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Key value for chemical safety assessment

Effects on fertility

Description of key information

A study on repeated dose toxicity according to OECD 408 in rats has been performed. In this subchronic gavage study pathological examinations included also reproductive organs in males and females. No treatment related effects were observed even at a dose level of 270 mg/kg bw/day inducing severe local effects and systemic effects secondary to the ulcerative gastritis & peritonitis. Moreover, it is assumed that test substance hydrolyses rapidly within the body and data for hydrolysis product are relevant for this endpoint. Systemic effects on reproduction are not expected after repeated dermal exposure of humans.

Data on toxicity to fertility of the products of hydrolysis are presented below.

The reproductive toxicity of ethylene glycol following ingestion has been investigated in a three-generation study in rats (DePass et al., 1986). The study was non GLP and non guideline but was carried out using similar methods to OECD Test Guideline 416. In the study, young adult F 344 rats aged approximately 7 weeks were fed diets containing ethylene glycol at either 0, 40, 200 or 1000 mg/kg bw/day. When the rats were approximately aged 14 weeks, 10 males were mated to 20 females in each dosage group (F0 generation). Litter size was randomly reduced to 10, if necessary, on day 4 postpartum. F1 rats were randomly selected within each dose group for the next mating. The F1 and F2 rats were administered ethylene glycol in the diet at either 0, 40, 200 or 1000 mg/kg bw/day from approximately 7 weeks of age and were mated at approximately 14 weeks of age. No effects on fertility were observed in any of the three generations of rats exposed to ethylene glycol orally at doses up to 1000 mg/kg bw/day. The NOAEL for the reproductive effects of ethylene glycol in rats exposed orally was therefore >1000 mg/kg bw/day (i.e. the highest dose tested). No adverse effects on the reproductive organs have been observed in adequate chronic oral dose toxicity studies in rats and mice (DePass et al, 1986).

The data for formaldehyde are presented as additional information. The effects are summarised there.

Link to relevant study records
Reference
Endpoint:
three-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
The hydrolysis studies demonstrate that the test substance "reaction product ethylene glycol and para-formaldehyde” hydrolyses rapidly and completely. Therefore, data from the hydrolysis products are regarded sufficient to fulfill the data requirements.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
reproductive performance
Remarks on result:
other: highest dose level tested (limit dose according to OECD 416)
Key result
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
reproductive performance
Remarks on result:
other: highest dose level tested (limit dose according to OECD 416)
Key result
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
histopathology: non-neoplastic
other: fertility, fecundity, and reproductive performance
Remarks on result:
other: highest dose level tested (limit dose according to OECD 416)
Key result
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
other: fertility, fecundity, or reproductive performance
Remarks on result:
other: highest dose level tested (limit dose according to OECD 416)
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Additional information

Data on formaldehyde

In a two-years drinking-water study of formaldehyde in rats (Til et al. 1989), which is comparable with OECD guideline 453, no adverse effects on the reproductive organs were recorded even at the high dose level of 109 mg/kg bw/day in males and 82 mg/kg bw/day in females inducing local effects in the stomach. These results are confirmed by Tobe et al. (1989) and further oral and inhalation studies in rats, mice and dogs.

Ward et al. (1984) investigated sperm count, morphology and fluorescent body frequency in occupationally exposed workers. No significant differences between exposed and non-exposed subjects were measured; however, the small number of subjects limited the detection power. In a study on women exposed to formaldehyde in the high exposure group, a longer time to pregnancy was reported (Collins et al. 2001).

No studies were available which are directly related to this endpoint (e.g. OECD guideline 415, 416, or 422). However, no studies are needed because it is not to be expected, that formaldehyde reaches the reproductive organs and there is no evidence for effects on fertility in experimental animals after oral or inhalation exposure. No conclusions can be drawn from the limited data in humans.

Effects on developmental toxicity

Description of key information

Evidence from published studies in rodents exposed to ethylene glycol via oral gavage during gestation suggests a consistent pattern of developmental effects including reduced fetal body weight and increases in malformations, particularly axial skeletal malformations, indicating that the developing fetus is a target for toxicity after oral exposures.  Effects were observed at doses at which maternal toxicity was not observed.  A single study of dermal exposure to ethylene glycol in pregnant mice did not indicate developmental effects. Reliable developmental studies following inhalation exposures to ethylene glycol are not available.  Of the available studies, the study by Neeper-Bradley et al. is considered to be well-conducted.  The study in mice identified the lowest LOAEL for developmental effects.  

