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Background <p>Toluene diisocyanates (TDIs) are high-production-volume chemicals widely used in polyurethane manufacturing. A typical commercial-grade TDI (TDI; 2,4-toluene diisocyanate: 2,6-toluene diisocyanate; 80:20), CAS: 26471-62-5, is mutagenic in <i>Salmonella typhimurium</i> with an S9 metabolic activation mix and induces chromosomal aberrations in Chinese hamster lung cells without S9 mix. While oral administration of TDI has been reported to be carcinogenic in female mice and rats of both sexes, its in vivo mutagenicity remains poorly understood. This study aimed to clarify the in vivo mutagenicity of orally administered TDI. In vivo mutagenicity was evaluated following the Organisation for Economic Co-operation and Development Test Guideline 488 (OECD TG488). MutaMouse females were orally dosed with TDI at 0 (corn oil; vehicle control), 250, 500, or 1,000&#xa0;mg/kg/day for 28 days. Mutant frequencies (MFs) in the liver and glandular stomach were analyzed three days post-final dosing. Positive controls received intraperitoneal injections of <i>N</i>-ethyl-<i>N</i>-nitrosourea (ENU) at 100&#xa0;mg/kg/day for two days, with MFs assessed ten days after the final dose.</p> Results <p>Significant increases in <i>lacZ</i> MFs were observed in the liver at 1,000&#xa0;mg/kg/day, while MFs in the glandular stomach remained unchanged. Positive controls demonstrated significantly elevated MFs in both the liver and glandular stomach.</p> Conclusions <p>These findings indicate that orally administered TDI is mutagenic in mice, supporting its classification as a mutagenic carcinogen.</p>

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Increased mutagenicity in the liver of MutaMouse females following oral treatment with commercial-grade toluene diisocyanate

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  • 发表日期：

    2025年7月1日

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  • Mariko Matsumoto,
  • Masakatsu Natsume,
  • Takako Iso,
  • Takaaki Umano,
  • Yasumasa Murata,
  • Kenichi Masumura,
  • Katsuyoshi Horibata,
  • Kei-ichi Sugiyama

摘要

Background

Toluene diisocyanates (TDIs) are high-production-volume chemicals widely used in polyurethane manufacturing. A typical commercial-grade TDI (TDI; 2,4-toluene diisocyanate: 2,6-toluene diisocyanate; 80:20), CAS: 26471-62-5, is mutagenic in Salmonella typhimurium with an S9 metabolic activation mix and induces chromosomal aberrations in Chinese hamster lung cells without S9 mix. While oral administration of TDI has been reported to be carcinogenic in female mice and rats of both sexes, its in vivo mutagenicity remains poorly understood. This study aimed to clarify the in vivo mutagenicity of orally administered TDI. In vivo mutagenicity was evaluated following the Organisation for Economic Co-operation and Development Test Guideline 488 (OECD TG488). MutaMouse females were orally dosed with TDI at 0 (corn oil; vehicle control), 250, 500, or 1,000 mg/kg/day for 28 days. Mutant frequencies (MFs) in the liver and glandular stomach were analyzed three days post-final dosing. Positive controls received intraperitoneal injections of N-ethyl-N-nitrosourea (ENU) at 100 mg/kg/day for two days, with MFs assessed ten days after the final dose.

Results

Significant increases in lacZ MFs were observed in the liver at 1,000 mg/kg/day, while MFs in the glandular stomach remained unchanged. Positive controls demonstrated significantly elevated MFs in both the liver and glandular stomach.

Conclusions

These findings indicate that orally administered TDI is mutagenic in mice, supporting its classification as a mutagenic carcinogen.