Reaction mass of 2,2'-(Ethylenedioxy)diethanol and 3,6,9-Trioxaundecane-1,11-diol

Endpoint summary

Description of key information

The NOAEL for repeated oral toxicity was determined to be 954.18 mg/kg bw/day (MW-corrected read-across data)

The NOAEC for repeated inhalation toxicity was determined to be 850 mg/m3 (MW-corrected read-across data)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Remarks:

sub-chronic and short-term

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Additional information is available in the endpoint summaries and the read-across justification (see section 13).

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

13 weeks, rat

Effect level:

954.18 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

urinalysis

Remarks on result:

other: Result from read across CAS 25322-68-3 (PEG 400)

Remarks:

Correction for molecular weight was applied

Dose descriptor:

NOAEL

Remarks:

13 weeks, rat

Effect level:

1 522 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

Remarks on result:

other: Result from CAS 112-27-6

Remarks:

No correction for molecular weight applied

Dose descriptor:

NOAEL

Remarks:

33 days, rat

Effect level:

>= 1 742.06 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Result from CAS 112-60-7 / Correction for molecular weight was applied

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

954.18 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation, other

Remarks:

sub-chronic and short-term

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

Additional information is available in the endpoint summaries and the read-across justification (see section 13).

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEC

Remarks:

13 weeks, rat

Effect level:

0.85 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Result from read across CAS 25322-68-3 (PEG200)

Remarks:

Correction for molecular weight is applied

Dose descriptor:

NOAEC

Remarks:

13 weeks, mouse

Effect level:

0.85 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Result from read across CAS 25322-68-3 (PEG200)

Remarks:

Correction for molecular weight is applied

Dose descriptor:

NOAEC

Remarks:

9 days, rat

Effect level:

1 036 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Result from read across CAS 112-27-6

Remarks:

No correction for molecular weight is applied

Dose descriptor:

LOAEC

Remarks:

9 days, rat

Effect level:

494 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical biochemistry

clinical signs

food consumption and compound intake

histopathology: non-neoplastic

organ weights and organ / body weight ratios

water consumption and compound intake

Remarks on result:

other: Result from read across CAS 112-27-6

Remarks:

No correction for molecular weight is applied

Key result

Critical effects observed:

no

Critical effects observed:

yes

Lowest effective dose / conc.:

494 mg/m³ air (analytical)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

850 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There is are no studies available on the repeated dose toxicity of the substance itself (target, EC 907-131-0). Therefore studies from four structural analogues (TEG, TetraEG, PEG 200, PEG 400) have been used to cover this endpoint.

Repeated dose toxicity: oral

A publication by Hermansky (1995) reported a 13-week study equivalent or similar to OECD guideline 408. PEG 400 was administered by gavage to 10 Fischer 344 rats per sex per dose. Animals were exposed to 1128, 2820 and 5640 mg/kg bw/day (equivalent to 1.0, 2.0 and 5.0 mL/kg/day, respectively) once daily, 5 days/week for a period of 13 weeks. The high dose and control groups contained an additional 10 animals/sex that were designated for a 6-week recovery period. Control animals were treated with 5.0 mL Milli-Q filtered water kg/day. During the treatment period, observations for mortality were made twice daily. Observations for overt clinical signs were made once daily throughout the study. Body weight, food and water consumption data and detailed clinical observations were collected weekly for all animals. On the day of killing, body weights were obtained to allow expression of relative organ weights. A complete autopsy was performed on all animals. Clinical chemistry analysis was performed on blood and urine samples. The only treatment-related clinical sign of toxicity observed during the study was loose faeces in the mid- and high dose groups. Some changes in (relative) organ weight and biochemistry were observed in the treated animals. Mortality was observed but was not attributed to chemical toxicity or changes in haematology or clinical chemistry findings. Based on the results, the NOAEL of PEG 400 was determined to be 1128 mg/kg bw/day. After correction for molecular weight the NOAEL for the target substance was determined to 954.18 mg/kg bw/day.

 

In a BRRC study (1990), male and female rats were given orally (feed) doses ranging from 0 - 3849 mg/kg bw/day over a study period of 13 weeks. Small increases in kidney weight (high dose group females) and kidney weight relative to body weight (all groups of males and mid and high dose group females) were considered to be probably treatment related. Haematology measurements were altered at the 13-week measurement period. These changes were considered to be of questionable biological significance based on a lack of similar effect in the females, the small magnitude of the changes, and the lack of corresponding effects in other cell indexes. Decrease in urine pH at all dose levels in males and the mid and high dose levels in females and an increase in urine volume in males from the high dose group were considered to be related to TEG treatment. Based on the lack of any other significant toxic effects, particularly the lack of histologic evidence of renal injury, hyperplasia, or hypertrophy, the altered urine measurements were considered to be most likely related to excretion of the large amounts of test material (or metabolites) during the course of this study. NOAELs were found to be 1522 mg/kg bw/day for male animals and 1699 mg/kg bw/day for female animals. Correction for molecular weight for the target substance was not performed, therefore the NOAEL was also determined to be 1522 mg/kg bw/day.

