ortho-Toluidine and Cancer

o-Toluidine is a man-made liquid. Its other name is 2-methylbenzenamine. Safety sheets list it as CAS 95-53-4. Fresh, it is pale yellow. It darkens quickly in air and light. It belongs to a family of industrial chemicals called aromatic amines. Several members of that family are known to cause bladder cancer, including benzidine and 2-naphthylamine.

Three uses account for most of it:

• Rubber chemicals. These are the additives that make rubber tough and slow to age.
• Pesticide building blocks, mainly 4-chloro-o-toluidine and 6-ethyl-o-toluidine. The second one is used to make the weed killers metolachlor and acetochlor.
• Dyes and pigments. More than 90 dyes and pigments are made from it, either directly or through other intermediates.

Smaller uses include making the local anesthetic prilocaine, staining tissue for the lab, and mixing a reagent that measures glucose in blood samples. It is a high-production-volume chemical. EPA data put combined US production and imports at 50 million to 100 million pounds in 2015.

The federal listing rests on six studies in people. Three followed dye workers over time (Case and Pearson 1954, Ott and Langner 1983, Pira and colleagues 2010). Two followed rubber-chemical workers (Sorahan 2008, Carreón and colleagues 2014). One was a population-based case-control study (Richardson and colleagues 2007).

NTP called one study the most informative of the set. It is the NIOSH study of US rubber-chemical workers published by Carreón and colleagues in 2014. It had the best measurement of how much o-toluidine workers actually met, and of the other chemicals they met at the same time.

Four of the studies allowed enough latency. Latency is the waiting time between first exposure and a cancer showing up, and a study that is too short will miss real cases. All four found extra bladder cancer. Risk went up with the level of exposure, with how long the exposure lasted, and with time since it started. Two studies found no excess. NTP judged that one of those had very little power to detect an effect, and that exposure was probably misclassified in both.

The Report on Carcinogens is the federal list kept by the National Toxicology Program. It has two levels. The lower one is "reasonably anticipated to be a human carcinogen." The higher one is "known to be a human carcinogen."

o-Toluidine started at the lower level. It was first listed in the Third Annual Report in 1982, based on animal studies alone. Its salt form, o-toluidine hydrochloride, had been listed a year before that. The human studies published later changed the picture. The listing moved up to "known to be a human carcinogen" in the Thirteenth Report in 2014. It sits at that level in the current Fifteenth Report.

Three strands hold that listing up. Human studies show bladder cancer. Animal studies show cancer at several sites, including the bladder in rats, so the target organ matches. Mechanism studies show a plausible way it could do the same thing in people.

IARC, the cancer research arm of the World Health Organization, reviewed it in Volume 100F, published in 2012. That volume re-examined agents already classified as carcinogenic to humans, which is IARC's Group 1, and o-toluidine is one of the agents it covers.

Two routes get this chemical into the body: breathing the vapor, and touching the liquid. Both OSHA and the ACGIH attach a skin notation to o-toluidine. That notation is a formal flag. It means enough of the chemical can pass through intact skin to matter, so testing the air alone can badly understate the real dose.

Urine testing shows how wide the gap is between a job and ordinary life. In one study, urinary o-toluidine ran more than 26 times higher in exposed workers than in unexposed ones. Biological monitoring also finds low levels in people with no job exposure, in smokers and non-smokers alike. Hospital and laboratory staff meet small amounts through the glucose reagent and tissue-staining uses.

• OSHA permissible exposure limit: 5 parts per million, averaged over a shift, with a dermal-absorption flag. This is the enforceable rule.
• ACGIH threshold limit value: 2 ppm, also with a skin notation. This is a guideline, not a law.
• NIOSH immediately dangerous to life and health level: 50 ppm. NIOSH also lists o-toluidine as a potential occupational carcinogen.

NTP adds a warning about the OSHA figure itself. That limit was adopted from a 1968 ACGIH value shortly after OSHA was created. NTP writes that it "may not reflect the most recent scientific evidence and may not adequately protect worker health."

Other federal rules attach as well. It is a hazardous air pollutant under the Clean Air Act. Its reportable quantity for a spill under CERCLA is 100 pounds. Its hazardous waste codes under RCRA are U222, U328, K112, K113 and K114. The Department of Transportation treats it as a hazardous material and a marine pollutant.

Sensible control follows from the skin route. That means closed transfer instead of open pouring, local exhaust at the point of release, chemical-resistant gloves and suits, immediate change out of splashed clothing, and washing before breaks.

Exposure that happened decades ago can still be the relevant history today, because bladder cancer often takes many years to appear. Two practical things follow.

First, put the job history in writing where your care team can see it: the industry, the years, and the tasks. A history of dye, rubber-chemical or pesticide-intermediate work changes how a doctor reads a finding like blood in the urine. Our page on bladder cancer covers how that symptom is worked up.

Second, do not treat this as one isolated chemical. Aromatic amines were often used together in the same plants, and exposure records are usually incomplete. Our pages on benzidine and on carcinogens at work explain how these exposures are grouped and why old job records matter.

• NTP Report on Carcinogens, Fifteenth Edition — o-Toluidine profile (PDF)
• IARC Monographs Volume 100F — Chemical Agents and Related Occupations
• OSHA Annotated Permissible Exposure Limits, Table Z-1
• NCI — Cancer-Causing Substances in the Environment