1.1- Dimethylhydrazine, carcinogenicity

Balansky R, Blagoeva P, Mircheva Z, et al. 1992. Effect of metabolic inhibitors, methylxanthines, antioxidants, alkali metals, and com oil on 1,2-dimethylhydrazine carcinogenicity in rats. Anticancer Res 12 933-940. 

Neither an inhalation nor an oral slope factor is currently available for monomethylhydrazine. Slope factors for 1,1-dimethylhydrazine and 1,2-dimethylhydrazine were available but have been withdrawn from the U.S. EPA Integrated Risk Information System (IRIS) (U.S. EPA 1986). For a preliminary carcinogenicity assessment, the withdrawn inhalation slope factor for 1,1-dimethylhydrazine (cited in ATSDR 1994) will be used as a surrogate for monomethylhydrazine. The assessment follows previously described methodologies (NRC 1985 Henderson 1992). 

Both isomers of dimethylhydrazine have been shown to be carcinogenic in rodents following chronic oral exposure and 6-mon inhalation exposure to 1,1-dimethylhydrazine. Increased tumor incidence was observed in mice, although these findings are compromised by the contaminant exposure to dimethylnitrosamine. An increased incidence of lung tumors and hepatocellular carcinomas was also seen in rats but not in similarly exposed hamsters. The U.S. Environmental Protection Agency (U.S. EPA) inhalation slope factors are currently unavailable for dimethylhydrazine. 

Verified inhalation and oral slope factors were unavailable from U.S. EPA for dimethylhydrazine. A cancer assessment based upon the carcinogenic potential (withdrawn cancer slope factors) of dimethylhydrazine revealed that AEGL values for a theoretical excess lifetime 10 4 carcinogenic risk exceeded the AEGL-2 values that were based on noncancer endpoints. Because the risk for dimethylhydrazine exposure was estimated from nonverified sources and because AEGLs are applicable to rare events or single once-in-a-lifetime expo... 

No data are available regarding the potential carcinogenicity of dimethylhydrazine in humans. 

Two oral studies in rodents demonstrated the carcinogenic potential of dimethylhydrazines. Results of an inhalation study in mice showing an increased tumor response following exposure to 1,1-dimethylhydrazine may be compromised by the contamination of the test article with dimethylnitrosamine. Both inhalation and oral slope factors for the dimethylhydrazines have been withdrawn from IRIS. 

The derivation of AEGL values based upon potential carcinogenicity is shown in Appendix C. The assessment, following the methods of the NRC (1985), utilized an inhalation slope factor for 1,1-dimethylhydrazine. This slope factor, however, has been withdrawn from the U.S. EPA IRIS and, therefore, is of uncertain validity. Nonetheless, the assessment shows that acute toxicity is clearly more relevant as a basis for calculation of dimethylhydrazine AEGLs. 

Because the AEGL-2 values based upon acute toxicity were equivalent to or lower than the 10 4 risk values derived based on potential carcinogenicity, the acute toxicity data were used for the AEGLs for dimethylhydrazine. For 1CT5 and ICE6 risk levels, the ICE4 values are reduced by 10-fold or 100-fold, respectively. 

Toxicology. 1,1-Dimethylhydrazine is a respiratory irritant and convulsant it is carcinogenic in experimental animals. 

The carcinogenic risk to humans has not been determined, but 1,1-dimethylhydrazine is classified as a suspected human carcinogen based on animal results. The National Institute for Occupational Safety and Health (NIOSH) has also noted that the role of nitrosodimethylamine, a contaminant of 1,1-dimethylhydrazine, must be considered in evaluating the tumorigenicity of 1,1-... 

The 2003 ACGIH threshold limit value-time-weighted average (TLV-TWA) for 1,1-dimethylhydrazine is 0.01 ppm (0.025mg/m ) with an A3 confirmed animal carcinogen with unknown relevance to humans designation and a notation for skin absorption. 

The reaction of 1,1-dimethylhydrazine with O, gave the carcinogen A,A-dimethylnitrosamine as the major product in 60% yields within 2- to 3-min reaction time (Tuazon et al., 1981). Minor products were HCHO, H202, HONO, and perhaps NOc. For a discussion of the complex mechanisms, the reader should consult the original reference. 

L2-Dimethylhydrazine was tested for carcinogenicity in mice, rats and hamsters following oral and subcutaneous or intramuscular administration, producing tumours at various sites (lARC, 1974). 

Dimethylhydrazine is metabolized by a sequence of oxidation steps, first dehydrogenation to azomethane, A -oxidation of this to azoxymethane and finally a C-oxidation to methylazoxymethanol (Fiala, 1975, 1977). This last metabolite decomposes to give the highly reactive methyldiazonium ion to which the carcinogenicity of the compound has been attributed. The sequential nature of these oxidation steps has been shown in the isolated perfused rat liver (Wolter Frank, 1982). Fiala (1977) showed that the C-oxidation of azoxymethane to methylazoxymethanol is catalysed by hepatic microsomes, while Schoental (1973) found that methylazoxymethanol was converted to the corresponding aldehyde by an NAD-dependent dehydrogenase. 

Dimethylhydrazine was studied for carcinogenicity in many experiments in rats and mice, mainly by subcutaneous, infrequently by oral and rarely by other routes of administration. 

No epidemiological data relevant to the carcinogenicity of 1,2-dimethylhydrazine were available. 

Albanese, R., Mirkova, E., Gatehouse, D. Ashby, J. (1988) Species-specific response to the rodent carcinogens 1,2-dimethylhydrazine and l,2-dibromo-3-chloropropanc in rodent bone-marrow mieronueleus assays. Mutagenesis, 3, 35-38... 

Cameron, I.L., Ord, V.A., Hunter, K.E., Padilla, G.M. Heitman, D.W. (1989) Suppression of a carcinogen (1,2-dimethylhydrazine dihydrochloride)-induced increase in mitotic activity in the colonic crypts of rats by addition of dietary cellulose. Cancer Res., 49, 991-995... 

Malaveille, C., Brun, G. Bartsch, H. (1983) Studies on the efficiency of the SalmonellaRst hepatocyte assay for the detection of carcinogens as mutagens activation of 1,2-dimethylhydrazine and procarbazine into bacterial mutagens. Carcinogenesis, 4, 449-455... 

Newaz, S.N., Fang, W.-F. Strobel, H.W. (1983) Metabolism of the carcinogen 1,2-dimethylhydrazine by isolated human colon microsomes and human colon tumor cells in culture. Cancer, 52, 794-798... 

Osswald, H. Kruger, F.W. (1969) Carcinogenic action of 1,2-dimethylhydrazine in the golden hamster. Arzneim. Forsch., 19, 1891-1892 (in German)... 

Sykora, I., Vortel, V. Tretinik, P. (1986) Postnatal carcinogenic study of 1,2-dimethylhydrazine dihydrochloride in rats. Neoplasma, 33, 273-282... 

Toth, B. Patil, K. (1982) A carcinogenicity dose response study by continuous administration of 1,2-dimethylhydrazine dihydrochloride in mice. Anticancer Res., 2, 365-368... 

---