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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive Toxicity Study:

This study was performed to evaluate and assess the effects of the test chemical on the reproductive health of the test animals. In this study, the male Fischer 344 rats were exposed to 0, 5000, 25,000, or 50,000 ppm test chemical in drinking water for 5 consecutive days in a dominant lethal assay, wherein 20 rats per group were included for the study.The respective daily consumption levels of the three doses of the test chemical were 425 ± 45, 2441 ± 328, and 5699 ± 1341 mg/kg.At the end of the 5-day dosing period, the test chemical mixed in drinking water was replaced with regular water. Beginning 24 h after the last test chemical exposure, the males were mated with two naive (non treated) virgin females. When those females showed evidence of copulation, they were replaced with two more females, until each male had mated with 10 females or until 10 weeks had passed. At the end of the 10th week after the test chemical exposure, males were killed for necropsy (observations of male toxicity are described in Short-Term Toxicity earlier in this report). The females were observed and killed on gestation day 15, at which time corpora lutea and implantation sites (resorptions and live embryos) were counted. Reproductive parameters, including number of fertile males and number of gravid females with viable implants, were not affected by test chemical treatment. There were no significant preimplantation losses or dominant lethal effects observed. A concurrent positive control group of males receiving an i.p. injection of 0.5 mg/kg of the positive control were bred with naïve females in a similar manner described above. The positive control group showed increased pre- and postimplantation loss, increased early resorptions, and significant dominant lethal effect.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from a secondary source.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
The above experiment was performed to evaluate and assess any toxicological property of the test chemical affecting the reproductive and developmental functions of the test animals
GLP compliance:
not specified
Justification for study design:
No Data Available
Specific details on test material used for the study:
Details on test material
- Name of test material (as cited in study report): Poly(oxy-1,2-ethanediyl),α-hydro-ω-hydroxy- Ethane-1,2-diol, ethoxylated / Poly(oxy-1,2-ethanediyl),α-hydro-ω-hydroxy- Ethane-1,2-diol, ethoxylated
- Molecular formula (if other than submission substance): (C2-H4-O)mult-H2-O
- Molecular weight (if other than submission substance): 44.0526 g/mol
- Substance type: Organic
- Physical state: No Data Available
- Impurities (identity and concentrations): No Data Available
Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
No Data Available
Sex:
male/female
Details on test animals or test system and environmental conditions:
No Data Available
Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
No Data Available
Details on mating procedure:
-Case 1: 1:2; Case 2: 1:10
Beginning 24 h after the last PEG-4 exposure, the males were mated with two naive (nontreated) virgin females. When those females showed evidence of copulation, they were replaced with two more females, until each male had mated with 10 females.

- Length of cohabitation: 10 weeks

Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Duration of treatment / exposure:
Males were dosed with the test chemical for 5 consecutive days. Female rats were exposed for 10 weeks.
Frequency of treatment:
No Data Available
Details on study schedule:
Deatils on study schedule
- F1 parental animals not mated until [...] weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were [...] days of age.
- Age at mating of the mated animals in the study: [...] weeks: No Data Available
Dose Concentration: 0, 5000, 25,000, or 50,000 Ppm
No of animals per sex per dose: 20 animals per dose group.
Details of controls animals: No Data Available
Remarks:
0 ppm (0 mg/kg bw), 5000 ppm (425 ± 45 mg/kg), 25,000 ppm (2441 ± 328 mg/kg), or 50,000 ppm (5699 ± 1341 mg/kg)
No. of animals per sex per dose:
20 animals per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
No data Available
Positive control:
A concurrent positive control group of males receiving an i.p. injection of 0.5 mg/kg triethylenemelamine (TEM).
Parental animals: Observations and examinations:
No Data Available
Oestrous cyclicity (parental animals):
No Data Available
Sperm parameters (parental animals):
No Data Available
Litter observations:
No Data Available
Postmortem examinations (parental animals):
At the end of the 10th week after the test chemical exposure, males were killed for necropsy. The females were observed and killed on gestation day 15, at which time corpora lutea and implantation sites (resorptions and live embryos) were counted.
Postmortem examinations (offspring):
No Data Available
Statistics:
No Data Available
Reproductive indices:
Implantation Index, Resorption Index, Mating Index.
Offspring viability indices:
No Data Available
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
Reproductive parameters, including number of fertile males and number of gravid females with viable implants, were not affected by the test chemical treatment.
Reproductive parameters, including number of fertile males and number of gravid females with viable implants, were not affected by the test chemical treatment. There were no significant preimplantation losses or dominant lethal effects observed.
Dose descriptor:
NOAEL
Effect level:
< 5 699 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
gross pathology
histopathology: non-neoplastic
reproductive performance
Remarks on result:
other:
Remarks:
Not Speciifed
Critical effects observed:
not specified
System:
other: Not Specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
No Data Available
Remarks on result:
not measured/tested
Critical effects observed:
no
System:
other: Not Specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Conclusions:
Based on all the observation, and all the results it was concluded that the NOAEL for the test chemical was found to be 5699 ± 1341 mg/kg.
Executive summary:

