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Administrative data

Description of key information

ORAL ROUTE (all rat)
- NOAEL 250mg/kg, LOAEL 1000mg/kg (90 day drinking water study)
- NOAEL 51-65mg/kg, LOAEL 254-327 mg/kg (90 day gavage study)
- NOAEL 891mg/kg (6 week gavage study)
- NOAEL 94mg/kg, LOAEL 650mg/kg (30 day drinking water study)
- NOAEL 2000mg/kg (13 week occlusive study) (<200mg/kg for local effects - irritation)
- NOAEL 2000mg/kg (13 week occlusive study) (600mg/kg for local effects - irritation)
- NOAEC 94mg/m3 (90 day study)
- NOEC 39mg/m3 (5 week study). NOAEC could be defined as 121mg/m3
- NOAEC 100mg/m3 (2 week rangefinder study)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
250 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
94 mg/m³

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
2 000 mg/kg bw/day

Additional information

The key study for the oral route is a recent 90 day sub-chronic guideline and GLP drinking water study in rats. Multiple, albeit mild, effects were seen at 1000mg/kg. At 250mg/kg, the only treatment related effects were equivocal changes in erythron that were statistically significant to unusually high concurrent controls but within historical control ranges. This dose level was therefore considered to be the no adverse effect level. In an older gavage study rats were given doses of 2 -(2 -butoxyethoxy)ethanol for 13 weeks. Mortality in the mid and high dose groups was very high and attributed to gavage trauma unrelated to treatment. In females of the mid and low dose groups a dose-related decreases in white blood cell count (WBC) and lymphocytes were observed. In males in the mid and low dose groups an increase in serum creatinine was observed. The authors established a NOAEL of 51 mg/kg bw/d. The effects observed in this study are not consistent with the toxicity profile of glycol ethers. Furthermore, there are doubts on the quality of the study, because of the high mortality. In a 6 week sub-acute gavage study significant toxicity was seen in the high dose group, suggesting that the MTD may have been exceeded. The only effects seen in the low dose group (891mg/kg) were equivocal changes in the kidney (proteinaceous casts and hemosiderin) and changes attributed to the dosing method (stomach hyperkeratosis). and this was therefore identified as a no effect level. In a briefly reported 30 day sub-acute study, rats were subject to doses of 2 -(2 -butoxyethoxy)ethanol up to 1830mg/kg in drinking water. Unidentified microscopic organ changes were reported at a dose of 650mg/kg meaning that the highest dose showing no adverse effects was 94mg/kg.

The key study by the dermal route was one designed to assess the sub-chronic and reproductive toxicity of 2 -(2 -butoxyethoxy)ethanol to rats by the dermal route. The only effect of note was dermal irritation at the site of repeated application which occured at all doses, albeit very slight at the low dose and only in males at towards the end of the study. There were no adverse systemic toxicity findings noted and the NOAEL was set at 2000mg/kg. In another study primarily to assess neurotoxicity by the dermal route, the only finding of note was scab formation on 5 females at the site of repeated application of the neat substance in the high dose animals. However, only a limited number of non-neurotoxicity end points were assessed.

The key study by the inhalation route was a 90 day guideline and GLP inhalation study where rats were exposed in 3 dose groups up to the maximum saturated vapour pressure of 2 -(2 -butoxyethoxyethanol). Satellite recovery groups were also included for all 3 dose groups and the controls. No adverse effects were seen in any dose group. The NOAEL was therefore 14ppm (94mg/m3), the maximum dose tested. In an older 5 week study, rats were exposed to a concentrations of 2 -(2 -butoxyethoxyethanol) up to and including the saturated vapour pressure. The only effect of note which was both statistically significant and biologically plausible was an slight increase in liver weight associated with slight gross and histopathological changes (pale liver coloration and slight vacuolisation consistent with fatty change). However, whilst this could be indicative of minimal hepatic toxicity it could also be due to secondary adaptive change, not directly associated with treatment. The toxicological significance isof this finding is therefore unclear, particularly as no effects were seen in males and the histopathological changes were seen in all female controls.

In a 14 day guideline GLP inhalation study rats were exposed to a single concentration of 350mg/m3 of 2 -(2 -butoxyethoxyethanol) in aerosol form. A satellite recovery group was also included for the dose group and the controls. Microscopic lesions were observed in the lungs, some of which were fully reversible (focal bronchiolisation) but some only partially reversible (multifocal perivascular and peribronchial accumulations of granulocytes. Note that these lesions were also seen in a number of control animals and that the incidence in time and severity became only slightly greater than controls after the recovery period. The aetiology and pathogenesis of the findings was unclear and whether they were substance specific or generic findings typical of any organic liquid inspired into the lungs in aerosol form.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other; digestive: liver

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification

No adverse effects are seen at the repeat dose levels associated with classification under either directive 67/548 or regulation 1272/2008