The NOAEL for the maternal toxicity of ethylene glycol in mice was considered to be >1500 mg/kg bw/day (i.e. > the highest dose used in the study).  The NOAEL for the developmental toxicity of ethylene glycol in mice was considered to 150 mg/kg bw/day based on reduced body weights and increased incidence of total malformations and bilateral extra ribs at 500 mg/kg bw/day.  

The data for formaldehyde are presented as additional information. The effects are summarised there.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
The hydrolysis studies demonstrate that the test substance "reaction product ethylene glycol and para-formaldehyde” hydrolyses rapidly and completely. Therefore, data from the hydrolysis products are regarded sufficient to fulfill the data requirements.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
3 549 mg/kg bw/day
Remarks on result:
other: no adverse effects observed up to highest dose level tested
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
3 549 mg/kg bw/day
Based on:
test mat.
Remarks on result:
other: no adverse effects observed up to highest dose level tested
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
The hydrolysis studies demonstrate that the test substance "reaction product ethylene glycol and para-formaldehyde” hydrolyses rapidly and completely. Therefore, data from the hydrolysis products are regarded sufficient to fulfill the data requirements.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day
Remarks on result:
other: no effect observed up to highest dose tested
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
skeletal malformations
other: total malformations
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: not specified
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
500 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
The hydrolysis studies demonstrate that the test substance "reaction product ethylene glycol and para-formaldehyde” hydrolyses rapidly and completely. Therefore, data from the hydrolysis products are regarded sufficient to fulfill the data requirements.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
mortality
histopathology: non-neoplastic
Dose descriptor:
LOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
mortality
histopathology: non-neoplastic
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Remarks on result:
other: no adverse effects observed up to highest dose level tested
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
The hydrolysis studies demonstrate that the test substance "reaction product ethylene glycol and para-formaldehyde” hydrolyses rapidly and completely. Therefore, data from the hydrolysis products are regarded sufficient to fulfill the data requirements.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
water consumption and compound intake
Dose descriptor:
LOAEL
Effect level:
2 500 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
water consumption and compound intake
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: not specified
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Additional information

Data on formaldehyde

Rats exposed to 0, 2, 5, 10 ppm formaldehyde for 6 h/day at gestation day 6-15 showed maternal toxicity (reduced weight gain) at the high dose level. However, no embryo- or fetotoxic effects and no external, visceral or skeletal malformations were reported at any dose level (Martin 1990). Even at doses up to 40 ppm (6 h/days at gestation day 6-20) no teratogenic effects were detected in rats; only effects on foetal weight are reported at ≥ 20 ppm (Saillenfait et al. 1989). However, at these dose levels maternal toxicity is obvious due to irritation of the upper respiratory tract in dams (OECD 2002). In a feeding study on Beagle dogs 3.1 or 9.4 mg/kg bw/day on day 4 to 56 after mating resulted in no external malformations nor embryo- or foetotoxic effects. No maternal toxicity was reported (but no data given on maternal weight gain; Hurni & Ohder 1973). In a developmental toxicity study on mice no embryo- or fetotoxic effects were reported after oral exposure at dose levels resulting in maternal toxicity (Marks et al. 1980).

There were inconsistent findings in epidemiological studies on spontaneous abortions; however, no conclusion can be drawn due to limitations of these studies (Collins et al. 2001).

There is no evidence for adverse effects of formaldehyde on embryo and foetal development at dose levels inducing no local maternal toxicity.

Mode of Action Analysis / Human Relevance Framework

Supporting information indicates that following maternal exposures to ethylene glycol the metabolite, glycolic acid, is the primary developmental toxicant in rodents.  The inverted yolk sac placenta, a stage in placental development that does not exist in humans or in rabbits, tends to concentrate weak acids such as glycolic acid in the embryonic fluids.  The data suggest that rodents have a greater sensitivity towards the developmental toxicity of ethylene glycol than humans or rabbits, on account of the tendency for glycolic acid to accumulate in the inverted yolk sac stage.  There is no evidence to indicate that ethylene glycol has the potential to exert developmental toxicity in humans: human embryo development does not involve an inverted yolk stage and accumulation of glycolic acid is therefore unlikely.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. According to Regulation (EC) No 1272/2008, the hydrolysis products ethylene glycol and formaldehyde are currently not classified for developmental toxicity. Based on these data, the substance is not considered to be classified for toxicity to reproduction under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EC) No 2017/776.