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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

There is no 2 -generation reproductive toxicity study available for 2 -(2 -methoxyethoxy)ethanol, although there is other relevant data available for use as supporting information. There is a 2 -generation reproductive toxicity study available for the closely related analogue 2 -(2 -ethoxyethoxy)ethanol plus good supporting information available on a number of other similar substances that justifies an analogue read across approach for this end point . A full and detailed justification for a this approach is attached to the read across object for this end point.  There is good data to show that within the glycol ether family, for all reprotoxicity end points, including adverse effects on fertility, toxicity decreases markedly as the lengths of the alkyl and alkoxy chains increase. For reproductive toxicity, the most sensitive effect is on the male testes, which manifest as testicular atrophy and arrestment of spermatogenisis.  All reproductive effects are caused by the alkoxyacetic acid metabolite rather than the parent glycol ether itself. From the available data, the most toxic member of the category is methoxyethanol. The trend towards manifest reproductive toxicity in the short chain glycol ethers is at least in part related to the trend for slower elimination of these metabolites with decreasing alkyl chain length and decreasing numbers of EO units in the molecule. The position of the source substances within the matrix of glycol ethers and the relation to the target is shown in the table below:



Number of EO units

Alcohol chain length























Substance with no suitable or useful data available

A summary of the available data is described below:

The two-generational study on the substance 2 -(2-ethoxyethoxy)ethanol investigated the effects in reproduction and fertility of 0%, 0.25%, 1.25%, and 2.5% 2 -(2 -ethoxyethoxy)ethanol in drinking water. Male and female CD-1 mice were continuously treated for 1 week prior to mating and for a 14 week breeding period followed by a 21 day holding period when they were separated and housed individually. There were two deaths among the male F0 animals treated at high dose and small decreases in the mean body weights. The body weights of the F1 offspring exposed to 2.5% level were slightly depressed at birth, at weaning and at 74 +/-10 days. 2 -(2 -ethoxyethoxy)ethanol did not have adverse effects on fertility and reproductive performance despite a 34% decrease in caudal epididymal sperm motility in the F1 males at 2.5%. The highest dose also increased liver weight and decreased brain weight in both sexes of the F1 generation. The NOAEL for F0 and F1 generations can be established at 1.25% 2 -(2 -ethoxyethoxy)ethanol based on systemic and reproductive (sperm motility) effects respectively (equivalent to 2200mg/kg), and 2.5% for the F2 generation.

In a well conducted single generation fertility study, diethylene glycol butyl ether (DEGBE) produced no signs of toxicity to reproduction in either male or female rats when tested with a dermally dose of 2000mg/kg bw/day. The only finding that was dermal irritation resulting from repeated application of the test substance to the same application site.  In a well conducted single generation fertility study which conformed to the basic requirements of the OECD guideline study, DEGBE produced no signs of toxicity to reproduction in either male or female rats when tested at oral doses up to 1000mg/kg. The only finding that was attributed to treatment was a small but statistically significant reduction in pup weight gain seen at the highest dose tested and at a single time point during gestation. The minor and transient nature of this finding was not deemed biologically significant.  In another and more recent guideline single generation reproductive toxicity study undertaken using DEGBE in drinking water in rats, there was no effect seen on any reproductive parameters up to the maximum tested dose of 1000mg/kg. Parameters used to assess the general toxicity indicated that males receiving DEGBE were more sensitive than females: effects included significantly greater, dose-dependent relative spleen weight, significant decrease in hematological parameters from 8% to 15% depending on the dose, were observed. Clinical chemistry parameters (HDL-cholesterol, BUN) and some markers of oxidative stress differ between the exposed groups and the control one, but without adverse health effect manifesting. No adverse histopathology was observed.  In a fertility study was undertaken by the same workers, DEGBE was dosed by oral gavage to assess the impact on the estrous cycle in the rat. There was no effect seen on any reproductive parameters up to the maximum tested dose of 1000mg/kg. Toxic effects were seen at the highest tested dose (reduced body weight gain and adverse clinical observations.

In a repeat dose study using triethylene glycol methyl ether’, tSprague-Dawley rats were treated via the drinking water for 13 weeks.  This produced moderate toxicity at 4.0g/kg/day and minimal to mild toxicity at 1.2 g/kg/day. There was evidence for adverse effects on the testes (histopathology) at 4.0g/kg.

