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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
The basis for this read-across approach is that the target substance is expected to undergo transformation into terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1). The toxicity of the metabolites will accurately predict the toxicity of the bis(2-hydroxyethyl)terephthalate (BHET; 959-26-2; 213-497-6). Refer to the JUSTIFICATION FOR READ-ACROSS OF TOXICOLOGICAL INFORMATION in Section 13 of this dossier for further details.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1989
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)
GLP compliance:
yes
Specific details on test material used for the study:
Test material was supplied by the Amoco Corporation.
Purity was not noted but typically exceeds 99%
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
Female rats weight 117-150 g
Route of administration:
inhalation: aerosol
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
Exposures were by whole body inhalation conducted in 2 m³ chambers with an airflow rate of 305-420 L/min. Test article was ground to respirable-sized particles using a Retsch Ultra-Centrifugal Mill. Chambers were sampled 2x/exposure period and TPA levels were determined by spectrophotometric analysis. Particle size was determined using a cascade impactor.
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
Female rats weight 117-150 g were quarantined and housed 2/cage with 1 male.
Confirmation of mating was via evidence of sperm in a vaginal smear (Day 0).
Duration of treatment / exposure:
days 6-15 of gestation
Frequency of treatment:
6 hours/day for 10 consecutive days
Duration of test:
20 days
Dose / conc.:
1 mg/m³ air (nominal)
Remarks:
0.90 mg/m³ (Time-weighted average)
Dose / conc.:
5 mg/m³ air (nominal)
Remarks:
4.73 mg/m³ (Time-weighted average)
Dose / conc.:
10 mg/L air (nominal)
Remarks:
10.4 mg/m³ (Time-weighted average)
No. of animals per sex per dose:
26-27 timed-pregnant dams per dose level
Control animals:
yes
Details on study design:
Confirmation of mating was via evidence of sperm in a vaginal smear (Day 0), after which females were housed singly. The study consisted of 26-27 timed-pregnant dams per dose level.

Temperature, humidity and airflow were measured hourly. Animals were observed twice daily and given detailed physical exams daily on days 0 and 6-20. Dams were weighed on Days 0, 5 (randomization into groups), 6 (exposure initiation), 11, 16, and 20 (study termination). Standard “guideline” post-mortem procedures were carried out on the females and their fetuses.
Statistics:
Data were analyzed in an appropriate statistical manner using log transformations, multivariate ANOVA, single factor ANOVA and Dunnett’s-“t”-test depending on the nature and type of end-point assessed. The dam was considered to be a random factor and the pup a nested factor within the dam.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No statistically significant differences in uterine weight
Pre- and post-implantation loss:
no effects observed
Dose descriptor:
NOAEL
Effect level:
10 mg/m³ air (nominal)
Based on:
test mat.
Basis for effect level:
other:
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
No statistically significant differences were noted in mean litter weights.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
No statistically significant differences were noted in pup viability
External malformations:
no effects observed
Description (incidence and severity):
External soft tissue examinations did not indicate any differences from control
Skeletal malformations:
no effects observed
Description (incidence and severity):
Internal examinations showed a slight increase in the incidence of rib anomalies in the middle dose (5.0 mg/m³) group. This was only significant when all the various types of rib anomalies were added together.

