o-Toluidine. Documentation of proposed values of occupational exposure limits (OELs)
Authors: Pałaszewska-Tkacz Anna , Świdwińska-Gajewska Anna , Czerczak Sławomir 
Published: September 2018

o-Toluidine is a substance produced in large amounts and used in rubber, dyeing and pharmaceutical industries and in the production of herbicide and other chemical compounds. The estimated number of people occupationally exposed to o-toluidine in EU is 5500, half of them is employed in chemical industry in the production of chemical fibers and rubber products.
In the conditions of occupational exposure, o-toluidine is absorbed by skin and by inhalation. Regardless of route of exposure this compound is excreted in urine.
The effects of acute inhalation exposure to high concentrations (>25 mg/m3) of o-toluidine are irritation of upper respiratory tract, irritation of eyes and skin, which is manifested by face, eyes and pharynx burning, cough, shortness of breath, weakness, nausea, vomit, headache and dizziness, tinnitus, methemoglobinemia, hematuria and hemorrhagic cystitis.
In epidemiological studies, the mostly analyzed group of substances was aromatic amines (including o-toluidine). Available data mainly refer to exposure in dyeing and rubber industries. Described effects of chronic exposure are methemoglobinemia, hematuria and damage of bladder epithelium leading to malignant tumor of this organ.
Carcinogenicity of o-toluidine was confirmed in tests on experimental animals, including rats and mice. Oral exposure to o-toluidine results in bladder cancer, primarily in female rats, to a lesser extent in male rats. In female rats F344 exposed to o-toluidine with feed, increase of the incidence of cancer from the bladder transitional cells was observed. Furthermore, in mice and rats fibromas and fibrosarcomas in subcutaneous tissue, angiomas and angiosarcomas in abdominal cavity and bladder, mesotheliomas of various organs, angiosarcomas in various organs, hepatocellular carcinomas and adenomas were observed.
In experimental animals, o-toluidine exhibits moderate acute toxicity, LD50 values for intragastric administration are within the range 670–2951 mg/kg bw. In acute toxicity studies, rats exposed by inhalation to o-toluidine had cyanosis, contractions and muscle tremor, difficulty in breathing, red-brown rhinorrhea, corneal opacification, body weight loss, body temperature decrease, lethargy and extreme exhaustion. The effects of subchronic and chronic exposure of experimental animals to o-toluidine described in the literature include changes in the spleen, hematopoietic system, kidneys and bladder.
Most of the mutagenicity tests in bacterial systems do not confirm mutagenicity of o-toluidine. A few works only described positive test result after metabolic activation. Both in vitro and in vivo studies confirmed induction of DNA damage by o-toluidine.
o-Toluidine has harmonized classification in the EU as a category 1B carcinogen with assigned phrase H350 – may cause cancer. SCOEL experts classified it to group A of carcinogens, which means carcinogens with genotoxic properties. In Germany, DFG has ranked o-toluidine into category 1 of carcinogens, so substances that cause cancer in humans and substances that are believed to significantly affect the risk of cancer. IARC classified it into group 1, compounds with confirmed human carcinogenicity.
On the basis of a quantitative assessment of the risk of cancer as a result of occupational exposure, it has been estimated that at a 40-year exposure period to o-toluidine at a concentration of 1 mg/m3, the additional risk of bladder cancer ranges from 2.4–3.1 · 10-4 (depending on the estimation method).
The values of the determining exposure limits of o-toluidine applicable in the EU member states and in the world are 0.5–0.9 mg/m3; 4.5–8.8 mg/m3 and 22 mg/m3. In Poland, the applicable OEL value is 3 mg/m3. In SCOEL, no BOELV had been proposed, considering o-toluidine as a genotoxic carcinogen. Directive 2017/2398 of the European Parliament and of the Council (EU) of 12 December 2017 amending Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work, a concentration of 0.5 mg/m3 was adopted (0.1 ppm) as a binding value for o-toluidine (based on socio-economic analysis, environmental risk assessment and risk of bladder cancer in professionally exposed workers).
It has been proposed to reduce the OEL value of o-toluidine to 0.5 mg/m3, which will affect a nearly tenfold reduction in the risk of bladder cancer workers. In addition, according to CSI (Chief Sanitary Inspectorate) data in Poland, no exposure to o-toluidine in concentrations >3 mg/m3 and >1.5 mg/m3 (0.5 OEL values) have been found in years 2015–2016, while in conditions of exposure to concentrations from within the range of 0.3–1.5 mg/m3 (0.1 ÷ 0.5 of the OEL value), a dozen or so people only worked.
There is no basis for determining the short-term exposure limit value (STEL). As a value of biological exposure index (BEI) of o-toluidine, it has been proposed to leave 2% level of the MetHb in the blood. The standard was labeled “skin” (the absorption of substances through the skin may be as important as in inhalation) and “Carc. 1B” (carcinogenic substance of category 1B).