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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Additional information

In a well conducted single generation fertility study which conformed to the basic requirements of an OECD guideline study, 2 -(2 -butoxyethoxy)ethanol 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 is not deemed biologically significant. A similar study by the dermal route of exposure showed no evidence of reproductive toxicity in either male or female rats when tested with a dermally dose of 2000mg/kg. The only finding that was dermal irritation resulting from repeated application of the test substance to the same application site.

Another single generation reproductive toxicity study was undertaken in drinking water following the OECD 415 guideline in rats with additional satellite groups for the analysis of clinical chemistry, haematology and oxidative stress markers. 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. The same authors also conduced a fertility study alongside the main study where the substance 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.)

A full 2 generation study is not available for 2 -(2 -butoxyethoxy)ethanol. However, in a continuous breeding study carried out to an NTP protocol, mice were exposed for a period of 14 weeks to the oral drinking water routes at doses from 720 to 2050mg/kg of the closely related substance 2 -butoxyethanol. Significant adverse reproductive effects were observed in the females at very high dose levels (1340 mg/kg and above) which also caused severe general toxicity, including death. Under the conditions of the study, the NOAEL for reproductive toxicity of 2-butoxyethanol (fertility) can be set as 720 mg/kg/day. For developmental toxicity, no NOAEL can be derived. A conservative LOAEL of 720 mg/kg/day can be taken as only a very slight decrease in pup weight was observed at this dose. At the lowest dose studied, the only adverse finding was a marginal statistically significant reduction in pup weight. However, since this reduction was only 3% compared to controls and was not repeated in the F1 generation, it was not considered a significant adverse finding. No NOAEL or LOAEL can be determined for systemic parental toxicity because this kind of study is not designed to assess systemic toxicity although it is of note that there were effects (reduced fluid consumption) even at the lowest dosage of 720 mg/kg/day. 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 (another structurally similar compound) 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. Of these two studies, the former is considered more conservative and would lead to a NOAEL based on a molecular weight equivalence basis of ~1000mg/kgbw/day, which is entirely consistent with the single generation studies available on 2 -(2 -butoxyethoxy)ethanol itself.

A full and detailed justification to use the read across approach is included as an attachment to the read across object in chapter 7.8.1 of the IUCLID of the lead registrant.


Short description of key information:
NOAEL >1000mg/kg/day (single generation study, oral, rats)
NOAEL >1000mg/kg/day (single generation study, oral, rats)
NOAEL >1000mg/kg/day (fertility study, oral, female rats)
NOAEL >2000mg/kg/day (single generation study, dermal, rats)

Effects on developmental toxicity

Description of key information

NOAEL>633mg/kg/day (developmental toxicity, rats, dietary study)
NOAEL>2000mg/kg/day (teratology study, rabbits, dermal)
NOAEL (fetotoxicity)>2050mg/kg/day (screening study, gavage)

NOAEL 480mg/kg/day (developmental toxicity, rats, sub-cutaneous)

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

In a study which conformed to the basic requirements of the relevant OECD guideline, 2 -(2 -butoxyethoxy)ethanol produced no significant evidence of developmental toxicity when fed to rats in their diet at doses up to 633mg/kg during the whole gestation period (GD0 -20). A small satellite group which looked at residual effects in pups after birth for up to 10 weeks also failed to show any effects on the parameters assessed. Another teratology study conforming to the basic OECD guideline showed no signs of developmental toxicity when tested at doses up to 1000mg/kg when applied by the dermal route. The only finding that was clearly attributed to treatment was significant irritation at the site of application manifest at doses from 300mg/kg upwards. Another study used sub-cutaneous dosing up to 699mg/kgbw/day over GD6 -15. Maternal toxicity was seen at the two highest doses, manifest as haemoglobinuria and reduced food intake, and at the highest dose as a small, but significant reduction in body weight and weight gain. The highest dose resulted in a significant reduction in pup weight, similar in magnitude to that sen in the dams along with an increase in the number of pups with minor skeletal variations in the top dose group (primarily reduced ossification and extra ribs, variations normally considered of low concern.) A Chernoff Kavlock screening study produced no signs of fetotoxicity or embryotoxicy when tested at doses up to 2050mg/kg by oral gavage. There was clear evidence of maternal toxicity (mortality) at the highest dose tested. The study did not examine offspring for teratogenicity.

Justification for classification or non-classification

There is no evidence that 2 -(2 -butoxyethoxy)ethanol has any reproductive or developmental toxicity when assessed in appropriate assays. Classification not required under either directive 67/548 or regulation 1272/2008

Additional information