Rib anomalies were not deemed to be an indicator of teratogenesis because they were common variations, were not elevated in a dose-related manner, and occurred at a rate that was within the range of laboratories own historical controls. Furthermore, no other signs of embryotoxicity were associated with this change.
Visceral malformations:
no effects observed
Dose descriptor:
NOAEL
Effect level:
10 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No statistically significant differences were noted at any dose group.
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
No evidence of maternal or developmental toxicity was seen in an inhalation study with rats exposed to terephthalic acid at levels of up to 10.4 mg/m³.
Reason / purpose for cross-reference:
read-across source
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:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Guideline:
other: Assessing the potential of ethylene glycol, when administered by gavage during major organogenesis, to cause maternal and developmental toxicity in rabbits, a common non-rodent test animal species.
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight: The range of actual body weights for females on GD 0 was 2470 to 4460 g
- Housing: Inseminated females were individually housed in stainless steel cages with mesh flooring
- Diet: Certified rabbit chow, ad libitum
- Water: filtered water, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.6 °C
- Humidity (%): 54.1% (range of 26.8 to 81.9%)
- Photoperiod (hrs dark / hrs light): Animal room lights were on from 7 to 19 hr for females and from 7 to 21 hr for males
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Artificially inseminated New Zealand white does were dosed daily with EG in vehicle or with the deionized/distilled water vehicle on the mornings of GD 6-19. Treatment was by gavage using a stainless steel dosing tube. A dose volume of 5 mL/kg body wt was used for all groups. The volume administered was adjusted according to daily body weights. All formulations were 93 -107% of theoretical for predosing analyses/for the postdosing analyses. All formulations were 91.6-109% of the predosing measured concentrations.
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
To induce ovulation, females received an intravenous injection of Pregnyl (0. 1 ml/kg) immediately prior to insemination. The day of insemination was designated as Gestational Day (GD) 0. Females were assigned to dose groups (23 -24 per group) by stratified randomization on GD 0 so that body weights did not differ among groups within any individual replicate. The study was performed in two replicates (11-12 inseminated females per dose per replicate) with two consecutive breeding days in each replicate. The last breeding date for the first replicate and the first breeding date for the second replicate were 5 weeks apart.
Duration of treatment / exposure:
gestation day 6 to 19
Frequency of treatment:
daily
Duration of test:
until gestation day 30
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
23 - 24
Control animals:
yes, concurrent no treatment
Details on study design:
The doses chosen were based on preliminary studies with nonpregnant rabbits and information from rodents which indicated developmental effects at much lower doses than maternal effects. Analyses of the dosing formulations indicated that they were homogeneous and stable for at least 3 weeks.
Maternal examinations:
Inseminated females were weighed on GD 0, 6-19, 25, and 30. Females were observed and maternal water consumption was measured daily throughout gestation GD 0-30. All surviving inseminated females were killed at scheduled necropsy on GD 30 by iv injection of a euthanasia solution into the marginal ear vein. The maternal liver, kidneys and intact uterus were weighed and corpora lutea counted. Uteri which presented no visible implantation sites were stained with ammonium sulfide (10%) to detect very early resorptions. Maternal kidneys were bisected and fixed in 10% neutral buffered formalin. Kidneys from 10 randomly selected does from the control through the 1000 mg/kg/day EG groups and all the kidneys from the 2000 mg/kg/day EG group as well as kidneys from all does which died during study were sectioned, stained with hematoxylin/eosin and evaluated histologically. The sections were also examined under polarized light for oxalate crystals.
Fetal examinations:
Live fetuses were dissected from the uterus and euthanized. They were weighed, examined for external morphological abnormalities including cleft palate and dissected for visceral examination and determination of sex by a fresh tissue dissection technique. Half of the fetuses were decapitated after dissection: the heads were fixed in Bouin's solution and then examined by a freehand sectioning technique. All fetal carcasses were skinned, cleared, stained with Alcian blue/alizarin red S. and examined for skeletal malformations and variations.
Statistics:
Analyses were performed using the doe or the litter as the experimental unit. General Linear Trend Models procedures were applied for the analysis of variance (ANOVA) of maternal and fetal parameters. Prior to GLM analysis, an arcsine-square root transformation was performed on all litter-derived percentage data and Bartlett's test for homogeneity of variance was performed on all data to be analysed by ANOVA.
Clinical signs:
no effects observed
Description (incidence and severity):
No clear treatment-related clinical signs of toxicity were observed.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
Maternal toxicity was observed at 2000 mg/kg/day, expressed as 42.1% mortality (8 of 17 pregnant animals). The 8 does which died at 2000 mg/kg/day died on GD 9 (one doe) and 11 (two does) and on GD 13, 14, 19, 21 and 25 (one doe each).
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Periodic maternal body weights and weight changes were statistically equivalent across all groups for all intervals evaluated.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Maternal water consumption, expressed as g/animal/day or as g/kg/day was also statistically equivalent across all groups for all intervals, although water consumption appeared slightly increased for all EG-dosed groups during the treatment period but not in a manner related to dose.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
At scheduled necropsy on GD 30 there were no significant effects of treatment on corrected (for uterine weight) maternal gestational weight change, gravid uterine weight, liver weight, or kidney weight at any dose. However, maternal absolute kidney weight (but not relative weight) was slightly increased at 2000 mg/kg/day to 106.3% of the control value for the right kidney (left kidney value was 107.6% of control).
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histologic evaluation of maternal kidneys revealed treatment-related renal lesions only at 2000 mg/kg/day. The lesions were limited to the cortical renal tubules and included intraluminal crystals (appearance consistent with oxalate), epithelial necrosis, and tubular dilatation and degeneration. The most severe findings, crystals (designated "marked") and necrosis, were observed in the does which died on study, but the renal tubular necrosis observed in these animals was not a postmortem event. The cause of death in these animals was determined to be renal failure.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
An increase in early deliveries with three does at 2000 mg/kg bw (and one each at all other doses) was observed. One dose at 2000 mg/kg/day aborted on GD 20 (no litters were aborted at any other doses). Increases in early deliveries and abortion are usually considered indicative of maternal stress in rabbits.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There were no treatment-related effects on any gestational parameters, including no effects on number of ovarian corpora lutea, on total non-live or live implantation sites per litter, or on pre- or post-implantation loss. There was a statistically significant increase in the number of corpora lutea at 500 mg/kg/day associated, as expected, with a slight increase in the number of implantation sites/litter and a slight increase in live litter size. This finding was not observed at higher doses and is considered most likely due to biologic variation. The values at 500 mg/kg/day are still well within historical control values for these parameters.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Pregnancy rate was high and equivalent across all groups from 0 - 1000 mg/kg/day (95.5, 95.7, 91.3, and 95.2%, respectively); pregnancy rate was slightly lower (8 1.8%) at 2000 mg/kg/day.
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
There were no statistically significant or biologically relevant differences among groups for prenatal mortality, expressed as resorptions or dead fetuses, or for prenatal toxicity, expressed as fetal body weight/litter for all fetuses or for male and female fetuses separately.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
There were no treatment-related alterations in incidence of malformations pooled as external, visceral (including craniofacial), or skeletal, or as total malformations or variations. Examination of fetal malformations and variations by individual findings also indicated no findings which were treatment- or dose-related and none which appeared predominantly or exclusively at higher doses.
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: There were no effects observed
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Ethylene glycol is not a developmental toxicant in the rabbit, no classification is warranted
Executive summary:

The sensitivity of NZW rabbits relative to that of Sprague-Dawley rats and Swiss mice for maternal and developmental toxicity from gavage administration of EG during organogenesis can be determined for maternal toxicity: rabbits > mice > rats, and for developmental toxicity: mice > rats > rabbits.



Given that glycolic acid disposition between the maternal blood and the embryo is driven by the polarity of MCT1 and MCT4 isoforms in the placenta, that glycolic acid is sequestered in the rat and not the rabbit, and that the rabbit and human placenta show similar polarity to each other and opposite to that of the rodent, it is proposed that the rabbit is the most appropriate species for the basis of classification. As such, and since ethylene glycol is not a developmental toxicant in the rabbit, no classification is warranted.

Data source

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis(hydroxyethyl) terephthalate
EC Number:
213-497-6
EC Name:
Bis(hydroxyethyl) terephthalate
Cas Number:
959-26-2
Molecular formula:
C12H14O6
IUPAC Name:
bis(hydroxyethyl) terephthalate
Test material form:
solid
Specific details on test material used for the study:
Bis(2-hydroxyethyl) terephthalate value is read-across from supporting terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1) data.

Test animals

Details on test animals or test system and environmental conditions:
Bis(2-hydroxyethyl) terephthalate value is read-across from supporting terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1) data.

Rabbit selected for the read-across as most sensitive species

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Ethane-1,2-diol (203-473-3; 107-21-1) is not a developmental toxicant in the rabbit, no classification is warranted.

No evidence of maternal or developmental toxicity was seen in an inhalation study with rats exposed to terephthalic acid (202-830-0; 100-21-0).

Based on the transformation products, BHET (959-26-2; 213-497-6) is not a developmental toxicant
Executive summary:

There was no evidence of terephthalic acid maternal or developmental toxicity in an OECD 414 GLP-compliant aerosol inhalation study with rats (OECD SIDS, 2001).  The rats were dosed at levels up to 10.4 mg/m3.  Administration of ethane-1,2-diol (203-473-3; 107-21-1) to New Zealand White rabbits (0, 100, 500, 1000, or 2000 mg/kg bw/day; p.o.) caused mortality in 42% of the does as a result of renal failure. In the offspring, no effects upon survival, foetal weight, or the incidences of external, visceral, or skeletal malformations or variations were observed at any dose level, including the progeny of surviving does treated with 2000 mg/kg/day ethane-1,2-diol. Ethane-1,2-diol resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology (Tyl, et al., 1993) yet no developmental effects were noted in the progeny. Given that glycolic acid disposition between the maternal blood and the embryo is driven by the polarity of MCT1 and MCT4 isoforms in the placenta, that glycolic acid is sequestered in the rat and not the rabbit, and that the rabbit and human placenta show similar polarity to each other and opposite to that of the rodent (Moore, et al., 2016; Settle et al., 2004), it is proposed that the rabbit is the most appropriate species for the basis of classification. As such, and since ethylene glycol is not a developmental toxicant in the rabbit, no classification is warranted. Information on the source substances was considered to be directly applicable to an equivalent molar amount of the target substance; therefore, BHET as not developmentally toxic. BHET is predicted to have a NOAEL greater than 1000 mg/kg bw/day.