| Front page | | Contents | | Previous | | Next |

Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

19   Animal toxicity

19.1   Single dose toxicity

19.1.1   Inhalation

The LC₅₀-value in rats was reported to be 164000 ppm (313000 mg/m³) after 4 hours of exposure (Daly & Kennedy 1987).

At exposure levels of 10000 ppm (19000 mg/m³), rats showed slight sedation and at 50000 ppm (96000 mg/m³) rats were asleep most of the time for exposures longer than 30 minutes (Daly & Kennedy 1987).

The LC₅₀-value in mice was reported to be 490000 ppm (936000 mg/m³) after 15 minutes of exposure and 380000 ppm (~726000 mg/m³) after 30 minutes exposure (Daly & Kennedy 1987).

The exposure to 120000 ppm (229000 mg/m³) for 20-25 minutes was reported to cause light narcosis in mice (Meyer & Gottlieb-Billroth 1921 - quoted from A&H 1995).

Besides effects on the central nervous system (CNS) and the blood profile, DME was reported to cause weak cardiac sensitisation in dogs exposed for 5 minutes to 200000 and 300000 ppm (382000 and 573000 mg/m³) DME, but not at 100000 ppm (~191000 mg/m³) (Daly & Kennedy 1987).

19.1.2   Oral intake

No data have been found.

19.1.3   Dermal contact

No data have been found.

19.1.4   Other routes

Intraperitoneal doses of 5 mg/kg of DME produced reversible anaesthesia in mice (no further details are given) (Gosselin et al. 1984).

19.2   Repeated dose toxicity

19.2.1   Inhalation

Rats exposed to up to 50000 ppm (96000 mg/m³) of DME (6 hours/day, 5 days/week, 2 weeks) showed the following effects: At 10000 ppm (19000 mg/m³), slight sedation. At 50000 ppm (96000 mg/m³), sedation, body weight gain suppression, minor haematological changes (a small increase in the number of leucocytes and perhaps a decrease in the number of red blood cells), and organ weight changes (in relative liver and kidney weights), but no histopathological organ changes. All changes seen during the two-week exposure period were completely reversed following a two-week recovery period. (Daly & Kennedy 1987).
In the same study, 4-week inhalation exposures of DME to rats and hamsters were conducted. Rats were exposed to up to 10000 ppm (19000 mg/m³) and hamsters to up to 20000 ppm (38000 mg/m³). There were no toxicological changes seen and particularly no signs of sedation in the hamsters exposed to 20000 ppm (38000 mg/m³) (Daly & Kennedy 1987).

In a 4-week study, rats were exposed to DME at concentrations of 1, 100, 1000, or 10000 ppm (1.9, 190, 1900, or 19000 mg/m³) for 6 hours/day, 5 days/week. Observations were made of behaviour, growth, food intake, haematology, urine composition, organ weights, and gross as well as microscopic pathology. None of the parameters investigated revealed any distinct treatment related effects. (Kruysse 1976 - quoted from IUCLID 2000).

In a study in which rats were exposed to DME (0, 2000, 10000, or 20,000 ppm - 0, 3800, 19000, or 38000 mg/m³) for up to 13 weeks, 6 hours/day, 5 days/week, altered blood profile (reduced percentage of lymphocytes and increase of neutrophilic white blood cells) was noted at the highest dose level (20000 ppm- 38000 mg/m³). Male rats of the top-level group showed a minimal, though statistically significant, increase in serum glutamate pyruvate transaminase (SGPT) activity. Total serum protein was slightly, but statistically significantly lower in females of the top-level group than in females of the control group. The reporters did not consider these changes biologically significant and thus, it was concluded that exposure of rats to 20000 ppm (38000 mg/m³) under the conditions of this study produced no effects of obvious toxicological significance. This conclusion was supported by the absence of chemically related significant gross toxic signs or abnormal histopathology. (Reuzel et al. 1981)

In a second 13-week study by Reuzel & Woutersen (1983 - quoted from IUCLID 2000), rats were exposed to DME at concentrations of 0, 1000, 5000, 10000 or 20000 ppm (0, 1900, 9600, 19000, or 38000 mg/m³). Health condition, behaviour and body weight did not change due to DME exposure. No toxicologically relevant significance was ascribed to a temporary difference in white blood cell counts in males. Neutrophil counts were higher in male rats at all test levels. A dose-effect relation could not be found. In view of the fact that increased neutrophil counts were also found in previous sub-chronic study, it was stated in the final conclusion that the no-effect level in rats was 10000 ppm (19000 mg/m³).

In a 13 week study in hamsters exposed to 0, 1000, 5000, 10000, or 20000 ppm (0, 1900, 9600, 19000, or 38000 mg/m³) for 6 hours/day, 5 days/week, the following observations were made: Exposures did not affect health condition, behaviour and body weights of hamsters. White blood cell counts and in particular absolute lymphocyte counts had decreased both in male and female hamsters, which had been exposed to 20000 ppm (38000 mg/m³). The difference concerning the absolute white blood cell counts was not statistically significant. The difference in absolute lymphocyte counts was only significant on day 56. A number of other measured haematological values (no further information given) showed a significant difference compared with values found in the animals of the control group. For several reasons the investigators considered these differences to be of no importance.The investigators concluded that the no-effect level for DME in hamsters was 5000 ppm (9600 mg/m³), as at concentrations of 20000 and 10000 ppm (38000 and 19000 mg/m³) a decrease in white blood cell counts and lymphocyte counts occurred. (Reuzel & Woutersen 1983 - quoted from IUCLID 2000).

