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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
2 200 mg/kg bw/day
Additional information

In a two-generational study 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.

A fertility study was conducted under ICH guidelines to evaluate the effects of 2 -(2 -ethoxyethoxy)ethanol on gonadal function, mating behaviour and reproductive performance in the rat. The test substance was administered at 0, 300, 1000 or 2000mg/kg/day by gavage from 63 days before mating, througout mating and up to the day before necropsy in males, and 14 days before mating, througout mating and until day 7 of gestation (inclusive) in females. All dose levels of 2 -(2 -ethoxyethoxy)ethanol up to 2000mg/kg/day were well tolerated, although minor effects on clinical condition and body weight were observed at the higher dose levels mainly in males. There were no effects of the test substance on gonadal function, fertility and reproductive performance and therefore, the NOAEL can be considered at greater than 2000mg/kg/day for these effects.

Short description of key information:
No effect level: 2200mg/kg (F1 generation.)

Effects on developmental toxicity

Description of key information

Oral no effect level: 5500mg/kg (maximum dose tested)
Dermal no effect level: 1400mg/kg (maximum dose tested)
Inhalation no effect level: 100ppm (maximum dose tested and maximum practically attainable)

Sub-cutaneous no effect level (excluding local effects): 527mg/kg.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Additional information

In a developmental toxicity study in rats conducted under ICH guidelines, 2 -(2 -ethoxyethoxy)ethanol was administered by gavage from day 6 to day 17 of gestation inclusive at dose levels of 0, 300, 1000, or 2000mg/kg/day. Animals were killed on day 20 of gestation for examination of their uterine contents including examination of the placentae. The high dose level of 2 -(2 -ethoxyethoxy)ethanol resulted in slight maternal toxicity characterised by reductions in body weight gain and food consumption. Evidence of embryo-fetal toxicity was restricted to minor skeletal findings which principally included a dose-related increase in the incidence of reduced ossification of cranial bones in the 1000 and 2000mg/kg/day groups, which were not considered to be indicative of a teratogenic potential of 2 -(2 -ethoxyethoxy)ethanol. Therefore, under the conditions of this study a NOAEL could be determined at 1000mg/kg/day for maternal toxicity and 300mg/kg/day for embryotoxicity based on dose related observations but 1000mg/kg based on statistical evaluation.

In another study, 2 -(2 -ethoxyethoxy)ethanol when administered by gavage to pregnant female mice during GD7-14 at a dose level of 5500mg/kg causes no significant embryotoxicity. Parameters unaffected compared to controls include litter viability, pups per litter, number of dead pups, pup survival and pup weight gain. Pup weight at birth was statistically significantly reduced, but since this change was only 6%, it is of limited biological significance. On the basis of this screening study, it was concluded that this substance was a low priority for further developmental toxicity studies and that developmental toxicity is not an important characteristic of this substance.

2 -(2 -ethoxyethoxy)ethanol when administered by inhalation to pregnant female rats over GD7 -15 produced no evidence of developmental or maternal toxicity at a single dose of 100ppm . This was the highest concentration that was achievable without generating aerosol. The tested concentration represents about 60% of the saturated vapour pressure.

A developmental toxicity study using 2 -(2 -ethoxyethoxy)ethanol applied by the dermal route did not show any evidence of developmental toxicity at the single dose tested of ~1400mg/kg/day. Extragestational weight gain was statistically significantly less than in the sham treated controls, which the authors reported as evidence of maternal toxicity. The result from this study is that this substance shows no evidence of developmental toxicity properties.

There is data available on both rats and mice. In the category approach justification document attached in chapter 13 that is used to justify use of surrogate substances for certain end points, it is clear that for the significant number of glycol ethers where developmental data is available in multiple species, there is no evidence for any species specific adverse effects, suggesting that data from a single species should be sufficient to characterise developmental effects. Testing on rabbits is therefore neither required nor justified for this substance bearing in mind both the data available for this substance and for the wider glycol ethers family.

In a developmental toxicity study broadly to guideline, pregnant rats were treated with sub-cutaneous doses of 133, 245, 527, 1066mg/kgbw/day 2 -(2 -ethoxyethoxy)ethanol over GD6 -15. A small satellite group was allowed to parturition and the pups observed for a further 21 days. Maternal toxicity was seen at the highest doses, manifest as reduced body weight/weight gain and reduced food intake. The highest dose resulted in a significant reduction in pup weight, similar in magnitude to that seen in the dams. There was also an increase in the number of pups with minor skeletal variations in the top dose group (primarily extra ribs, and slightly reduced levels of ossification - variations normally considered of low concern.) There were no significant findings from the satellite group. Overall, the substance did not appear to exhibit any specific developmental toxicity in this study. It should be borne in mind that this method of dosing is not possible to extrapolate to normal routes of exposure.

An epidemiology study assessed the link between exposure to glycol ethers and malformations in babies. Exposure assessment was through the measurement of urinary metabolites of glycol ethers. The results from the study were inconclusive. A statistical link was reported between two malformations and levels of ethoxyethoxyacetic acid in the urine, but the confidence intervals were very wide and only just above one. Such a link seems biologically implausible bearing in mind the negative data in animals. In addition, the study did not show a link between malformations and the urinary metabolites of glycol ethers known to be developmental toxins.

Justification for classification or non-classification

In a multi-generation fertility study, there was evidence of a marginal reduction in sperm motility of the F1 generation (P generation not examined, not seen in F2 generation) beyond normal background variation. This was not sufficient to cause any reduction in manifest fertility and was also seen only in the high dose animals receiving 4400mg/kg/day where other toxic effects were also seen. These limited effects seen at such high dose levels well above what would normally be considered a limit dose are considered to be of low toxicological significance and not sufficient to warrant any justification for classification for fertility.

In a guideline study using oral gavage dosing in pregnant rats, a dose of 2000mg/kg showed some minor but statistically significant skeletal variations, primarily reduced ossification in the cranium. There was some evidence of this trend at 1000mg/kg but at no point did it reach statistical significance. The NOAEL for maternal toxicity (body weight gain and food consumption reductions) was 1000mg/kg. This study did not produce clear evidence of adverse effects, certainly not at doses of 1000mg/kg and certainly not in the absence of maternal toxicity. None of the supporting studies available provided any other evidence of developmental effects. On this basis, there does not appear to be any justification for classification for developmental effects.

Additional information