 

A publication by Schladt (1998) reported a 4-week study equivalent or similar to OECD guideline 407. TetraEG was administered by gavage to 10 Fischer 344 rats per sex per dose. Dose groups were 220, 660 and 2000 mg/kg bw/day. Control animals were treated with water. Complete necropsies were performed on all animals at the end of the study. Clinical signs, body weights, haematology, clinical chemistry and urinalysis were evaluated. No mortality was observed thoughout the study. No other signs of toxicity were noted. Based on the results, the NOAEL of TetraEG was determined to be > 2000 mg/kg bw/day. After correction for molecular weight the NOAEL of the target substance was determined to be >=1742.06 mg/kg bw/day.

Repeated dose toxicity: inhalation

Chemical System Laboratory (CSL; 1981) reported a 13-week inhalation study with Fischer 344 rats. Groups of 72 animals were whole body exposed 6 hours per day, 5 days a week to 0.1 mg/L or 1 mg/L PEG 200 in aerosol form. The control group was treated with air. Groups were divided into three subgroups: (a) 6-week exposure group of 24 animals, (b) 13-week exposure group of 24 animals, (c) a group of 24 animals to be held for 30 days after the 13-week exposure. The exposed and control animals were observed daily for toxic signs and death. The animals used were weighed individually at approximately 2-week intervals. At necropsy, tissues were examined and pathological and haematological parameters were evaluated. It was concluded that PEG 200 produced no positive effects in rats at the 100 and 1000 mg/m3 concentrations over the 13 weeks of exposure used in this study. The NOAEL was determined to be 1 mg/L air. After correction for molecular weight the NOAEL of the target substance was determined to be 0.85 mg/L.

Chemical System Laboratory (CSL; 1981) reported another 13-week inhalation study but with B6C3F1 mice. Groups of 30 animals were whole body exposed 6 hours per day, 5 days a week to 0.1 mg/L or 1 mg/L PEG 200 in aerosol form. The control group was treated with air. Groups were divided into three subgroups: (a) 6-week exposure group of 10 animals, (b) 13-week exposure group of 10 animals, (c) a group of 10 animals to be held for 30 days after the 13-week exposure. The exposed and control animals were observed daily for toxic signs and death. The animals used were weighed individually at approximately 2-week intervals. At necropsy, tissues were examined and pathological parameters were evaluated. It was concluded that PEG 200 also produced no positive effects in mice at the 100 and 1000 mg/m3 concentrations over the 13 weeks of exposure used in this study. The NOAEL was determined to be 1 mg/L air. After correction for molecular weight the NOAEL of the target substance was determined to be 0.85 mg/L.

BRRC (1994) reported a GLP-compliant 9 -day inhalation study with Sprague-Dawley rats. Groups of 10 animals per sex per dose were whole body exposed 6 hours per day to 494, 2011 and 4824 mg/m3 TEG in aerosol form. The control group was treated with a concurrent vehicle. Clinical observations, ophthalmological examinations, body and organ weights, haematalogic and serum clinical chemistry evaluations, urinalysis, and macroscopic and microscopic evaluations were performed throughout the study. Exposure to the highest concentration resulted in mortality after 2 -4 days. Signs of toxicity at 4824 mg/m3 included 4824 mg/m3 included ataxia, prostration, unkempt fur, labored breathing (males only), ocular discharge, swollen periocular tissue, perinasal and periocular encrustation and blepharospasm in both sexes. At 494 mg/m3 and 2011 mg/m3, there were swollen periocular tissues and perinasal encrustations. Among other results, significant changes in body weight, food and water consumption, clinical biochemistry were observed at 494 and 2011 mg/m3. In this study a NOAEL could not be established. The LOAEL was determined to be 494 mg/m3. Since preening of the fur at these high aerosol concentrations exposures might have led to a confounding factor from the resultant oral intake, another 9-day repeated aerosol study was conducted, but by nose-only exposure of Sprague-Dawley rats for 6 hours per day to TEG aerosol concentrations of 102, 517 and 1036 mg/m3 (BRRC 1994). Again, clinical observations, ophthalmological examinations, body and organ weights, haematalogic and serum clinical chemistry evaluations, urinalysis, and macroscopic and microscopic evaluations were performed throughout the study. No mortality was observed at all doses and no exposure-related clinical signs were observed in the male or female animals. The NOAEC was determined to be > 1036 mg/m3. No correction for molecular weight was performed, therefore the NOAEC for the target substance was also determined to be >1036 mg/m3.

Justification for classification or non-classification

Based on the available information classification for repeated dose toxicity is not warranted in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.