Exposure limits and carcinogenic classifications have been recommended for hydrazines by such organizations as ACGIH, ATSDR, the US Environmental Protection Agency (EPA), IARC, NRC, and the Occupational Safety and Health Administration (OSHA). Those limits and classifications are summarized in Table 9.2.
Animal studies using inhalation, dermal, and oral exposures have been conducted on the absorption, distribution, metabolism, and excretion of hydrazines. The toxicokinetics of hydrazines appears to differ among animal species (ATSDR 1997), and there are differences in the metabolic pathways of hydrazine, UDMH, and MMH (ATSDR 1997).
Hydrazines are rapidly absorbed into the blood, and they and their metabolites are distributed to various tissues, such as the kidney, liver, lung, muscle, bladder, and pancreas (ATSDR 1997; Kaneo et al. 1984; Pinkerton et al. 1967). Plasma concentrations in male rats given UDMH subcutaneously at 50 mg/kg rapidly decreased after exposure, with a half-life of about 1 hour (Fiala and Kulakis 1981). UDMH was detectable in the blood of dogs within 30 sec of application (at 5–30 mmol/kg) to their shaved chests, but blood concentrations did not start to rise substantially for about 5 minutes (Smith and Clark 1971). Similar results were reported for cutaneous absorption of hydrazine (at 3–15 mmol/kg) (Smith and Clark 1972).
There does not appear to be preferential accumulation in specific tissues. Hydrazines with a free amino group are able to react with endogenous alpha-keto acids, which can produce adverse health effects (ATSDR 1997). Hydrazine undergoes acetylation and can react with cellular molecules in vivo (Kaneo et al. 1984; Llewellyn et al. 1986; Preece et al. 1991). UDMH undergoes demethylation and can react with cellular molecules (Mitz et al. 1962).
Evidence suggests that at least some hydrazines are metabolized by both enzymatic and nonenzymatic pathways (ATSDR 1997; Godoy et al. 1984; Tomasi et al. 1987). The metabolic process may be dose-dependent and saturable (Preece et al. 1992). Three cytochrome P450 isozymes (CYP2E1, CYP2B1, and CYP1A1/2) are involved in metabolism of hydrazine (Delaney and Timbrell 1995; Jenner and Timbrell 1994; Timbrell et al. 1982). Hydrazine has also been shown to be metabolized by another enzymatic pathway (peroxidases) and by a nonenzymatic pathway (a copper-ion-mediated pathway) (Sinha 1987). Hydrazine metabolism produces free radicals and carbonium ion intermediates that may be responsible for adverse health effects (ATSDR 1997). Koizumi et al. (1998) found that metabolism of hydrazine in humans is affected by genotypes of an isozyme of N-acetyltransferase, NAT2.
Hydrazines and their metabolites are excreted in urine and in expired air (ATSDR 1997). Llewellyn et al. (1986) reported that unchanged hydrazine, acetyl hydrazine, and diacetylhydrazine were found in the urine of hydrazine-treated animals.