Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

The clinical significance of elevated levels of abnormal spermatozoa caused by certain substances in the non-guideline study performed in male C57BL mice by Land (1981) is not clear. Nonetheless, in the case of diethyl ether, no increased numbers of abnormal spermatozoa above the control animals was observed, after 4h/day for 5 consecutive days exposure at concentrations of 3200, 16,000, or 32,000 ppm.

The single dose inhalation study in Wistar rats conducted by Arena (2002) is considered not to be reliable due to the uncontrolled manner of exposure to diethyl ether. It cannot be ruled out that the effects observed, including a reduction in wet weight of seminal vesicles, a significant reduction in spermatids and spermatozoa in males, and a 26% reduction in pregnancy rate compared to controls, are the result of hypoxia on the developing animal, either due to the anaesthesia itself, or physical displacement of oxygen from the "exposure chamber" by the heavier diethyl ether vapour. Similar effects on development and fertility but caused by other non-chemical stressors, were cited from the literature by the authors. Again, the significance of a positive result in such a study design, and its relevance to humans, has not been validated and is unclear.

Short description of key information:

According to REACH (REGULATION (EC) No 1907/2006), a two-generation reproductive toxicity study is required according to column 1 of Annex IX, if the 28-day or 90-day study indicates adverse effects on reproductive organs or tissues. Based on observations of increased relative weights of testes/epididymides in rats treated with diethyl ether by oral gavage for 90 days (U. S. EPA, 1997) and of an increased number of abnormal sperm in rats exposed to diisopropal ether by inhalation for 90 days (Dalbey and Feuston, 1996), the registrant is proposing to read-across to a study to be performed using di-isoprpopyl ether according to OECD 416 (2-gene¬ration reprotoxicity study) resp. OECD 443 (extended one generation reproductive toxicity) whichever will be approved by ECHA.

Effects on developmental toxicity

Description of key information

430 ppm, NOAEC for rat, 6 hours/day on days 6 to 15 of gestation (Dalbey and Feuston)

73000 ppm, rat, 1 hour anaesthesia (Schwetz); no significant effects

65000 ppm, mouse, 1 hour anaesthesia (Schwetz); no significant effects

Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
1 800 mg/m³
Additional information

A key, non-GLP subchronic and developmental toxicity study of vaporized diisopropyl ether in rats was conducted equivalent to OECD Guideline 414 (Dalbey and Feuston 1996).

The registered substance, and the two read-across substances, DME and DIPE, all belong to the class of aliphatic ethers, each possessing two aliphatic alkyl groups connected by a single oxygen atom. Transition from DME to DEE and DIPE occurs with elongation of the aliphatic alkyl groups. DME possesses two methyl (C1) groups, DEE two ethyl (C2) groups and DIPE two isopropyl (C3) groups. These three mono-functional substances are considered to be members of a homologous series of aliphatic ethers, within which in general the properties of the individual homologues are expected to vary in a predictable manner, and in particular, the properties of DEE are expected to lie between those of the smaller DME and the larger DIPE. This expectation is supported by the known physicochemical properties.

Considering their structural similarities in sharing a common functional group, and given that their physicochemical properties follow a pattern, DME, DEE and DIPE can be considered as a “group”. As such, DME and DIPE are expected to be appropriate surrogates for DEE.

Sprague-Dawley rats were exposed to 0 (untreated), 0 (sham controls), 430, 3095, or 6745 ppm (0, 0, 1800, 12940, or 28200 mg/m³) of diisopropyl ether for 6 hours/day on Days 6 to 15 of gestation and were killed on gestation Day 20.

There were no treatment related changes in serum chemistry parameters, macroscopic examinations, or reproductive parameters (i.e. number of pregnant females, percent preimplantation loss, percent resorptions, and litter sizes). Lacrimation and salivation were noted in a few DIPE-exposed females at the highest concentration during, or immediately following, exposures. The animals returned to normal appearance shortly after cessation of each daily exposure. In general, animals housed in chambers gained less weight and consumed less food during the exposure period than the untreated controls (statistically significant at 6745 ppm relative to both of the control groups). Statistically significant decrease in body weight gains were seen on gestation days 6 to 16 at all dose levels (compared to untreated controls for the low- and mid-dose groups and compared to both controls at the high-dose group). Statistically significant decrease was seen in food consumption on gestation days 6 to 16 at the mid- and high-dose groups (compared to untreated controls on gestation days 6 to 13 and compared to both control groups on gestation days 13 to 16).

Foetal body weight was not affected by exposure. Evaluations of foetal skeletons revealed a significant increase in rudimentary (small, discrete ossification) or short (less than one-half the length of the preceding rib) 14th ribs in foetuses exposed to DIPE at concentrations of 3095 and 6745 ppm. No other exposure-related findings were noted at the time of foetal evaluations. The study authors have stated that "the observed increase in the incidence of rudimentary 14th ribs does not appear to be indicative of an adverse effect on development" at the concentrations tested. 

A NOAEC was not reported by the study authors. Review of the study data suggests that a NOAEC of 430 ppm can be derived for maternal toxicity based on the decrease in body weight gain and food consumption at higher concentrations, and a NOAEC of 430 ppm can be derived for foetal toxicity based on increases in rudimentary/short 14th ribs at higher concentrations (although the authors argue that this "variation" is not conclusive evidence of developmental toxicity).

The results of the study by Schwetz (1970) are based on a conference-proceedings abstract, from which only limited information is available. Pregnant Sprague-Dawley rats and Swiss-Webster mice were anesthetised for 1 hour, during early or late organogenesis, at 73000 ppm and 65000 ppm of 1,1’-dioxyethane, respectively. The animals were sacrificed one day prior to normal parturition; no significant effects were observed.

The available information on the inhalation study carried out by Garcia (1990) in Sprague-Dawley rats is too limited to make an evaluation.

The study design by Smith (1968), single-dose exposure at various concentrations of 1,1’-dioxyethane for 5 to 6 hours on day 1, 2, 3, or 4 of incubation for up to 18 days in white leghorn chicken embryos, has not been validated and the relevance of any potential findings to humans, even at more realistic concentrations, is not known. While teratogenic effects were observed, none-were considered organ specific, apart from a prevalence of eye abnormalities. The results were considered to be normal for exposure close to the embryo's LD50. Exposures were in the range 90000 ppm to 300000 ppm for 5 to 6 hours.

With the exception of the Dalby and Feuston (1996) study, the concentrations used in the above experiments were not relevant for humans: all were in the explosive range for air-vapour mixtures, all were above the minimum alveolar concentration (i.e. anaesthesia would be induced), and all would cause maternal mortality.

Justification for classification or non-classification

While the developmental studies indicate that the acceptable read-across substance does not affect the development of the offspring, there is no information available concerning the affect to sexual function and fertility in adult males and females. As a result, data is lacking for classification according to Regulation (EC) No 1272/2008, Annex I section 3.7.