5.1. Exposure data

1,2-Dichloropropane is a synthetic, chlorinated solvent that is a by-product of the manufacture of propylene oxide. 1,2-Dichloropropane is used primarily as a chemical intermediate in the production of other organic chemicals, such as propylene, carbon tetrachloride, and tetrachloroethylene. It is also used as solvent in several uses including paint stripping. Until 2012, it was used as a printing-press cleaner in Japan. There are no data as to whether it has been used for this purpose in other countries. 1,2-Dichloropropane was formerly used as one component of a grain and soil fumigant, although this use is no longer permitted in Europe and the USA. Inhalation is the primary route of exposure in occupational settings, and dermal contact can also occur. Occupational exposures of > 1 g/m³ have been estimated. Little information is available on exposure of the general population to 1,2-dichloropropane from environmental sources, but environmental air concentrations are likely to be very low.

5.2. Human carcinogenicity data

Investigations into the carcinogenicity of 1,2-dichloropropane were prompted by the recognition of a cluster of 17 cases of cancer of the biliary tract (identified histologically as cholangiocarcinoma) in a small offset-printing plant in Osaka, Japan. Subsequently, epidemiological and occupational hygiene investigations identified seven additional cases from four other small printing plants in Japan. Age of death or diagnosis for these cases was about 20–60 years; cancers of the biliary tract usually occur at later ages in the general population. Based on the results from the Osaka plant alone, the estimated relative risk for this rare and generally fatal cancer is extraordinarily high. Most workers at these plants were exposed to both dichloromethane and 1,2-dichloropropane at levels well above current international limit values, as well as to other solvents and inks. No studies of the association of cancer in humans with exposure to 1,2-dichloropropane in other countries or industries were available to the Working Group.

The exposure distribution of the full cohort in the Osaka plant was not described, but in the follow-up of about 100 workers until 2012, 17 cases were observed, of which 6 had no known exposure to dichloromethane. The Working Group estimated relative risks of approximately 900 for exposure to 1,2-dichloropropane. Seven additional cases of cancer of the bile duct were identified in subsequent reports from other Japanese printing plants. Of these, one case was exposed to high levels of dichloromethane without exposure to 1,2-dichloropropane. The other six cases were all exposed to 1,2-dichloropropane, four to both dichloromethane and 1,2-dichloropropane, and two to 1,2-dichloropropane with only negligible exposure to dichloromethane (< 1 ppm).

Given the rarity of the outcome, the young ages at diagnosis, the absence of other known risk factors among the cases, and the very high relative risk, as well as the specificity and apparent intensity of the exposures, the finding of a large excess of cancer of the biliary tract among the printing workers is extremely unlikely to be the result of chance and very unlikely to be due to bias or confounding.

5.3. Animal carcinogenicity data

There were two studies of carcinogenicity with 1,2-dichloropropane in mice: one study of oral administration (gavage) in males and females, and one study of inhalation in males and females. 1,2-Dichloropropane increased the incidences of hepatocellular adenoma and/or carcinoma in male and female mice after oral administration, of bronchiolo-alveolar adenoma and/or adenocarcinoma in male and female mice exposed by inhalation, and of splenic haemangiosarcoma in male mice exposed by inhalation. 1,2-Dichloropropane induced histiocytic sarcoma and Harderian gland adenoma in male mice exposed by inhalation.

There were two studies of carcinogenicity with 1,2-dichloropropane in rats: one study of oral administration (gavage) in male and female rats and one study of inhalation in males and females. 1,2-Dichloropropane increased the incidence of adenocarcinoma of the mammary gland in female rats after oral administration, and of papilloma of the nasal cavity in male and female rats exposed by inhalation, and probably induced rare olfactory neuroblastoma in the nasal cavity of male rats exposed by inhalation.

5.4. Mechanistic and other relevant data

1,2-Dichloropropane is a volatile lipophilic compound that is readily absorbed after oral, inhalation, or dermal exposure. After absorption, 1,2-dichloropropane is extensively distributed systemically, and metabolized to mercapturates excreted in the urine and in carbon dioxide in exhaled breath. Multiple pathways involving cytochrome P450 (CYP) and glutathione S-transferase-mediated conjugation with glutathione (GSH), both individually and in combination, may be responsible for the metabolism of 1,2-dichloropropane. Metabolites formed through the combination of GSH conjugation and CYP oxidation, or through CYP alone, do not appear to be reactive. The pathway involving GSH conjugation alone is plausible, based on similarities to other halogenated hydrocarbons such as trichloroethylene and methyl chloride, and may lead to formation of reactive, genotoxic metabolites. However, there is no direct evidence for the activity of the GSH conjugation-only pathway for 1,2-dichloropropane.

Genotoxicity with 1,2-dichloropropane has been observed in vitro in some mammalian (e.g. Chines hamster ovary cells) and non-mammalian systems (some strains of Salmonella), as well as in some in-vivo experiments in mice. No data on genotoxicity in humans or human-derived cells were available. While there was some evidence of genotoxicity in vivo and in vitro, the data were mixed and limited in extent.

1,2-Dichloropropane causes hepatic and renal toxicity, and haemolytic anaemia, in humans and rodents. Nasal, but not lung, toxicity has been reported in mice and rats exposed to 1,2-dichloropropane via inhalation. These data suggest that the hepatic, renal, haematopoietic, and respiratory systems are potential target tissues. Non-genotoxic mechanisms of carcinogenesis have not been identified.

Overall, given that there was some evidence for genotoxicity, the Working Group considered that the mechanistic evidence for 1,2-dichloropropane carcinogenesis is moderate.