Registration Dossier

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Species:

rat

A one generation study and a developmental study are available on Dimethylcarbonate (DMC).

The one-generation reproductive toxicity study was performed by the Research Toxicology Centre, Italy, on behalf of Polimeri Europa, Italy, to assess the effects of the test substance Dimethylcarbonate on reproduction in rats. The study was conducted in compliance with GLP, and in accordance with OECD test guideline 415.

The test substance was administered by oral gavage at levels 5, 50, and 500 mg/kg/day, and a vehicle control group was also used. Males were dosed for 10 weeks before pairing until the day before sacrifice, and females were dosed 2 weeks before pairing, during gestation and lactation until day 21 post partum. Males were sacrificed after mating, and females and pups were sacrificed on day 21 post partum.

The results of the study indicate that the test item, Dimethylcarbonate at the dosages administered did not induce negative effects on male or female rats or on the development and behaviour of their offspring. On the basis of these results a dosage of 500 mg/kg/day can be judged as the NOEL.

It was noted that the OECD guideline test 415 was not the typical test used to screen for reproductive toxicological effects; OECD 421 is the test suggested in the REACH Legislation (Annex VIII, endpoint 8.7.1). For the purposes of REACH registration, this OECD 415 test will be used in place of the OECD 421 test, as it is a more robust test assessing a compatible toxicological endpoint.

In the developmental study by inhalation in CD-1 mice, maternal toxicity and fetal malformations occurred at the highest concentration of 3000 ppm (achieved dose estimated to be approx. 3810-3975 mg/kg bw/day, according to the formula in Alexander 2008); no effects were seen at 1000 ppm (achieved dose estimated to be approx. 1270-1325 mg/kg bw/day, according to the formula in Alexander 2008).

Some or all of the fetal findings at 3000 ppm could be attributed to methanol that is expected to be generated when DMC is dosed at very high concentrations. A possible mechanism for the appearance of methanol at this dose would be the saturation of catalase and consequent steep increase in blood levels of methanol between 1000 and 3000 ppm.

Fetal malformations related to treatment occurred only at the highest, maternally toxic, dosage. It is considered likely that these high-dose effects can be attributed to methanol formed by metabolism of DMC.

Waiving of the 2-generation study:

According to the SIDS 2003 assessment, the main route of exposure would be the inhalation route: “There is potential for inhalation exposure to DMC in the workplace (…). Occupational exposures via dermal and oral routes are considered to be very low in relation to doses causing acute lethality in animal studies.”

The 2-generation study by oral route is very unlikely to bring additional information, as no sign of reproductive toxicity was observed in the one-generation study or in the 90-day repeated dose study.

According to the SIDS 2003,“The occupational exposure levels since 1997 to 1999, for 8 hours TWA, were always below 2 ppm^[1]”.The NOEL in the developmental inhalation study on mice being 1000ppm - which is 500 times higher than the existing exposure levels, the margin of safety is sufficiently important to assume that no toxic effect will occur. As no human exposures (worker or general population) will occur at such high levels on a daily basis, it would be not relevant to test such high doses in a two-generation study (unrealistic conditions). At lower concentrations (1000ppm and below), no toxicity is expected.

In cases of accidental releases (which are not supposed to be considered in the Risk assessment in REACh), workers could possibly be exposed to higher concentrations. But in those situations, DMC is not expected to be in contact during two generations or even an entire gestation period.

The two generation study is therefore scientifically unjustified and is proposed to be waived. We therefore meet one of the aims of REACh, which is reducing the number of animals used for testings.

[1]EniChem unpublished data

Alexander D.J., Collins C.J., Coombs D.W., et al. (2008). Association of Inhalation Toxicologists (AIT) working party recommendation for standard delivered dose calculation and expression in non-clinical aerosol inhalation toxicology studies with pharmaceuticals. Inhalation Toxicology, 20, 1179-1189.

Short description of key information:
In a one generation study, conducted according to OECD 415 guideline and in compliance with GLP, realised in rats to assess the effects on reproductive performance of the test material Dimethylcarbonate (Research Toxicology Centre 2007, 9039), the NOEL for F0 parent animals and F1 offspring were both considered to be 500mg/kg/d.

In a pre-natal development study, conducted according to OECD 414 guideline and in compliance with GLP, CD-1 mice were treated with Dimethylcarbonate during and beyond the organogenesis phase of gestation (Exxon 1982, report 107334, cited in the SIDS 2003 on Carbonic acid dimethylester CAS No. 616-38-6). Maternal toxicity and fetal malformations occurred at the highest concentration of 3000 ppm (achieved dose estimated to be approx. 2500 mg/kg bw/day); no effects were seen at 1000 ppm (achieved dose estimated to be approx. 820 mg/kg bw/day). The NOEL for both maternal toxicity and teratogenicity was 1000 ppm (3684 mg/m3).

In the pre-natal development study, conducted according to OECD 414 guideline and in compliance with GLP, CD-1 mice were treated with Dimethylcarbonate during and beyond the organogenesis phase of gestation (Exxon 1982, report 107334, cited in the SIDS 2003 on Carbonic acid dimethylester CAS No. 616-38-6).

Some or all of the fetal findings at 3000 ppm could be attributed to methanol, that is expected to be generated when DMC is dosed at very high concentrations.

A possible mechanism for the appearance of methanol at this dose would be the saturation of catalase and consequent steep increase in blood levels of methanol between 1000 and 3000 ppm.

DMC shows fetal effects only at a dose that is also maternally toxic. This should allow you to say that DMC should not be classified for developmental toxicity, because effects reported occurred at maternally toxic dosage.