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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
three-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
it was conducted between August 1976 and the end of 1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
To fulfill information requirements on reproductive and prenatal toxicity for butyl glycolate by using data from substance produced in the metabolic pathway e.g., glycolic acid and substances with similar main metabolites in the metabolic pathway(NTP 2004, see assessment in Section 13.2) .

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Three-Generation Reproduction and Dominant Lethal Mutagenesis Studies of Ethylene Glycol in the Rat1
Author:
L. DEPASS, M. D. WOODSIDE, R. R. MARONPOT, and C. S. WEIL
Year:
1986
Bibliographic source:
FUNDAMENTAL AND APPLIED TOXICOLOGY 7, 566-572 (1986
Reference Type:
publication
Title:
NTP-CERHR Expert Panel report on the reproduction and developmental toxicity of ethylene glycol
Author:
Center for the evaluation of Rixks to Human Reproduction
Year:
2004
Bibliographic source:
Reproductive Toxicology 18(2004) 457-532

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Animals were randomly assigned to receive 1.0, 0.2, or 0.04 g og EG/kg/day
Two diet control groups, designated 0.0A and 0.0B
Administration of EG to the F0 rats of both sexes began at approximately 7 weeks of age.
At approximately 100 days of age, 10 males were mated to 20 females in each dosage group. On the day of parturition, the number of live and dead newborn were recorded for each litter. The appearance and behavior of dams and pups were observed daily. Litter size was randomly reduced to 10, if necessary, on Day 4 postpartum. Offspring were weighed as litters at 4 and 14 days and individually at 21 days postpartum, the day they were weaned.
Fl rats were randomly selected within each dosage group for the next mating. Each litter was represented except for those conceived very late in the mating period.
The Fl and F2 rats were treated as described for the F0 animals until approximately 100 days of age, at which time the animals were cohabited. Brother and sister matings were avoided for each generation.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
When this studye was conducted, authors were not aware of another reproductive study in vivo in rats with EG available. The objective of the study was to evaluate the effect of EG on fertility and reproductive parameteres in male and female rats.

Test material

Constituent 1
Chemical structure
Reference substance name:
Butyl glycollate
EC Number:
230-991-7
EC Name:
Butyl glycollate
Cas Number:
7397-62-8
Molecular formula:
C6H12O3
IUPAC Name:
butyl glycolate
Constituent 2
Reference substance name:
Polysolvan O
IUPAC Name:
Polysolvan O
Details on test material:
name of substance: butyl glycollate
Specific details on test material used for the study:
Polyester grade EG was received from Union Carbide Corporation, Hahnville, Louisiana, on January 22, 1975. The sample was 99.93% monoethylene glycol by analysis.

Test animals

Species:
rat
Strain:
Fischer 344
Remarks:
Charles River Breeding Laboratories
Sex:
male/female
Details on test animals or test system and environmental conditions:
- young adult nulliparous Fischer 344 rats
- housed two per cage in stainless-steel wire cages at 20-24°C
- controlled lighting (12 hr light) and
- fed Purina Formulab 5008 Chow (Ralston Purina Co., St. Louis, Mo.)
- city water ad libitum