This study was performed to evaluate and assess the effects of the test chemical on the reproductive health of the test animals. In this study, the male Fischer 344 rats were exposed to 0, 5000, 25,000, or 50,000 ppm test chemical in drinking water for 5 consecutive days in a dominant lethal assay, wherein 20 rats per group were included for the study. The respective daily consumption levels of the three doses of the test chemical were 425 ± 45, 2441 ± 328, and 5699 ± 1341 mg/kg. At the end of the 5-day dosing period, the test chemical mixed in drinking water was replaced with regular water. Beginning 24 h after the last test chemical exposure, the males were mated with two naive (non treated) virgin females. When those females showed evidence of copulation, they were replaced with two more females, until each male had mated with 10 females or until 10 weeks had passed. At the end of the 10th week after the test chemical exposure, males were killed for necropsy (observations of male toxicity are described in Short-Term Toxicity earlier in this report). The females were observed and killed on gestation day 15, at which time corpora lutea and implantation sites (resorptions and live embryos) were counted. Reproductive parameters, including number of fertile males and number of gravid females with viable implants, were not affected by test chemical treatment. There were no significant preimplantation losses or dominant lethal effects observed. A concurrent positive control group of males receiving an i.p. injection of 0.5 mg/kg of the positive control were bred with naïve females in a similar manner described above. The positive control group showed increased pre- and postimplantation loss, increased early resorptions, and significant dominant lethal effect.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5 699 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The data is Klimisch 2 level.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive Toxicity Study:

The reproductive toxicity data from the supportive studies are as follows:

Reproductive Toxicity Study 1:

This study was performed to evaluate and assess the effects of the test chemical on the reproductive health of the test animals. In this study, the male Fischer 344 rats were exposed to 0, 5000, 25,000, or 50,000 ppm test chemical in drinking water for 5 consecutive days in a dominant lethal assay, wherein 20 rats per group were included for the study.The respective daily consumption levels of the three doses of the test chemical were 425 ± 45, 2441 ± 328, and 5699 ± 1341 mg/kg.At the end of the 5-day dosing period, the test chemical mixed in drinking water was replaced with regular water. Beginning 24 h after the last test chemical exposure, the males were mated with two naive (non treated) virgin females. When those females showed evidence of copulation, they were replaced with two more females, until each male had mated with 10 females or until 10 weeks had passed. At the end of the 10th week after the test chemical exposure, males were killed for necropsy (observations of male toxicity are described in Short-Term Toxicity earlier in this report). The females were observed and killed on gestation day 15, at which time corpora lutea and implantation sites (resorptions and live embryos) were counted. Reproductive parameters, including number of fertile males and number of gravid females with viable implants, were not affected by test chemical treatment. There were no significant preimplantation losses or dominant lethal effects observed. A concurrent positive control group of males receiving an i.p. injection of 0.5 mg/kg of the positive control were bred with naïve females in a similar manner described above. The positive control group showed increased pre- and postimplantation loss, increased early resorptions, and significant dominant lethal effect.

Reproductive Toxicity Data 2:

The study was designed to investigate the reproductive effects of the test chemical to Wistar Rats by oral route were assessed in a three generation of rats in an overall two year study period. Four groups received aqueous solutions of the test chemical in place of drinking water, in concentrations of 1690 mg/kg bw; 270 mg/kg bw; 59 mg/kg bw; 15 mg/kg bw, while the control group was given plain water. The animals were weighed weekly during the period of active growth and monthly thereafter.The animals were allowed to breed and a record was kept of litters born to each female. Some pups from early litters were used to establish an F1 generation of three males and three females at each dosage level, and later a F1 generation of the same size. A total of 28 animals were studied at each dosage level. Blood counts were performed at intervals of about three months upon some rats in each group. Pooled urine samples were examined for sugar and albumen after three, six, and twenty-four months. Resulted in no injury to albino rats when administered in the drinking water over a two-year period. The results obtained were considered together after demonstrating statistically that there was no significant difference in the responses of the three generations. Therefore, based on all the conclusions from the observations made, the NOAEL for the test chemical was considered to be 1690 mg/kg bw.