In two studies specifically designed to look at effects on the testes, which are known to be the target organs for certain other glycol ethers, no testicular effects were seen in mice and rats following sub-acute administration of 2 -(2 -methoxyethoxy)ethanol or the major metabolite 2 -(2 -methoxyethoxy)acetic acid. It should be noted that in a sub-chronic study (see Krasavage, chapter 7.5.1) that reduced testes weight and testicular atrophy was seen at a dose of 3600mg/kg, which suggests that this substance may ultimately have adverse testicular effects but only at extremely high doses, well beyond those that would now be used as a maximum in current guideline studies.

There is some supportive data on DEGME itself.  A sub-acute study exposed mice to drinking water containing DEGME for  25 days. There was no evidence of toxicity or of effects on the testes as indicated by body and organ weight measurements or of a reduction in white blood cell count. 2 -methoxyethanol was tested alongside as a positive control and showed marked evidence of haematotoxic and testicular toxicity.  In another study specifically designed to examine to potential for testicular toxicity, male rats were exposed to DEGME at a single daily dose of 5.1mmol/kg (equivalent to 612mg/kg) for a period of up to 20 days. The testes of these animals showed no gross or microscopic abnormalities.  The same study also reported results for the main metabolite of DEGME,  2 -(2 -methoxyethoxy)acetic acid,which was given at the same a single daily dose of 5.1mmol/kg (equivalent to 683mg/kg) for a period of up to 20 days. The testes of these animals also showed no gross or microscopic abnormalities.

The data available provides sufficient robust information to meet the data requirements for this end point and to conclude that toxicity to reproduction is unlikely to be a significant property of the substance 2 -(2 -methoxyethoxy)ethanol.

Short description of key information:
Testicular toxicity: NOAEL 18-29 day RDT studies) >612mg/kg (rat), >4500mg/kg (mouse)
Analogue substances: NOAEL>1000mg/kg/day.

Effects on developmental toxicity

Description of key information

NOAEL (mouse, oral) <4000mg/kg

NOAEL (rat, oral) 200mg/kg (maternal toxicity 600mg/kg); <720mg/kg

NOAEL (rat, sc) >1ml/kg

NOAEL (rabbit, dermal) 50mg/kg (maternal toxicity 250mg/kg)

Effect on developmental toxicity: via oral route
Dose descriptor:
200 mg/kg bw/day
Effect on developmental toxicity: via dermal route
Dose descriptor:
50 mg/kg bw/day
Additional information

In a study to examine the developmental toxicity of 2 -(2 -methoxyethoxy)ethanol by the dermal exposure route, pregnant rabbits were exposured during GD6 -18. Some evidence of maternal toxicity was seen in the high dose animals, mainly manifest as adverse haematological changes. The percentage of resorbed implantations increased markedly at 750 mg/kg b.w. At terminal examination a significantly increased incidence of pups with mild forelimb flexure, dilated renal pelvis, retrocaval ureter was observed at the highest dose. The incidence of delayed ossification of the hyoid and sternebrae and cervical spur were observed at 250 and 750 mg/kg b.w. The NOAEL for maternal toxicity was 250 mg/kg b.w and that for fetotoxicity was 50 mg/kg b.w from this study. No teratogenic effects were observed. No teratogenic effects were observed. The developmental effects produced are seen primarily in conjunction with maternal toxicity and are in the range of what might be expected from compromised mothers. The variations seen are consistent with those associated with maternal toxicity.

In a study to examine the developmental toxicity of 2 -(2 -methoxyethoxy)ethanol, pregnant rats were given doses up to 1800mg/kg during GD7 -17 of gestation.. The high dose animals showed some signs of maternal toxicity (small but significant weight reduction, more marked reduction in thymus weight). The high dose animals showed clear evidence of developmental toxicity, with a significant reduction in the number of live fetuses and their weight and an increase in the incidence of both early and late stage resorptions, an increase in gross malformations and anomalies, an increase in visceral malformations and 100% incidence of visceral variations and an increase in skeletal malformations and variations and an decrease in ossification. The mid dose animals (600mg/kg) showed far fewer effects and more minor effects but there was still evidence of a significant increase in some skeletal and visceral variations and a reduction in fetal weight. There were no effects in the low dose group. The same publication also carries details of the range finder studies carried out for the main study using both pregnant and non-pregnant rats at doses from 125 -4000mg/kg. In the non-pregnant rat range finder study, urinary pH turned acidic even at the lowest doses (control pH 8.0-8.5, 125mg/kg pH 7.0-8.0, 4000mg/kg pH 5.0-6.0). It can be presumed from knowledge of the metabolism, that this was due to the main metabolite, which may well also cause metabolic acidosis. The doses of 3000 and 4000mg/kg also produced statistically significantly adverse effects on blood parameters, although the trend of reducing RBC, WBC, Hb and Ht concentrations was evident from 1000-2000mg/kg onwards. 

