ortho-Toluidine is a high-production-volume synthetic chemical used to manufacture rubber chemicals, herbicide intermediates, dye intermediates, and the local anesthetic prilocaine. People are exposed to high levels of ortho-toluidine via inhalation or through the skin in workplaces that use it. ortho-Toluidine is found in urine and blood of individuals without known occupational exposure to the chemical, indicating more widespread exposure. Potential sources of exposure include smoking, medical and consumer products, and the environment.
The National Toxicology Program (NTP) conducted a cancer hazard evaluation of ortho-toluidine using systematic review methods to identify studies, evaluate study quality, integrate evidence across studies, and integrate evidence across data streams (human, animal, and mechanistic data). Using the Report on Carcinogen listing criteria, NTP reached conclusions on the strength of evidence for the carcinogenicity of o-toluidine from studies in experimental animals and humans, and the overall listing recommendation.
Results and discussion
Human cancer studies
Epidemiological studies provide evidence of a causal relationship between exposure to ortho-toluidine and urinary bladder cancer based on consistent findings across diverse cohorts with different exposure conditions. Moreover, cancer risk increased with increasing level or duration of exposure, and the magnitude of the effect was large across studies.
Cancer studies in experimental animals
NTP concluded there was sufficient evidence of carcinogenicity of ortho-toluidine from studies in experimental animals. Dietary exposure to ortho-toluidine caused tumors (malignant or combined malignant and benign) of the urinary bladder and connective tissue (sarcoma) in rats of both sexes, subcutaneous tissue and mesothelium in male rats, blood vessels in male and female mice, and liver in female mice.
The mechanisms by which ortho-toluidine causes cancer are not fully understood. They likely include metabolic activation to reactive metabolites that bind DNA and proteins, mutagenicity, oxidative DNA damage, chromosomal damage, and cytotoxicity. Metabolic activation and genotoxic effects occur in both experimental animals and exposed humans.
NTP cancer hazard conclusion
The conclusion of the cancer hazard evaluation was that ortho-toluidine should be listed as known to be a human carcinogen in the RoC. The Secretary of Health and Human Services approved the listing of ortho-toluidine in the 13th RoC. The rationale for the listing was sufficient evidence from studies in humans and supporting studies demonstrating the biological plausibility of mechanisms of its carcinogenicity in humans.
National Toxicology Program (NTP). 2014. Report on Carcinogens monograph on ortho-toluidine. Research Triangle Park, NC: National Toxicology Program. RoC Monograph 04. https://doi.org/10.22427/ROC-MGRAPH-04