Dimethyl sulphate

Carcinogenicity

Description of key information

EU RISK ASSESSMENT – DIMETHYL SULPHATE

Justification for classification or non-classification

According to EC criteria DMS is classified as a category 2 carcinogen and labelled with R45.

Additional information

Oral

No data on carcinogenic properties of DMS after oral administration are reported.

 

Dermal

Dermal application of 0.1 mg DMS in 0.1 ml acetone 3 times per week for a period of 385 or 475 days in ICR/Ha Swiss mice (n=20) did not lead to of papillomas or carcinomas. Even when DMS was combined with the tumour promotor phorbol myristate acetate (2.5μg/0.1 ml acetone (n=20)) the number of papillomas and carcinomas did not exceed that in controls. The number of animals in these studies was limited and only one dose was tested. No findings on non-neoplastic changes were reported (Van Duuren, 1974). The study cannot be evaluated with regard to carcinogenic potential of DMS after dermal exposure.

 

Inhalation

BD-rats (sex unspecified) were exposed to 55 mg/m3(n=27) and 17 mg/m3(n=20) DMS in an inhalation chamber for 130 days (1 hr/d, 5 d/wk). It has to be noted that the concentrations mentioned were calculated, maximum concentrations and that the decrease of this maximal concentration with time was not taken into account. Several deaths due to inflammation of the nasal cavity or pneumonia were reported. Five of fifteen surviving rats in the high dose group developed malignant tumours: three squamous cell carcinomas of the nasal cavity, one tumour in the cerebellum, and one lymphosarcoma of the thorax with multiple lung metastases. In the low dose group of 12 surviving animals three were found with a squamous cell carcinoma of the nasal cavity, a brain neurinoma, or an esthesioneuroepithelioma of the olfactory nerve, respectively (Druckrey, 1970). This study points to carcinogenic properties of DMS, although only two dose groups were used, the number of animals was small and pathological examinations were minimal.

The very limited reporting of study design and results makes the evaluation of the study impossible.

In a 6 month-inhalation study groups of 90 male and female mice (CBAxC57BC/GI) were exposed to DMS at concentrations of 0.38±0.08, 1.62±0.17, or 20.26±1.34 mg/m3(2 hr per day, 5 days per week). A statistically significant increase in tumours was observed in the high and intermediate dose groups (mainly lung adenoma) (Molodkina et al., 1986). The very limited reporting of the study design and results makes the evaluation of the study impossible.

Male and female rats (Wistar), mice (NMRI), and hamsters (Syrian Golden) were exposed to 2.6 mg/m3DMS (6 hr/d, 2d/wk), to 10.5 mg/m3(6hr/d, 1d/2wk), or to a sublethal concentration (4 times per year for 1 hour, 178 mg/m3(rats), 252 mg/m3(mice), 105 mg/m3(hamsters)) for about 15 months (Schlögel, 1972). Animals were observed for at least 30 months after start of exposure. Examinations included clinical signs, mortality, body weights, lung weights, macroscopy, and histopathology. Histopathological examination was restricted to lungs and trachea. When gross examination revealed a tumour in other tissues/organs, this tissue/organ was included for histopathological examination.

After exposure, the behaviour of exposed animals was affected: animals were apathic, eyes were half-open or closed and breathing problems were apparent. These effects clearly showed a concentration dependency in severity, total duration and time of onset. Body weight gain in DMS-exposed hamsters, rats and mice was distinctly lower than in control animals. In general, survival in groups exposed to DMS was lower than in controls, but the mean survival time varied considerably between the various groups. A remarkable finding was the very low survival time in male and female rats of the 2.6 mg/m3group which was distinctly lower than the survival time in rats of the control or the 10.5 mg/m3group. The same phenomenon was seen in mice although less pronounced. The lower survival time in the 2.6 mg/m3group is probably due to the initial high exposure regimen applied to this exposure group.

