Ethanol, 2-ethoxy-, manufacture of, by-products from

Endpoint summary

Description of key information

ORAL NOAEL (mg/kgbw/day) rats
90 day study: 750
90 day study (substance 2-(2-(2-methoxyethoxy)ethoxy)ethanol: 400 (equivalent to 434 for substance in question)
90 day study (substance 2-(2-ethoxyethoxy)ethanol: 800 (equivalent to 1062 for substance in question)
DERMAL (rat, mg/kgbw/day)
90 day study (substance 2-(2-(2-methoxyethoxy)ethoxy)ethanol: 4000 (equivalent to 4340 for substance in question)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

434 mg/kg bw/day

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

6 100 mg/kg bw/day

Additional information

There is no repeat dose toxicity data available on this UVCB substance. Chapter 13 of the IUCLID dossier submitted by the lead registrant contains a full and detailed justification for using a category approach to fulfil the data requirements for glycol ethers and to specifically justify the use of read across for certain end points, including this one. The situation is complex for the repeat dose end point as more than one toxic effect is seen and there are different trends within the glycol ether family for each end point. However, significant repeat dose toxic effects are generally limited only to the monoethylene glycol alkyl derivatives and toxicity declines with increasing numbers of EO units in the molecule. On this basis, it would seem to be scientifically justified and conservative to use extrapolate and/or interpolate using available data from close triethylene glycol and diethylene glycol analogues within the glycol ether family in order to fulfil the data requirements for this substance.

ORAL ROUTE

In a very old oral repeat dose study, male albino rats were exposed to 2-(2-(2-ethoxyethoxy)ethoxy)ethanol (TEGEE, a major component of the UVCB substance) in their drinking water at 0.0, 0.12, 0.5, 2.0, or 8.0% levels ad libitum for 30 days. Actual corresponding calculated doses taking into account the water consumption were 0.0, 0.18, 0.75, 3.30, or 3.29g/kg/day. Animals at 8% consumed the water sparingly and all died. At 2% solution, animals gained less weight than controls and some showed higher blood urea concentrations. Based on this study the NOAEL for male rats can be determined at 0.75g/kg/day. This study is considered reliable but its age means many end points normally examined today were not reported on. This data can be supplemented by more recent results for closely related substances.

In a guideline (OECD 408) and GLP study, exposure to triethylene glycol methyl ether (TGME) in the drinking water of rats for 90 days resulted in decreases in mean food consumption, body weight, and body weight gain for males and females in the 4 g/kg/day treatment group and trends for decreased food consumption and body weight for males in the 1.2 g/kg/day treatment group. Water consumption tended to be decreased at each measurement period for females in the 4 g/kg/day treatment group. Small decreases in mean food consumption, body weight, and body weight gain were also apparent for females in the 1.2 g/kg/day treatment group. One female animal from the 4 g/kg/day treatment group died on study Day 37 without apparent cause. Dose-related increases in mean liver weight were observed for male animals in all three TGME treatment groups. Associated microscopic changes included hepatocellular cytoplasmic vacuolization and/or hepatocellular hypertrophy, for males in the 4 g/kg/day treatment group. Vacuolization or hypertrophy (minimal or mild severity) were also observed in the livers of some males in the 0.4 g/kg/day and 1.2 g/kg/day treatment groups and females in the 4 g/kg/day treatment group. Hypertrophy can be considered a physiological adaptation due to large subchronic doses of the test material, which is likely to be metabolized by alcohol dehydrogenase and aldehyde oxidase in the liver. Treatment-related degeneration and/or atrophy of seminiferous tubules were observed for most males in the 4 g/kg/day treatment group. The cell types affected in the tubules were spermatocytes and developing spermatids. Similar lesions were not observed for males in the 0.4 g/kg/day or 1.2 g/kg/day treatment groups. On the basis of these findings 1200 mg/kg bw/day l is considered to be a subchronic LOAEL for TGME and 400mg/kg bw/day a NOAEL under the conditions of this study. This would be equivalent to a NOAEL of 434mg/kgbw/day for TEGEE.