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
1.0, 0.2, or 0.04 g of EG /kg/day
Fresh diet was prepared every 2 weeks with the percentage of EG adjusted, based on the group mean body weight and food consumption, so as to maintain a relatively constant dosage level.
EG concentration in the diet was not changed during gestation or during the first week of lactation, but was reduced two- and threefold during the second and third weeks of lactation, respectively, to adjust for increased food consumption by the dams. This change in concentration was based on earlier data.
EG administration to the F0 rats of both sexes began at approximately 7 weeks of age. At approximately 100 days of age, 10 males were mated to 20 females in
each dosage group.
Fl and F2 rats were treated as described for the F0 animals until approximately 100 days of age.
Details on mating procedure:
F0 rats of both sexes began at approximately 7 weeks of age. At approximately 100 days of age, 10 males were mated to 20 females in each dosage group.
Fl rats were randomly selected within each dosage group for the next mating.
The Fl and F2 rats were treated as described for the F0 animals until approximately 100 days of age.
Brother and sister matings were avoided for each generation.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
The weekly calculated dosages ranged from 1.0 to 1.3,0.2 to 0.3, and 0.04 to 0.05 g/kg/day for males and from 0.9 to 1.2, 0.2 to 0.3, and 0.04 to 0.06 g/kg/day for females.
Duration of treatment / exposure:
For all dosages:
F0: administrtaion of EG started at approximately 7 weeks of age. At approximately 100 days of age, 10 males were mated to 20 females in each dosage group.
F1 & F2: The Fl and F2 rats were treated as described for the F0 animals until approximately 100 days of age.
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
1 000 mg/kg bw/day
Dose / conc.:
200 mg/kg bw/day
Dose / conc.:
40 mg/kg bw/day
No. of animals per sex per dose:
F0: 10 males were mated to 20 females in each dosage group
F1 & F2: as described for the F0
Control animals:
yes
Details on study design:
see above in Principles of the method
Positive control:
no

Examinations

Parental animals: Observations and examinations:
Body weights and diet consumption were recorded weekly except during gestation and lactation.
Date of parturition and the number of live and dead newborn were recorded for each litter.
Appearance and behavior of dams and pups were observed daily.
Oestrous cyclicity (parental animals):
not specified
Sperm parameters (parental animals):
not specified
Litter observations:
Litter size was randomly reduced to 10, if necessary, on Day 4 postpartum.
Postmortem examinations (parental animals):
Necropsies were performed on five males and five females randomly selected from each dosage level of the F2 parents.
Microscopic examinations were performed on sections of liver, kidneys, lung, heart, adrenals, thyroid, trachea, accessory sex glands, adipose tissue, lymph nodes, pituitary, thymus, and testes and epididymis, or uterus and ovaries.
Postmortem examinations (offspring):
Necropsies were performed on five males and five females randomly selected from each dosage level of F3 weanlings.
Microscopic examinations were performed on sections of liver, kidneys, lung, heart, adrenals, thyroid, trachea, accessory sex glands, adipose tissue, lymph nodes, pituitary, thymus, and testes and epididymis, or uterus and ovaries.
Statistics:
Continuous data such as body weights were compared by analysis of variance validated by Bartlett's test for homogeneity of variance. Duncan's multiple range test was used to identify individual mean differences when indicated by a significant F value. Where Bartlett's test indicated heterogeneous variances, t tests for equal or unequal variances were used to delineate differences between groups. Pup weights were compared by the method of Weil (Weil, 1970). Discontinuous
data such as implantations and reproductive indices were compared by a multiple sum of ranks test. Frequency data were compared by the x2 test and by Fisher's
exact test. The following reproductive indices were calculated and evaluated statistically by the previously described nonparametric methods: fertility index (male and female), days from first mating to parturition, gestation index (fraction of pregnancies that resulted in Utters with live pups), gestation survival index (fraction of newborn pups alive at birth), 0 to 4-day survival index, 4 to 14-day survival index, 4 to 21-day survival index. The last four indices are summarized in the tables as means for ease of understanding and presentation, although the nonparametric statistical methods did not include a comparison of means.
Reproductive indices:
The reproductive indices for all three generations are presented in Table 1. No treatment treatment-related effect was observed for any of the indices. Also, EG treatment did not affect neonatal body weight at Days 4, 14, or 21 postpartum.
Offspring viability indices:
There were no significant differences among the treatment groups at any time when compare to the controls.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects were observed

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Effect levels (P1)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects were observed

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Sexual maturation:
no effects observed
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
no effects observed

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
no effects observed

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Sexual maturation:
not specified
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Developmental neurotoxicity (F2)

Behaviour (functional findings):
no effects observed

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not specified

Effect levels (F2)

open allclose all
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects
Dose descriptor:
NOAEL
Generation:
other: F3
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
No reproductive effects associated with the inclusion of as much as 1000 mg/kg/day of ethylene glycol in the diet were found. The NOAEL for parental animals and for offsprings was found to be > 1000 mg/kg/day.