Dimethyl ether

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Based on stability of DME and lack biological interaction, there is no MoA available for DME below concentrations that are relevant for hazard testing of gases of 20'000 ppm (OECD GD 39).

An extended (including full litter exposures up to weaning) OECD 422 study with DME at 1.6% (the maximum attainable concentration based on LEL of 3.2%). The NOAEC for fertility and reproductive performance as well developmental toxicity in the offspring was at least 1.6% (16000 ppm) for male and female Wistar rats.

The authors of two available independently performed PNDT studies in rat conclude that DME did not induce any teratogenic effect in rat fetuses following pre-natal exposure up to 4% in the air, and DME was not demonstrated to represent a unique hazard to the rat conceptus.

No adverse effects on reproductive organs or tissues were observed in a 2-year repeated inhalation study involving exposure to DME up to 2.5% for 6 hr/day.

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Quality of whole database:

Study is technically not feasible.

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

16 000 ppm

Study duration:

subchronic

Species:

rat

Quality of whole database:

GLP, Guideline study. DME has shown consistent lack of effects up to concentrations relevant for hazard testing of gases of 2% or 20'000 ppm (OECD GD 39) in developmental toxicity studies and a reproduction study involving exposure of litters up to weaning.

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Quality of whole database:

Study is technically not feasible.

Additional information

In a modified OECD 422 study, the test compound Dimethyl ether was administered daily as gas to groups of 10 male and 10 female healthy young Wistar rats (F0 animals) by whole-body exposure to screen for potential systemic, reproductive and developmental toxicity. After a two-week premating period, these parental animals were mated and the females were allowed to give birth and bring up the offspring until sacrifice on PND 4, PND 13 or shortly after weaning. Selected offspring (subsets II and III) was subjected to specific neurotoxicity testing and neuropathological investigations.

Target concentrations were 0%/ 0 ppm (test group 0), 0.2%/ 2000 ppm (test group 1), 1%/ 10000 ppm (test group 2) and 1.6%/ 16000 ppm (test group 3). The level of 16000 ppm was 50% of the LEL (Lower Explosive Limit). 

The duration of treatment covered a 30 days in-life period in males, including a 2-weeks premating period and mating period. In females the duration of treatment covered a 2-weeks premating period as well as the mating, gestation and lactation periods (with a break from GD 20 until PND 3), in total about 51 days of exposure were reached. Pups were exposed directly from PND 4 until PND 21.

Test item concentrations in the inhalation atmospheres were 0%/ 0 ppm (test group 0), 0.2%/ 2000 ppm (test group 1), 1%/ 10000 ppm (test group 2) and 1.6%/ 16000 ppm (test group 3). Real time surveillance confirmed the overall accuracy and stability of the test item concentrations in the inhalation atmospheres.

Dimethyl ether caused temporary signs of reduced well-being in male parental animals (decreased food consumption) at a concentration of 16000 ppm at the beginning of treatment. This was, however, considered part of the adaptation of these animals to the inhalation procedure and not as systemic toxicity. Thus, the no observed adverse effect concentration (NOAEC) for general systemic toxicity was at least 1.6%/16000 ppm for male and female Wistar rats.

No findings were noted on reproduction or development. The NOAEC for fertility and reproductive performance was at least 1.6%/16000 ppm for male and female Wistar rats.

Slightly decreased mean body weight/body weight gain of F1 offspring at 16000 ppm was considered to be a consequence of the direct exposure of the animals and not as developmental toxicity. The NOAEC for developmental toxicity in the offspring was therefore at least 1.6%/16000 ppm.

The NOAEC for neurotoxicity and developmental neurotoxicity was at least 1.6%/16000 ppm for male and female F0 and F1 Wistar rats.

 

Supportive data indicating lack of adversity comes from a 2-year chronic study with DME. In this study male and female rats were exposed to either 0, 0.2, 1 or 2.5% (v/v) DME via inhalation for 24 months. No histopathological or weight changes were observed in reproductive organs at any concentration tested.

