Registration Dossier

Administrative data

Description of key information

Oral route (surrogate substance with mol wt correction: LOAEL=94mg/kgbw/day.
Dermal route (surrogate substance with mol wt correction: LOAEL=203mg/kgbw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEL
94 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEC
206 mg/m³

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEL
203 mg/kg bw/day

Additional information

ORAL ROUTE

There is no data available on repeat dose toxicity of butylglycol acetate by the oral route. Glycol ether acetates are rapidly hydrolysed in vivo to the parent glycol ethers by plasma esterases and are thus likely to exhibit the same systemic toxicity profile as the parent glycol ether. Good oral sub-chronic toxicity data is available for the parent glycol ether of 2 -butoxyethyl acetate, i.e. 2 -butoxyethanol in both rats and mice. Repeat dose oral toxicity testing with the latter has given the following results: body weight reduction, haemolysis, hepatic effects and local irritation effects. Overall, a LOAEL of  69 and 82 mg /kg bw/d (in males and females respectively) can be established. On a molar basis, an extrapolation of this LOAEL to an equivalent for 2 -butoxyethyl acetate would be 94 and 111 mg/kg, for males and females respectively with effects being solely attributed to the direct or indirect effects of haemolysis.

DERMAL ROUTE

There is no repeat dose toxicity data available for 2 -butoxyethyl acetate (BEA) by the dermal route. Since the critical effects are haematotoxicity, which is associated with the metabolite 2 -butoxyethanol (2BE), the data for the latter, which is much more extensive and reliable, can be taken into account. The results obtained in these studies are summarised in the next paragraph.

Two studies are available on rabbits to assess the toxicity of repeated doses of 2BE administered dermally. In one study, signs of toxicity were recorded and were limited to transient signs of haemolysis on rabbits. This study led to a NOAEL of 450 mg/kg bw/d due to haematological effects seen at 900 mg/kg bw/d. Given that this study was performed for only 9 days, the NOAEL of the second study on rabbits, which was performed for 13 weeks, is regarded as more reliable for drivation of a DNEL. This NOAEL was 150 mg/kg bw/d. The equivalent on a mole basis for BEA is 203mg/kg/day.

INHALATION ROUTE

In sub-acute and chronic studies performed with 2 -butoxyethyl acetate (BEA), signs of haematotoxicity and associated kidney lesions were seen in rats and rabbit. Rabbits seemed particularly sensitive to these adverse effects. However, the studies available only used a single exposure concentration so it is not possible to derive a meaningful NOAEC from them. Since the critical effects are haematotoxicity, which is associated with the metabolite 2 -butoxyethanol (2BE), the data for the latter, which is much more extensive and reliable, can be taken into account. The results obtained in these studies are summarised in the next paragraph.

There are a number of substantial studies are available for 2BE in rats, and mice. Robust summaries for the key studies identified are included here. (A number of other less well reported short exposure studies using dogs, guinea-pigs and non human primates have also been conducted, but since these do not impact the derivation of the DNEL for 2BE they are not included in this dossier.) Similar effects are seen in both rats and mice. These effects are similar to those observed following acute administration.  The main effect is haemolysis, which is consistently observed and sometimes associated with secondary hepatic effects (Kupffer cells pigmentation and absolute and relative liver weight increases). Other effects include decreases of body weight gain, hyaline degeneration of the olfactive epithelium, effects on the forestomach and effects on the WBC sub-populations (T lymphocyte). From these studies on 2BE, a NOAEC of 25 ppm in rats and a LOAEC of 31 ppm in mice and rats can be established (based on haemolysis, as the only significant primary effect seen at any exposure concentration examined). The LOAEC of 31 ppm ( from a six month satellite group in the NTP, 2000 104-week study) is taken into account for the risk characterisation of both 2BE and BEA with an appropriate assessment factor to acknowledge that there is a NOAEC of 25ppm available and no other lesion was identified that could be specifically attributed to treatment to 2BE.

OTHER

In selecting an appropriate assessment factor it should be borne in mind that humans fall into the group of species that are resistant to the haemolytic effects of 2BE whilst rats, mice and rabbits are very sensitive to this effect and that no toxic effects other than haemotoxicity could be attributed to treatment in any repeat dose study.

Justification for classification or non-classification

The no effect levels established, bearing in mind the critical effects at the LOAEL and their relevance to humans, do not meet the criteria for classification for repeat dose toxicity.