Reproductive Toxicity Study 3:

A multigeneration study was performed on Swiss ICF Mice to asssess and evaluate the effects of the test chemical on the reproductive and developmental parameters of the animals.10 male and 30 female ICR Swiss Mice (F0) were administered with the test chemical in their drinking water continuously throughout the study. And after this mating, 10 male and 30 female ICR Swiss Mice (F1b) were administered with the test chemical in their drinking water continuously throughout the study. After 35 days on dosing of the test chemical solution, the mice were randaomly mated to produce F1a litters. Two weeks following the weaning of the F1a litters, the F0 mice were rerandomized and mated to produce F1b litters. Then the F0 mice were mated randomly again 2 weeks after the weaning of the F1b litters to produce F1c litters. 10 males and 10 female weanling mice from the F1b litters also were administered with the test chemical in their drinking water and were mated in non-sibling matched to produce F2a litters. F1c and F2b matings were also performed to screen for dominant lethal and teratology effects. Body weight and Fluid consumption were observed for parental animals. Also, litter observation such as Mean litter size, Postnatal  body weights and survival indices were performed. Maternal animals were sacrficed and gross necropsy was performed to observe number of fetal implants, early and late resorptions. Viable fetuses and dominant lethal factors of the fetus were determined. Fetuses were removed and individually evaluated for gross defects and one third of them were examined for skeletal and visceral malformations. No significant changes in reproductive performance were observed in any of the matings. No adverse effects were observed when fetuses were analysed for Mean litter size, postnatal body weight and pup survival indices. The only significant change observed in both the dominant lethal and teratology  screenings was an increase in the ratio of dead fetuses to live fetuses. Thus, based on all the observations and results, NOAEL for the Swiss ICF mice was considered to be 1% (1667 mg/kg bw) of the test chemical for the parental generation and the offspring generation.

Effects on developmental toxicity

Description of key information

Developmental Toxicity Study:

A teratogenic study was conducted to evaluate the foetal body weight,foetal loss and any kind of malformation by the test chemical to female rats orally dosed on gestational days 6-14 or 11-16 with 1.5 -5 ml/animal/day (equivalent to 1500 -5000 ng/kg bw/d). The test chemical was shown to have negative teratogenic effects as Foetal loss and foetal body weight remained within normal limits and no malformations were observed in rats after administration of dosage 1.5 -5 ml/animal/day (equivalent to 1500 -5000 mg/kg bw/d) of the test chemical. Since LOAEL (Low observed adversed effect level) is 1.5 -5 ml/animal/day (equivalent to 1500 -5000 mg/kg bw), it is regarded that there is no teratogenic effectsin the fetuses at concentrations 1.5 -5ml/animal/day (equivalent to 1500 -5000 mg/kg bw/d) when administered orally.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
In developmental toxicity test the teratogenic effects of the test chemical to female rat by oral route were assessed in a one generation in an overall estimation of 6-14 or 11-16 days of gestation.
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Molecular weight (if other than submission substance): 200 daltons
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
No Data Available
Route of administration:
oral: unspecified
Vehicle:
unchanged (no vehicle)
Details on exposure:
Rats were orally dosed on gestation days 6-14 or 11-16 with 1.5 to 5 ml/animal/day.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Details on mating procedure:
Time Mated females were used in the study.
Duration of treatment / exposure:
6-14 or 11-16 days of gestation
Frequency of treatment:
Daily
Duration of test:
20 days
Remarks:
Doses / Concentrations:
1.5 - 5 mg/animal/day
Basis:

No. of animals per sex per dose:
No Data Available
Control animals:
not specified
Details on study design:
No Data Available
Maternal examinations:
Maternal animals were observed for any mortality.
Ovaries and uterine content:
No Data Available
Fetal examinations:
Body weight and Fetal loss were examined.
Statistics:
No Data Available
Indices:
No Data Available
Historical control data:
No Data Available
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
Maternal death were observed at administered doses.
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
No Data Available
Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal deaths occured at mentioned dosages.
Remarks on result:
not measured/tested
Abnormalities:
not specified
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
-Foetal loss and foetal bodyweight remained within normal limits.
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
-Foetal loss and foetal bodyweight remained within normal limits.
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
-Foetal loss and foetal bodyweight remained within normal limits.
- No malformations were observed.
Dose descriptor:
NOAEL
Effect level:
1 500 - 5 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Conclusions:
The negative teratogenic effects on foetal body weight,foetal loss and malformation by the test chemical was observed at dose concentration 1.5 - 5 ml/animal/day (equivalent to 1500 -5000 mg/kg bw/d) in 6-14 or 11-16 days of gestation period. Thus, LOAEL (No observed adversed effect level) for teratogenicity study is considered to be 1.5 - 5 ml/animal/day (equivalent to 1500 -5000 ng/kg bw/d).
Executive summary:

A teratogenic study was conducted to evaluate the foetal body weight,foetal loss and any kind of malformation by the test chemical to female rats orally dosed on gestational days 6-14 or 11-16 with 1.5 -5 ml/animal/day (equivalent to 1500 -5000 ng/kg bw/d). The test chemical was shown to have negative teratogenic effects as Foetal loss and foetal body weight remained within normal limits and no malformations were observed in rats after administration of dosage 1.5 -5 ml/animal/day (equivalent to 1500 -5000 mg/kg bw/d) of the test chemical. Since LOAEL (Low observed adversed effect level) is 1.5 -5 ml/animal/day (equivalent to 1500 -5000 mg/kg bw), it is regarded that there is no teratogenic effectsin the fetuses at concentrations 1.5 -5ml/animal/day (equivalent to 1500 -5000 mg/kg bw/d) when administered orally.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The data is from Klimisch 2 source.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental Toxicity Study:

The developmental toxicity data from the supportive studies are as follows:

Developmental Toxicity Study 1:

A teratogenic study was conducted to evaluate the foetal body weight,foetal loss and any kind of malformation by the test chemical to female rats orally dosed on gestational days 6-14 or 11-16 with 1.5 -5 ml/animal/day (equivalent to 1500 -5000 ng/kg bw/d). The test chemical was shown to have negative teratogenic effects as Foetal loss and foetal body weight remained within normal limits and no malformations were observed in rats after administration of dosage 1.5 -5 ml/animal/day (equivalent to 1500 -5000 mg/kg bw/d) of the test chemical. Since LOAEL (Low observed adversed effect level) is 1.5 -5 ml/animal/day (equivalent to 1500 -5000 mg/kg bw), it is regarded that there is no teratogenic effectsin the fetuses at concentrations 1.5 -5ml/animal/day (equivalent to 1500 -5000 mg/kg bw/d) when administered orally.

Developmental Toxicity Study 2:

A teratogenic study was conducted to evaluate the external, visceral and skeletal malformations by the test chemical of female mice orally dosed on gestation days 6-17 with 500 and 700 mg/kg/day .The test chemical was shown to have teratogenic effects as severe malformations of the skull (exencephaly, fissure in the median facial line), of the paws (dysgenesis of long bones and digits) and of the thoracic skeleton (joined ribs and vertebrae) and Mean foetal body weight was lower in treated groups compared with controls in mice after administration of dosage 500 mg/kg/day of the test chemical. Since LOAELwas considered to be 500 mg/kg/day, it is regarded that there might be lesser teratogenic effects in the fetuses at concentrations 500 mg/kg/day when administered orally.  

Developmantal Toxicity Study 3:

The study was conducted to investigate theteratogenic toxicityeffects of the test materialon 10 day-old rat embryos by using metabolic activating system.The test material was added to activated medium with or without S9-mix from rat to parent female rat up to 48 hours culture period at dose concentration of 250,500,750,1000,2000 mg/kg bw (0.25%,0.5%,0.75%,1%,2% (V/V))(rat serum).Viability, development and abnormalities of rat embryo during study period were evaluated. The test chemicalproved to be embryo lethal at 500 and 750 mg/kg bw with any S9-mix sample and the concentration of 1000 mg/kg bw of the test chemical was always embryo lethal. But at 250 mg/kg bw no such toxicity result were observed in rat embryos.Thus, on the basis of overall discussion of the study the 'No Observed Adverse Effect Level' (NOAEL) forteratogenicitywas considered to be 250 mg/kg bw.

Justification for classification or non-classification

Based on all the results and observation on the studies performed, it can be concluded that the test chemical may not be classified as the reproductive and developmental toxicant according to the CLP regulation.

Additional information