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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). KEY 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 65mg/kg (F), 165mg/kg (M), LOAEL (marginal) 165mg/kg (F), 440mg/kg (M) approx. 28 day feeding study

DERMAL

- 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)

INHALATION

- 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)

- LOAEC (aerosol form, 4 weeks) 254mg/m3

- LOAEC (aerosol form, 4 weeks) 350mg/m3

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Organ:
kidney
liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
94 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Effects only seen when substance present in aerosol form above NOAEC. No adverse effects seen from exposure up to saturated vapour concentration.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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. In a sub-acute feeding study in Carworth Wistar rats using dietary levels of 2 -(2 -butoxyethoxy)ethanol up to 2.0%, the most sensitive end point observed was haemolysis. This was manifest through the deposition of haemosiderin in the hepatic Kupffer cells and in red pulp macrophages in the spleen, with the latter the most sensitive and females more sensitive than males. The NOAEL in females was 0.12% in females (approximately 65mg/kgbw/day) and in males 0.3% 165mg/kgbw/day. It should be noted that the effects seen at the NOAELs were likely of marginal statistically significance but clearly of biological significance. It should also be noted that only the pathology report is available for this study and, with no information available on the experimental conditions, it is not a suitable key study. This effect was not seen in other studies and haemolysis induced by other glycol ethers (notably 2 -butoxyethanol) does not tend to worsen with longer exposures and the effect is not considered relevant to humans.

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. In a guideline GLP sub-acute study, male and female rats were exposed for 4 weeks to 2 -(2 -butoxyethoxy)ethanol in aerosol form at measured concentrations between 250 and 5000mg/m3. Exposures were for only 2 hours per day and only a summary report is available of the study. The only treatment related observations were to blood glucose levels (seen in all but low dose animals) and histopathological - liver (males only in two highest dose groups) and lungs - all dose groups showed irregularity of the bronchiolar epithelium. The authors concluded that this study did not provide sufficient basis for the establishment of a no effect level for exposure to the substance in aerosolised 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 but only following exposure to aerosol

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 regulation 1272/2008.