In another study to examine the developmental toxicity potential of 2 -(2 -methoxyethoxy)ethanol, pregnant rats were dosed by oral gavage at doses of 720 and 2165mg/kg during GD7 -16. The was sporadic but no consistent evidence of maternal toxicity. The was some evidence of malformations at the top dose. A significant increase in reduced cranial ossification and reduced ossification of the appendicular skeleton was seen and the incidence of dilated renal pelvis was increased in the low dose group. From this study, a NOAEL could not be determined.

In the range finder study for this study, pregnant rats were dosed by oral gavage at doses of 1000, 1495, 2235, 3345 and 5175mg/kg during GD7 -16. The was clear evidence of maternal toxicity at the highest dose and some evidence at the next dose down. The most sensitive finding was an increase in delayed ossification of the cranium, a variation that occurs spontaneously in control animals. It should be noted that no effects were seen at 1000mg/kg, which is normally regarded as a limit dose for testing using current protocols. Together, these two studies along with the level of statistical significance of the findings in the main study suggest that the NOAEL is not substantially lower than the LOAEL from the main study.

In another screening study to assess the developmental toxicity of 2 -(2 -methoxyethoxy)ethanol, pregnant rats were exposed by the sub-cutaneous route to doses up to 1ml/kg and allowed to litter naturally. There was a slight but not statistically significant drop in the number of live pups per litter in the high dose group but no other notable finding. Overall a no adverse effect level of 1ml/kg was identified.

2 -(2 -methoxyethoxy)ethanol when administered by gavage to pregnant female mice during GD7-14 at a dose level of 4000mg/kg causes significant embryotoxicity, manifest by a reduction in the number of viable litters and number of live pups per litter and by a reduction in the survival rate of surviving pup.  This dose also produced expected maternal mortality but not at a level which would suggest that it contributes to the substantial developmental toxicity observed.  The result however cannot be considered definitive on their own as this is a single, extreme dose screening study used to identify candidates for further, more refined studies.

In an assay using Zebrafish designed as a screening test for mammalian developmental toxicity, the metabolite of DEGME,. 2 -(2 -methoxyethoxy)acetic acid did not show any evidence of developmental toxicity. This was in contrast to the substance 2 -methoxyacetic acid which is known to cause developmental toxicity and which showed clear evidence of teratogenicity in this study when used as a positive control.

However, whilst existing data was considered sufficient when this substance was first registered, concerns have been raised by a member state, as part of a discussion on classification and labelling that these older studies (not to current guidelines) do not have the statistical power to interpret low level findings seen at doses below 1000mg/kgbw/day.  They are therefore not considered adequate to reach an unequivocal decision on whether there is a hazard or not to rodent species. Since it would be poor science to extrapolate from effects seen at high doses well above 1000mg/kg to assess hazard to humans at more relevant doses at or below 1000mg/kgbw/day, a new study is now deemed necessary with the number of animals specified in the current guideline and limited to a top dose of 1000mg/kgbw/day. A testing proposal is now included with this dossier to fill this perceived data gap.

Justification for classification or non-classification

The is some evidence to suggest that 2 -(2 -methoxyethoxy)ethanol (DEGME) may be a developmental toxicant. However, the data indicates that it is of very low potency (effects not clearly seen until doses are greater than 1000mg/kg) and those effects seen below 1000mg/kg are usually either small variations or delays. Across species, there is no clear evidence for significant effects in rats or mice at levels <1000mg/kg, although evidence suggests that rabbits may exhibit developmental effects at lower doses than this and in the absence of significant maternal toxicity. These findings could be due to the small amounts of methoxyacetic acid, a known developmental toxicant, that is produced as a metabolite of DEGME).  Therefore, an appropriately cautious approach would be to classify as a category 2 toxicant under the EU GHS regulation. Based on the hypothesis that it is the small amounts of the metabolite methoxyacetic acid that cause the developmental effects seen at high dose, it also seems appropriately precautionary to also include a classification category 2 for fertility on the basis that methoxyacetic acid is also known to cause adverse effects for this end point. This is an appropriate classification based on the currently available data. A testing proposal has been submitted to perform a new PNDT study in rats to clarify the appropriate classification.

In practice, there is not likely to be a risk by inhalation as exposure to the concentrations necessary to cause the limited effects seen is going to be impossible by this route bearing in mind the relatively low vapour concentration of the substance

Additional information