Phenylhydrazine and its salts – calculated on phenylhydrazine. Documentation of proposed values of occupational exposure limits (OELs)

Phenylhydrazine at room temperature is a colorless or yellow oily liquid, at lower temperatures it occurs in a form of a crystalline Phenylhydrazine is used in an organic synthesis as a powerful reducing agent or as an intermediate in synthesis of other chemical compounds, such as dyes and drugs. Phenylhydrazine is also used as a chemical reagent. At the beginning of the 20th century, phenylhydrazine was used as a drug in polycythemia vera and other blood disorders. Occupational exposure to phenylhydrazine and its salts may occur during the production, further processing and distribution of these compounds, and also during their use. In 2014, 711 people were exposed to phenylhydrazine in Poland (including 531 women), of which 2 people only were exposed to phenylhydrazine in the air at a concentration range> 0.1–0.5 of the MAC value (20 mg/m3) . Phenylhydrazine is classified as a toxic substance after oral administration, in contact with skin and after inhalation. The available literature describes several cases of human poisoning with phenylhydrazine with inhalation and through the skin. Adverse effects of phenylhydrazine exposure are progressive hemolytic anemia with hyperbilirubinaemia and urobilinemia, presence of Heinz bodies in red blood cells, impairment of renal and hepatic function as secondary symptom to the haemolytic activity of phenylhydrazine. Methemoglobinemia and leukocytosis sometimes occurred. General symptoms of poisoning included dizziness, diarrhea, general weakness and reduced blood pressure. Phenylhydrazine irritates the skin. Several cases of skin hypersensitivity reactions to phenylhydrazine and its hydrochloride have also been described. It has been shown that phenylhydrazine gives cross-reactions with hydrazine salts. In animals, the main symptoms of acute phenylhydrazine poisoning were the formation of significant amounts of methaemoglobin and its consequences: hemolysis, Heinz bodies formation, reticulocytosis, bone marrow hyperplasia, splenomegaly and liver damage. Motor excitation and tonic-clonic spasms were also observed. As a result of repeated exposure, it was found that phenylhydrazine also causes hemostatic disorders in addition to haemolytic anemia and leads to acute pulmonary thrombosis. The dose-effect relationship cannot be derived from existing data nor the NOAEL value be determined. Phenylhydrazine is an in vitro mutagen and some evidence points to its genotoxic activity in vivo (DNA methylation and fragmentation ). Phenylhydrazine and its salts have been classified as category 2 mutagenic substances. In the available literature and databases, no information was found on the carcinogenic activity of phenylhydrazine and its salts in humans. Carcinogenic activity of phenylhydrazine has been demonstrated in experimental animals. Exposure of mice via oral route resulted in the occurrence of lung tumors and tumors of blood vessels. The International Agency for Research on Cancer (IARC) does not classify phenylhydrazine and its salts as carcinogenic. In the European Union, phenylhydrazine and its salts have been classified as category 1B carcinogens. There is also insufficient data on the effect of phenylhydrazine on reproduction and developmental toxicity, so it is difficult to assess whether these effects may occur in humans exposed to phenylhydrazine and its salts. Based on the observed systemic effects in humans and animals exposed to phenylhydrazine and its salts, it can be assumed that these compounds are absorbed into the body by inhalation, oral route, through the skin and after parenteral administration. There are no quantitative data on the absorption efficiency of individual routes. The main metabolic pathways of phenylhydrazine are hydroxylation to p-hydroxyphenylhydrazine and formation of phenylhydrazones by reaction with natural keto-acids. Metabolites in the form of glucuronides are mainly excreted in the urine. The existing two studies of the carcinogenic activity of phenylhydrazine hydrochloride have shown that the compound administered via the oral route caused a significant increase in the formation of lung tumors or tumors of blood vessels. In the second study, despite the longer exposure time, no significant increase in lung cancer was observed. Although the results of both studies seem to be unreliable in the light of current criteria and are limited to one species (mice) only and one dose, on the basis of them, phenylhydrazine was classified in the EU as a carcinogen category 1B with the assigned phrase H350 - may cause cancer. A quantitative evaluation of phenylhydrazine carcinogenicity was performed using data on the incidence of lung cancer in mice of both genders exposed to phenylhydrazine hydrochloride, administered intragastrically at 1 mg/day. The model adopted for calculations shows that exposure to phenylhydrazine, at the level of the adopted MAC value in Poland (20 mg/m3) over 40 years of work, corresponds to the risk of lung cancer at the level of 5.7 · 10-2. Such risk is unacceptable. From the estimation of cancer risk, it appears that the current value of MAC for substance should be reduced. The existing database on the toxicity of phenylhydrazine and its salts is insufficient to derive a MAC value based on NOAEL/LOAEL values. Due to the mechanism of action and the main toxic effects (haematotoxicity), phenylhydrazine has an aniline-like toxicological profile. It was proposed that the MAC value for phenylhydrazine should be taken analogously to the MAC value for aniline, i.e. 1.9 mg/m3, which corresponds to the risk of lung cancer in occupational exposure conditions of 5.4 · 10-3. Due to the dermal absorption of phenylhydrazine, the "skin" notation has been proposed (absorption through the skin may be as important as in the case of inhalation). Additionally, due to irritating, sensitizing, carcinogenic and mutagenic effects of phenylhydrazine, the normative should be marked with the letters "I" (substance with an irritating effect), "A" (a substance with sensitizing effect), Carc. 1B (carcinogenic substance category 1B) and Muta. 2 (mutagen category 2). There are no evidence to establish the STEL and BEI values.