An increase in the incidence of inflammation of the lungs was reported in DMS-exposed animals in all species. Bronchiopneumonia occurred to about the same degree in control and DMS exposed animals.

DMS exposure resulted in an increased incidence of malignant tumours in the respiratory tract (nose and lungs). Rats were most sensitive to the tumour inducing activity of DMS, while hamsters were the least sensitive. In all three animal species females appeared more sensitive than males. In female rats of the 10.5 mg/m3group the incidence of lung adenomas was slightly higher than in control females. There were no indications that DMS exposure induced an increase in subcutaneous fibromas. The highest incidence of animals with treatment-related malignant respiratory tract tumours was found in rats exposed to 10.5 mg/m3group. The incidence in the 2.6 mg/m3group was distinctly lower although the total dose in the low dose group was comparable or higher than that in the 10.5 mg/m3group. This lower incidence might be related to the lower mean survival time in the 2.6 mg/m3group, which in its turn may be a consequence of the initially high exposure scheme applied to this group.

Exposure to the sublethal DMS concentrations induced treatment-related tumours in rats only. In this context it must be realised that the exposure scheme applied for the sublethal concentrations leads to a lower total dose than that used with the 2.6 - and 10.5 mg/m3-groups. Moreover most animals of the sublethal groups have been exposed four times only. The study design does not fulfil to the requirements of OECD 451. However, the results of this study can be used to give a indication on the carcinogenic potential of DMS.

 

Other routes

BD-rats (no data on sex) were injected subcutaneously once a week (8 mg/kg, n=12, 394 days; 16 mg/kg, n=8, duration not indicated). In the low dose group one animal died preliminary of a liver carcinoma with metastases in lung and spleen; in the high dose group 2 rats died of pneumonia. A majority of surviving animals developed local (at the site of injection) sarcomas (all survivors at 16 mg/kg and 7 of 11 surviving animals at 8 mg/kg). After necropsy three of the surviving rats in the low dose group showed also metastases in the lung, lymph nodes, or kidneys, respectively. Two of the animals with local sarcomas in the high dose group were reported to have metastases in the lung (Druckrey, 1966).

A single dose of 50 mg/kgcaused death in 7 of 15 BD-rats between post-dosing days 314 and 740. The animals had large local sarcomas and three of them had multiple lung metastases (Druckrey, 1970).

Weekly dosing of 2 and 4 mg/kg DMS i.v. in BD-rats (12 per dosing group) for a period of 800 days did not induce any tumours (Druckrey, 1970). However, the report was very limited and several shortcomings in the study design were found.

Eight pregnant rats were dosed with DMS (single 20 mg/kg bw i.v.) at day 15 of gestation. The offspring (n=59) showed no apparent abnormalities and was raised for one year. During this period 7 animals developed malignant tumours in the brain, thyroid gland, liver and uterus. No other toxicological endpoints except carcinogenicity were evaluated (Druckrey, 1970). No information on controls was provided.

 

Conclusion

A number of carcinogenicity studies with DMS is available. However, the quality of these studies is limited; the number of animals is limited, dose-levels are high, and duration of exposure is in almost all cases short. Moreover, the studies suffer from limited reporting (e.g. no or limited information on histopathological findings). It is noted that OECD guidelines were not compulsory at the time the carcinogenicity studies with DMS were conducted. However, the inhalation study from Schlögel is considered only suitable for giving indication on the carcinogenic potential of DMS.

Information obtained from human studies is minimal and cannot be used for risk assessment. IARC concluded that DMS produces mainly local tumours in rats following inhalation or subcutaneous injection and that there is sufficient evidence to classify DMS as an animal carcinogen (2A). This conclusion is in agreement with the conclusion of the rapporteur. IARC’s statement on tumours of the nervous system after prenatal exposure of laboratory animals could not be verified by the rapporteur, because the data (Druckrey et al., 1970) submitted to the rapporteur were too scarce to allow a proper evaluation. Given the results of the mutagenicity studies, it is assumed that DMS acts via a genotoxic mechanism.