In a 30-week study, rats were exposed to 0.02%, 0.2%, or 2% v/v (0, 200, 2000, or 20000 ppm – 0, 380, 3800, or 38000 mg/m³) of DME in air, 6 hours/day, 5 days/week. There was no evidence that exposure to DME at any dose level had a toxicologically significant effect on body weight or food consumption. There were no toxicologically significant clinical signs in animals from any of the groups during the 30 weeks of the experiment nor were there any significant ophthalmoscopic findings. (Collins et al. 1978).
The only abnormalities in blood chemistry concerned the SGPT and SGOT (serum glutamate oxaloacetate transaminase) levels. At 24 weeks, there were abnormally high SGPT values in a few rats in both the male and female high-dose groups, suggesting the possible onset of a hepatotoxic effect of DME. At week 27, SGPT levels showed no differences between groups for either sex. However, at the end of the study there was a statistically significant increase in SGPT for both males and females of the high dose group (20000 ppm - 38000 mg/m³) when compared with the control group. There was a statistically significant increase in SGOT levels in the male medium dose group (2000 ppm- 3800 mg/m³).
The only organ weight measurement that indicated a toxicological effect was that of the liver of the high dose male rats. There was a statistically significant reduction in liver weight relative to body weight in this group compared with the control group (P< 0.05). The unusual event, that decreased liver weights are accompanied with increased GPT levels, was explained as a possible hepatic fibrosis, which was insufficiently severe to be detected by routine histopathological examination. There were no histopathological changes seen that were considered to be related to exposure of the rats to DME.

Rats were exposed to DME by inhalation for 104 weeks, 6 hours/day, 5 days/week. The concentrations were 2000, 10000, or 25000 ppm (3800, 19000, or 48000 mg/m³). There was no specific tissue damage, as indicated by either clinical function studies or morphologic studies of the tissues examined at the end of the study. Haematology and clinical pathology studies conducted at three-month intervals during the two years showed no evidence of change. Female animals in both the 10000 and 25000 ppm (19000 and 48000 mg/m³) groups showed a slight decrease in mean survival time. The decrease was not statistically significant, but it was different from that seen either at the low level or in the control subjects. According to the authors, the no-effect level was 20000 ppm (38000 mg/m³). (Daly & Kennedy 1987).
It should be noted that the no-effect level concluded by the authors is not one of the concentrations used in the study.

19.2.2   Other routes

No information on repeated dose toxicity following oral, dermal or other routes of exposure were found.

19.3   Toxicity to reproduction

19.3.1   Inhalation

Two developmental studies have been reported for DME.

In the first study, female rats were exposed to concentrations of 0, 1250, 5000, 20000, or 40000 ppm (0, 2400, 9600, 38000, or 76000 mg/m³) of DME, 6 hours/day, from days 6 to 15 of gestation. Animals exposed to 5000 ppm (9600 mg/m³) or more showed some evidence of narcotic effect, somewhat proportional to dose. At a concentration of 40000 ppm (76000 mg/m³), these female animals showed a suppression of body weight gain. There was no evidence of any teratogenic effect on the foetuses. There was no increase in foetal resorption. At concentrations of 20000 and 40000 ppm (38000 and 76000 mg/m³), there was some evidence that the foetuses were somewhat smaller, and that foetal variations such as ossification of the rib bones and some of the phalangeal bones in the extremities of these animals was somewhat retarded. These findings the reporters considered as variations reflecting developmental delay rather than a specific effect on the foetus. (Daly & Kennedy 1987).

In the second study, female rats were exposed to concentrations of 0, 20000, or 28000 ppm (0, 38000, or 53000 mg/m³) of DME from days 6 to 15 of gestation. The researchers did not find any signs of narcosis in the maternal animals. Maternal body weight gain was normal. There was a slight increase in the number of extra ribs in the foetuses at both levels tested; the increase was statistically significant, yet there was no dose-response. No gross malformations were noted in these offspring, and embryo mortality was not reflected by increased resorptions. (Daly & Kennedy 1987).

19.3.2   Other routes

No information on reproductive and developmental effects following oral, dermal or other route of exposure were found.

19.4   Mutagenic and genotoxic effects

19.4.1   In vitro studies

DME was not mutagenic when tested in the Ames test with and without metabolic activation in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 at a concentration of 119000 ppm (Willems 1978 - quoted from IUCLID 2000).

Mutagenic effect of DME could not be shown in V79 Chinese hamster cells in suspension with 230, 460, 1150 and 3450 mg/l DME (Kramers et al 1981 - quoted from IUCLID 2000).

No induction of DNA-repair synthesis was observed at any dose level when primary rat liver cells were exposed to 230, 460, 1150, 2300, or 3450 mg/l DME (Kramers et al. 1981 - quoted from IUCLID 2000).

19.4.2   In vivo studies

Progeny examination led to the conclusion that DME was not mutagenic under the test conditions when Drosophila melanogaster was exposed to 8000 or 28000 ppm (15000 or 53000 mg/m³) for 3 days or 28000 ppm (53000 mg/m³) for 14 days (Kramers et al. 1981 - quoted from IUCLID 2000).
In the host mediated assay in mice, exposure to 10000 or 20000 ppm (19000 or 38000 mg/m³) for 3 hours gave negative results (DGF 1992  - quoted from A&H 1995).

19.5   Carcinogenic effects

In a 104-week study in rats exposed to 2000, 10000, or 25000 ppm (3800, 19000, or48000 mg/m³) of DME, there was no evidence of increased tumour formation in any of the tissues or organs of the animals (Daly & Kennedy 1987).

No data on carcinogenic effects following oral, dermal or other route of exposure were found. 

| Front page | | Contents | | Previous | | Next | | Top |