 

Further supportive data comes from two available PNDT studies. The authors of these two independently performed PNDT studies in rats concluded that DME did not induce any teratogenic effect in rat fetuses following pre-natal exposure up to 4% in the air, and DME was not demonstrated to represent a unique hazard to the rat conceptus.

 

 

DME is a gas, which does not show biological interactions, doesn't bind to receptors, and thus also doesn't undergo metabolic transformation. In these respects, is differs from DEE, and does more resemble the noble gases.

DME is well soluble in water. Presence in the body comes from completely passive diffusion from concentrations in the air, leading to an equilibrium of the partial DME pressure in the tissues and in the air. At very high concentrations the passive presence of DME in the membranes of cells, can lead to neuro-depression and at increasing concentrations even to narcosis. After bringing the organism back in fresh air without DME the DME will just as fast completely diffuse out of the body again, leading to a complete recovery. The same as is the case with noble gases.

Important to note for this is that the rapidity of the development of these symptoms ensures that the acute narcotic effects of DME is due to DME itself and not to metabolites. Repeated dose studies can be seen as consecutive daily (6-hour) acute toxicity studies. After ceasing the exposure, no DME is left in the body to exert any effect.

The highest possible exposures comes from spraying applications from the use of DME as propellant. The maximum concentration (ConsExpo web 1.1.0- propellants in spray paints) is estimated to be 230 ppm (440 mg/m3).
For DME, no toxicological hazard has been identified up to 25'000 ppm, above the limit concentrations of 20'000 ppm for gases in air relevant for hazard testing. Current safety guidelines prohibit the testing of DME above 1.6% (being 50% of the LEL of DME od 3,2%) it is clear that further testing for reproduction parameters would not lead to useful additional data. Also in view of lack of relevant exposures, further studies are not called for.

Effects on developmental toxicity

Description of key information

There are two independently performed PNDT studies in rats performed from which is concluded that DME does not induce any teratogenic effect in rat fetuses following pre-natal exposure up to 4% in the air, and that DME does not represent a unique hazard to the rat conceptus.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Quality of whole database:

Study is technically not feasible.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

75 370 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Two studies of appropriate quality are available. The information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Quality of whole database:

Study is technically not feasible.

Additional information

There are two independently performed PNDT studies in rats performed from which is concluded that DME did not induce any teratogenic effect in rat fetuses following pre-natal exposure up to 4% in the air, and that DME does not represent a unique hazard to the rat conceptus.

 

DME- Developmental toxicity / teratogenicity rat, Haskell, HLR-459-81, 1981

Groups of pregnant rats were exposed to the test substance by inhalation at concentrations of 0, 5000, 20000 and 40000 ppm (Part I - RF) and 0, 1250, 5000, and 20000 ppm (Part II - full study) from days 6 -15 of gestation. Before sacrifice, data were collected on clinical signs, feed consumption and body weight. On day 21 of gestation, all surviving dams were sacrificed and examined for gross pathologic changes, and their reproductive status was determined. Their fetuses were weighed, sexed, and examined for external, visceral, and skeletal alterations.

Part 1 (RF):

Dams exposed to the test substance at the 40000 ppm level showed no response to a sound stimulus during exposure and gained significantly less weight during the early exposure period than did the control dams. In the groups exposed to the lower levels, the only test substance-related effect demonstrated among the dams was a slight decrease in response to sound at 20000 ppm: the response of the 5000 ppm exposure group was described as ‘equivocal’.

Fetuses: weighted, sexed, examined for external, visceral and skeletal alterations.

Results: at 4% no response to sound stimuli and lower increase in BW; other groups were indistinguishable.

No maternal organ changes observed; no differences in liver weight all groups. No effects on reproductive status.

 

Part 2 (Main study):

(4% was not selected because the safety precautions in view of explosion risks used in Part I could not be employed in the larger chambers needed for Part II.)

Fetuses: weighted, sexed, examined for external, visceral and skeletal alterations.