In a 90 -day subchronic study male and female rats were fed a diet containing 0%, 0.25%, 1.0% or 5% 2 -(2'-ethoxyethoxy)ethanol. Standard body weight and food consumption measurements and haematology, blood urea and urinalysis were conducted as well as necropsy, organ weight determination and histopathology. In the high dose group a decrease in body weight gain associated with lower food intake, and renal effects in the form of increase kidney weight, raised levels of GOT, proteinuria in males, and hydropic degeneration were observed. The high dose group also presented testicular edema and fatty liver changes. No treatment related changes were seen at 0.25% and 1.0% dose groups. The NOEL was established at 1.0% diet, approximately 800 mg/kg/day, which is equivalent to a dose of 1062mg/kgbw/day for the substance TEGEE.

Based on these findings, it is scientifically justifiable to use a weight of evidence approach and to interpolate between the available data on 2-(2-(2-methoxyethoxyethoxy)ethanol and 2-(2-ethoxyethoxy)ethanol, along with the older, less robust data on 2-(2-(2-ethoxyethoxy)ethoxy ethanol to meet the data requirements for this end point. Data from the first analogue is from the most recent study and would lead to the most conservative outcome so this is used as the basis for deriving the key parameter. After scaling for molecular weight differences, conservatively based on the lowest molecular weight of the two major components of this UVCB substance, the NOAEL derived is 434mg/kg/day.

 

DERMAL ROUTE

In a guideline and GLP study, dermal exposure of rats to TGME (>10% of total body surface area, shaved, occluded) at doses up to 4000 mg/kg bw/day for 6 hours/day, 5 days/week (except holidays) for 13 weeks produced no clearly-defined indications of systemic toxicity, even with additional emphasis on lymphoid, hematopoietic and reproductive organs. Parameters evaluated included in-life clinical observations, dermal irritation, body weights, feed consumption, hematology, clinical chemistry, urinalysis, estrous cyclicity, selected organ weights, gross pathology and histopathology. The only treatment-related effects noted in this study consisted of focal areas (<2 mm) of dermal irritation in nearly all animals administered TGME. The dermal irritation was considered secondary to small abrasions induced by repeated clipping of the fur. Areas of the skin that were not abraded by clipping were unaffected by treatment with TGME. All dermal observations noted during the course of the study were not evident at necropsy. Moreover, microscopic examination of tissue from the dermal test site did not indicate pathologic changes. Based on these findings, 4000 mg/kg bw/day is considered a subchronic dermal NOEL for TGME systemic toxicity. It is reasonable to extrapolate from this result to predict that 2-(2-(2-.ethoxyethoxy)ethoxy)ethanol would be of similar toxicity. A correction for molecular weight would lead to a NOEL of 4340mg/kg bw/day.

In a sub-acute repeat dose toxicity study, rabbits were exposed to 2-(2-(2 -ethoxyethoxy)ethoxy)ethanol by occlusive dermal application for a period of 21 days. Daily application of a single 1000mg/kg dose did not produce systemic toxicity in males or females, including haematological or testicular effects. The only significant adverse effects seen were dermal irritation associated with repeat application at the same site. These were not manifest for 6 days and exhibited as slight erythema and oedema although only the erythema persisted until the end of the study.

Based on these findings, it is scientifically justifiable to extrapolate to the available data on the close analogues 2-(2-(2-methoxyethoxyethoxy)ethanol and (2-(2-(2-ethoxyethoxy)ethoxy)ethanol to meet the data requirements for this end point.

Data from the first analogue is from the most recent study and would lead to the most conservative outcome so this is used as the basis for deriving the key parameter. The second study is also a limit study. After scaling for molecular weight differences, conservatively based on the lowest molecular weight of the two major components of this UVCB substance, the NOAEL derived is 434mg/kg/day.

INHALATION ROUTE

The vapour pressure of this substance is so low that no significant exposure is likely via the inhalation route from known uses and therefore no hazard would be expected by the inhalation route , bearing in mind the low toxicity by other routes. In these circumstances and according to column 2 of annexes VIII and IX of the REACH regulation, a study would not normally be required by this route.

Justification for classification or non-classification

The available data indicates that this substance does not warrant classification for repeat dose effects.