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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No adverse effects seen up to a limit dose of 1000mg/kgbw/day

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 190 mg/kg bw/day
Study duration:
subchronic
Species:
mouse
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 370 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

A full 2 generation study is not available for 2-(2 -butoxyethoxy)ethyl acetate (DEGBEA). Read across is normally used from 2-(2-butoxyethoxy)ethanol (DEGBE) as there is good data available to show that the former rapidly metabolises to the latter in vitro (data appended in chapter 13 of IUCLID). There is also no full 2 generation or extended one generation study available. There are however a number of single generation studies on DEGBE that either comply with or are similar to the OECD415 guideline. This is supplemented with other data on the toxicity of DEGBE to the reproductive organs.

A recent single generation reproductive toxicity study was undertaken using (DEGBE) in drinking water in rats following the OECD 415 guideline 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. In conclusion, treatment of rats with a limit dose of 1000mg/kgbw of DEGBE for 9 -10 weeks did not impair fertility or viability of offspring. (Sitarek, 2012). The same authors performed a fertility study using DEGBE 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. Significant general toxic effects were seen at the highest tested dose (rmortality, reduced body weight gain and food consumption and adverse clinical observations.)

In a well conducted single generation fertility study which conformed to the basic requirements of an 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 is not deemed biologically significant (Nolen, 1985.) In a well conducted single generation fertility study, 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 (Auletta, 1993).

There are two similar substances that do have multi-generation reproductive toxicity studies available and these can be used as read across sources to supplement the data on DEGBE and confirm the lack of reproductive toxicity of the latter. These two source substances are 2-butoxyethanol (EGBE) and 2-(2-ethoxyethoxy)ethanol (DEGEE). A comprehensive justification as to why such a read across is valid is included in this chapter of the IUCLID dossier.

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 EGBE. 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 (Morrissey, 1988). The NOAEL for reproductive toxicity was set at 720mg/kg/day – equivalent to 1171mg/kgbw/day of DEGBEA.

Further data showing a lack of reproductive toxicity for EGBE is available from a reliable 90 day repeat dose study using oral exposures via drinking water up to 450 -470mg/kg/day in male and female rats, a number of reproductive parameters were examined in the animals that survived to termination. In males, a decrease in epididymal weights was noticed but this was in proportion to overall reduced body weight. Sperm concentrations were also reduced by approximately 5 -10% in all dose groups but there was no dose response relationship evident. There were no effects on estrous length but some evidence that the two highest dose group animals spent more time in the diestrus stage. This correlated with the smaller uterine size, which was attributed to a secondary consequence of reduced body weight gain. In addition, the lack of effect on overall estrous cycle length and absence of histopathologic lesions suggest that the effects on estrous cycle length are unlikely to indicate a specific treatment-related reproductive effect. Thus, the effects on male and female rat reproductive endpoints are not considered to be indications of selective reproductive system toxicity.  The effects seen were minor in nature, not seen in males and only occurred in the presence of other significant systemic toxicity (i.e., decreased body weights, marked haematotoxicity).  In conclusion, the study does not indicate any primary effects on fertility that can be directly attributed to treatment with EGBE (NTP, 1993).

In a two-generational study investigated the effects in reproduction and fertility of 0%, 0.25%, 1.25%, and 2.5% DEGEE 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 (NTP, 1984). This can be translated into a predicted lack of effects from exposure to DEGBEA at doses of at least 2000mg/kg.

Overall, it can be concluded that doses of up to 1200mg/kg (converting to molecular weight equivalent) of DEGBEA would not cause reproductive toxicity.

Effects on developmental toxicity

Description of key information

Data for surrogate substances:

NOAEL>633mg/kg/day (developmental toxicity, rats, dietary study.) Equivalence on a molar basis to dossier substance: 797mg/kg/day

NOAEL>1000mg/kg/day (teratology study, rabbits, dermal.)  Equivalence on a molar basis to dossier substance: 1260mg/kg/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Species:
rat
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
Dose descriptor:
NOAEL
1 185 mg/kg bw/day
Species:
rabbit
Additional information

There is no developmental toxicity data available on 2 -(2 -butoxyethoxy)ethyl acetate (DEGBEA). However data on the primary metabolite that is produced rapidly in vivo, i.e 2 -(2 -butoxyethoxy)ethanol (DEGBE) can reliably be used as a surrogate to predict the in vivo toxicity of DEGBEA. A detailed justification for read across to DEGBE for end points involving systemic toxicity is contained in a report attached to chapter 13 of this IUCLID dossier. The data summarised below is for DEGBE:

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 in rabbits 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. In a Chernoff Kavlock screening study, 2 -(2 -butoxyethoxy)ethanol produced no signs of fetotoxicity or embryotoxicy when tested at doses up to 2050mg/kg by oral gavage im mice. There was clear evidence of maternal toxicity (mortality) at the highest dose tested. The study did not examine offspring for teratogenicity but on the criteria of the screening study, the results would indicate a low potential for such developmental effects.

These studies provide convincing evidence that 2 -(2 -butoxyethoxy)ethyl acetate has no significant developmental toxicity potential.

Justification for classification or non-classification

There is no evidence that 2 -(2 -butoxyethoxy)ethyl acetate has any potential for reproductive or developmental toxicity.