Results: 2% showed slightly decreased response to sound. No difference in BW.

No maternal organ changes observed; no differences in liver weight all groups; no differences in incidence of pregnancy, corpora lutea,

implantations, resorptions, stunted fetuses, or in the number of live fetuses per litter. However at 2% fetal weight was only just significant lower in one specific statistical test (one-tailed Mann-Whitney U test; p = 0.045) (See attached graph: no effects at 2%)

Not teratogenic at any level.

At 0.5% and 2% showed an increased incidence of several skeletal variations. The reports therefore select NOEC of 0.125%.

"The skeletal changes noted were those regarded as being normal variants which signified that the dam was stressed sufficiently to express developmental instability inherent in the species. In comparison to maternal effect levels, DME was not demonstrated to represent a unique hazard to the rat conceptus."

(Separate report in which the investigators of both Haskell and TNO jointly evaluated both PNDT studies from Haskell and TNO concludes that in this study 2.0% is the NOAEC)

Conclusion: NOAEC = 2.0% DME in air

 

DME - Developmental toxicity / teratogenicity rat, TNO, V81.064, 1981

In a second developmental toxicity study via inhalation, pregnant Wistar rats were exposed to test atmospheres containing 0 (control), 2.0 or 2.8% (0, 20000 or 28000 ppm) for 6 hours/day from day 6 -16 of pregnancy in a preliminary and a final study. No abnormalities in condition or behaviour were observed in either the preliminary or the final study. There was a slight reduction in BW gain in females of the high concentration group during the exposure period. Food consumption, autopsy findings and litter data were comparable between all groups in both studies. Visceral examination of foetuses of the final study did not reveal any abnormality attributable to the treatment. Skeletal examination revealed an increased incidence of supernumerary lumbar ribs in both the 2.0 and 2.8 percent concentration groups. It was concluded that under the conditions of the present embryotoxicity/teratogenicity studies the test substance at concentrations of 2.0 and 2.8% in the atmosphere induced only a non-concentration-related increase in the incidence of supernumerary lumbar ribs but did not have any teratogenic effect on rat fetuses. The NOEC for maternal toxicity was considered to be 2.0% (20000 ppm), the NOAEC for developmental toxicity 2.8% (28000 ppm, ca. 54000 mg/m3).

 

 

DME is a gas, which does not show biological interactions, doesn't bind to receptors, and thus also doesn't undergo metabolic transformation. In these respects, it differs from DEE, and does more resemble the noble gases.

DME is well soluble in water. Presence in the body comes from completely passive diffusion from concentrations in the air, leading to an equilibrium of the partial DME pressure in the tissues and in the air. At very high concentrations the passive presence of DME in the membranes of cells, can lead to neuro-depression and at increasing concentrations even to narcosis. After bringing the organism back in fresh air without DME the DME will just as fast completely diffuse out of the body again, leading to a complete recovery. The same as is the case with noble gases.

Considering that for DME no toxicological hazard has been identified up to 25'000 ppm, above the limit concentrations of 20'000 ppm for gases in air relevant for hazard testing, in several species tested (rat, mouse, hamster), and that the inert properties of DME are such that this will not be different in other species and sensitive individuals.

 

The highest possible exposures come from spraying applications from the use of DME as propellant. The maximum concentration (ConsExpo web 1.1.0- propellants in spray paints) is estimated to be 230 ppm (440 mg/m3).

For DME, no toxicological hazard has been identified up to 25'000 ppm, above the limit concentrations of 20'000 ppm for gases in air relevant for hazard testing. Current safety guidelines prohibit the testing of DME above 1.6% (being 50% of the LEL of DME od 3,2%). With lack of biological interactions further testing for developmental toxicity in other species would not lead to useful additional data. Also in view of lack of relevant exposures, further studies are not called for.

Justification for classification or non-classification

The test substance did not adversely affect reproductive organs and was not uniquely toxic to the developing fetus. The substance does not need to be classified for reproductive toxicity according the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.