability. Next, we tried using an in vitro short-term exposure (STE) test method to assess the skin irritation potential of skin lotions. By changing the test-substance exposure concentrations and exposure times in the STE test method, we were able to obtain results that correlated with those obtained by the modified RhE test method. In conclusion, both alternative methods were helpful for assessing the possibility of developing skin irritation of skin lotions. They may also be useful for screening formulations being developed and as means of evaluation before proceeding to human patch tests.

A survey of on the use of genotoxicity and carcinogenicity testing packages for ophthalmic drug development Vol.10, No.3, p.105-112
Haruna Tahara , Yu Haranosono
Released: May 12, 2023
Abstract Full Text PDF[726K]

For the non-clinical safety evaluation of pharmaceuticals for new drug applications (NDA), various toxicity studies must be conducted at each stage, from clinical trials to NDA. For topically applied drugs, the level of exposure at the administration site is high because the drug is administered directly to the administration site. However, because systemic exposure to ophthalmic drugs is generally lower than that of systemic drugs, systemic effects may not be adequately assessed. The bone marrow and liver are generally evaluated after systemic administration in in vivo genotoxicity tests, and local genotoxicity studies are conducted on a case-by-case basis. Therefore, we surveyed packages of genotoxicity and carcinogenicity tests for ophthalmic drugs approved in Japan from 2004 to 2021 to assist in the decision of test packages for the development of ophthalmic drugs. There were no major differences in genotoxicity test packages compared to systemic drugs; however, an unscheduled DNA synthesis test using the cornea after ocular instillation was conducted in some products as a test specific to ophthalmic drugs. In the development of ophthalmic drugs, if a positive result is found in an in vitro genotoxicity test, the safety margin between the positive concentration and the clinically applicable concentration (eye drop concentration) is required for safety assessment. If the safety margin cannot be ensured, additional tests may support safety assessment.

Original Article
Derivation of human health hazard assessment values of 1,2-dichloroethane under the Japan Chemical Substances Control Law Vol.10, No.3, p.91-103
Akira Kawashima , Kaoru Inoue , Kazuo Ushida , Kaoru Kai , Hiroshi Suzuki , Lucia Satiko Yoshida-Yamashita , Akihiko Hirose , Kenichi Masumura
Released: April 14, 2023
Abstract Full Text PDF[706K]

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.