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Administrative data

Key value for chemical safety assessment

Effects on fertility

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

There is no toxicity to fertility data available on the substance 2 -butoxyethyl acetate. In view of the rapid hydrolysis of this substance to the parent glycol ether 2 -butoxyethanol under physiological conditions, the sytemic toxicity potential of 2 -butoxyethyl acetate in vivo is likely to be similar to that of 2 -butoxyethanol. A summary of the key study for the latter, that is presented as a summary in this chapter, is presented here:

In all sub-acute, sub-chronic and chronic studies, not all reported in this chapter, no direct effects were seen on male or female reproductive organs at all doses tested (even sub-lethal doses). Unlike 2-methoxyethanol and 2-ethoxyethanol, 2-butoxyethanol seems to have no specific effects on fertility (no effects were seen in the continuous breeding study using dosing by drinking water and neither macroscopic nor microscopic effects on reproductive organs in the repeated dose toxicity studies at doses which does not exhibit severe general toxicity.) A NOAEL of 720 mg/kg was derived from the continuous breeding study for fertility effects. It should be noted that effects seen at the higher doses used in this study are due to general toxicity. This is equivalent on a molar basis to a NOAEL for 2 -butoxyethyl acetate of 977mg/kg.

There were no effects on the testis/epididymis in a 14-week rat repeat dose toxicity study in mice.  Some changes were seen in male rats but these were mild effects on the testis and epididymi and were not regarded as specific toxicity to the reproductive organs, as numerous tissues were affected and systemic toxicity was significant; therefore reproductive effects were secondary to primary general toxicity. Similarly, no specific toxicity was seen in females, with the only possible effects seen in female rats attributed to unusual results for control animals.

In all sub-acute, sub-chronic and chronic studies no direct effects were seen on male or female reproductive organs at all doses tested (even sub-lethal doses). Metabolism of 2-butoxyethanol leads to the formation of mainly butoxyacetic acid, which is not a male reproductive toxic substance, unlike methoxyacetic acid or ethoxyacetic acid (main metabolites of 2-methoxyethanol and 2-ethoxyethanol respectively).


Short description of key information:
Information from reliable studies:
Continuous breeding study: NOAEL=720mg/kg/day (mice)
90 day study with reproductive toxicity end points-mouse: NOAEL >694mg/kg/day (males), >1306mg/kg/day (females)
90 day study with reproductive toxicity end points-rat: NOAEL >452mg/kg/day (males), >470mg/kg/day (females)

Effects on developmental toxicity

Description of key information
NOAEL (rat, oral): 30mg/kg/day (maternal), 100mg/kg/day (developmental)
NOAEL (rat, inhalation): 50ppm (maternal), 100ppm (developmental)
NOAEL (rabbit, inhalation): 50ppm (maternal), 100ppm (developmental)
Additional information

There is no developmental toxicity data available on the substance 2 -butoxyethyl acetate. In view of the rapid hydrolysis of this substance to the parent glycol ether 2 -butoxyethanol under physiological conditions, the sytemic toxicity potential of 2 -butoxyethyl acetate in vivo is likely to be similar to that of 2 -butoxyethanol. A summary of the key studies for the latter, that are presented as summaries in this chapter, are presented here:

ORAL ROUTE

One study is available in rats. The lowest foetal NOAEL is 100 mg/kg/day in the RTI (1988) rat study. It is based on effects seen at 200 mg/kg/day: increase foetal lethality without malformations. These effects were seen with maternal toxicity (haemolytic anaemia) and retarded body weight gain evidenced from 100 mg/kg/day. The maternal NOAEL is 30 mg/kg/day in this study.

INHALATION ROUTE

In the most reliable studies, a developmental NOAEL of 100 ppm can be taken into account for the risk assessment based on the data from rats and rabbits. These effects are seen in presence of clear maternal toxicity (haemolytic anaemia) which was seen at 100 ppm and higher. The maternal NOAEL for this effect was 50 ppm.

OVERALL CONCLUSION

For developmental toxicity, studies performed on animals via various administration routes did not demonstrate any teratogenic potential, but foetotoxicity and embryotoxicity (lethality and resorptions) were often observed in relation with maternal toxicity (regenerative haemolytic anaemia). Other effects seen on foetuses were an increase in the incidence of skeletal variations which are generally described as ossification delays. In vitro studies showed some adverse effects on development with 2-butoxyethanol and its metabolite BAA, but only in conjunction with growth effects. Effects seen in foetuses are certainly related to maternal toxicity. Some supporting studies, including those with another substance, clearly demonstrate that anaemia itself can produce very similar effects to those seen with 2 -butoxyethanol at doses that cause maternal haemotoxicity (resorption, growth retardation and variations).

Haemotoxicity (typical adverse effect seen in animals with this compound) generally occurred at low doses of 2-butoxyethanol whatever the route of administration used. In theses studies, data on haemolysis were often observed with acute dosing. Developmental toxicity studies would require daily dosing with test material, which may produce more marked effects on haematopoietic parameters. In addition, female mice and rats were more affected by 2-butoxyethanol haemolysis than males. Thus, these data demonstrate that the concentrations of 2-butoxyethanol used in these developmental toxicity studies were sufficient to produce severe maternal anemia of the magnitude sufficient to trigger effects on embryo/fetal survival. These data give sound support to the hypothesis that the effects seen in developmental toxicity studies with 2-butoxyethanol were due to haemolysis and subsequent maternal anemia.

Overall, it is not therefore not possible to obtain a meaningful NOAEL for developmental toxicity relevant for humans that is based on animals studies. From the data available, it can be concluded that 2 -butoxyethanol does not share the same profile of toxic effects seen in the lower monoalkyl glycol ethers and that by analogy with other glycol ethers that show neither these specific effects nor haemotoxicity that developmental toxicity due to 2-butoxyethanol in humans could not be expected without maternal toxicity (a conclusion that was reached in the EU risk assessment). Consequently, there is no concern for this end-point and any DNEL derived for repeat dose toxicity will be protective for any theoretical developmental effects.

Justification for classification or non-classification

No evidence for direct developmental toxicity. Any effects that are seen have been established as secondary to maternal toxicity. No classification therefore required.