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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: EPA TSCA Testing Guidelines (1985; 1987)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,2'-(ethylenedioxy)diethanol
EC Number:
203-953-2
EC Name:
2,2'-(ethylenedioxy)diethanol
Cas Number:
112-27-6
Molecular formula:
C6H14O4
IUPAC Name:
2-[2-(2-hydroxyethoxy)ethoxy]ethan-1-ol
Test material form:
liquid
Specific details on test material used for the study:
purity: > 99%

Test animals

Species:
mouse
Strain:
CD-1

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Timed-pregnant dams were dosed daily with undiluted TEG or vehicle alone on gestation days 6 - 15. All treatments were administered by gavage. The dose volume was based on the dose group and the individual animals' most recent body weight. The doses employed based on results from a dose range-finding study, also performed on timed-pregnant mice. Vehicle control animals were dosed with deionized water at the top dose volume.
All females on study were weight on g.d. 0, 6, 9, 12, 15 and 18. Food and water consumption were measured at 3-day intervals throughout g.d. 0 - 18. All females were examined daily for clinical signs of toxicity. The treatment period for all study females was g.d. 6 - 15.
The gravid uterus, ovaries (including corpora lutea), cervix, vagina and abdominal and thoracic cavities were examined grossly. Ovarian corpora lutea af pregnancy were counted. Maternal liver and uterine weights were determined. Maternal kidneys were also weighed, and then bisected (left longitudinally, right transversely) and fixed in buffered neutral 10% formalin for possible subsequent histopathologic examination (kidneys from high-dose and control group dams were subsequently examined by light microscopy). The uterus was externally examined for signs of hemorrhage, removed from the abdominal cavity and dissected longitudinally to expose the contents. All live and dead fetuses and resorption sites were noted and recorded. Uteri from females that appeared non-gravid were placed in a 10% ammonium sulfide solution for detection of early resorptions.
Details on mating procedure:
Mice were mated 1:1 (one male:one female) in stainless steel wire-mesh cages (23.-5 cm:x 20.0 cm x 18 cm high) und the paperboard beneath the cages was checked daily for dropped copulation plugs. Each male was used only once in this study. Successfully mated (plug-positive) females were housed singly in animal room 147 for the duration of the study. The day a dropped copulation plug was found was desigated gestation day (gd) 0. Thirty plug positive females were assigned to each experimental group by a randomization procedure stratified by body weight such that all groups were equivalent in both mean body weight and body weight range on g.d. 0.
Duration of treatment / exposure:
gestation day 6 - 15
Frequency of treatment:
daily
Duration of test:
until g.d. 18
Doses / concentrationsopen allclose all
Dose / conc.:
0.5 other: mL/kg bw/day
Remarks:
Nominal concentration
Dose / conc.:
5 other: mL/kg bw/day
Remarks:
Nominal concentration
Dose / conc.:
10 other: mL/kg bw/day
Remarks:
Nominal concentration
No. of animals per sex per dose:
Total: 206
Control animals:
yes, concurrent vehicle
Details on study design:
Because of the lack of toxicity observed from a probe study, a dose (11,000 mg/kg) at approximately 11 times the limit test (1000 mg/kg) had to be used to produce maternal and fetal toxicity. At a dose approximately 6 times the limit test, fetal toxicity was observed. It is extremely unlikely that there is any reasonably foreseeable application or use at which humans would be exposed to such high levels of TEG.

Examinations

Maternal examinations:
All females an study were weighed on gd 0, 6 (prior to onset of dosing), 9, 12, 15 (during the dosing period) and 18. Food and water consumption were measured at three-day intervals throughout gestation (gd 0-18). All females were examined daily for clinical signs of toxicity. The treatment period for all study females was gd 6 through 15.
Ovaries and uterine content:
The gravid uterus, ovaries (including corpora lutea), cervix, vagina and abdominal and thoracic cavities were examined grossly. Ovarian corpara lutea of pregnancy were counted. Maternal uterine weights were determined.
Fetal examinations:
All live fetuses were weighed and sexed. All fetuses were examined for external variations and malformations including cleft palate. All live fetuses in each litter were examined for thoracic and abdominal visceral ahnormallties by modification of methods described by Staple (1974). One-half of the live fetuses in each litter were decapitated and their heads ware fixed In Bouin's solution for examination of craniofacial structures by sectioning methods modified from Wilson (1973). All fetuses (50% intact, 50% decapitated) in each litter were eviscerated, fixed In ethanol, processed for skeletal staining with alizarin red S (Crary, 1962; Paltzer and Schareain, 1966), and examined for skeletal malformations and variations.
Statistics:
The unit of comparison was the pregnant female or the litter (Weil, 1970).
Results of the quantitative continuous variables (e.g. maternal body weights, organ weights, etc.) were intercompared for the three TEG-exposed groups and the vehicle control group by use of Levene's test for equal variances (Levene, 1960), analysis of variance (ANOVA), and t-tests with Bonferroni probabilities for pairwise comparisons. When Levene's test indicated homogeneous variances and the ANOVA was significant, the pooled t-test was used. When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances (Brown and Forsythe, 1974) followed, when necessary, by the separate variance t-test.
Nonparametric data obtained following laparohysterectomy were statiatically treated using the Kruskal-Wallis test (Sokal and Rohlf, 1969) followed by the Mann-Whitney U test (Sokal and Rohlf, 1969) when appropriate. Incidence data were compared using Fisher's Exact Test (Sokal and Rohlf, 1969). For all statistical tests, the probability value of p < of 0.05 (two-tailed) was used as the critical level for significance.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
Clinical observations of the dams were recorded daily. There were no statistically significant treatment-related clinical signs of toxicity. However, treatment-associated clinical signs were observed in 2 dams at 10.0 mL/kg/day. These included hypoactivity in both dams, and audible and rapid respiration in one dam.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No females aborted or died prior to scheduled sacrifice. One female, at 10.0 mL/kg/day, delivered early (on g.d. 18), was euthanized, and removed from the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Periodic maternal body weights and body weight changes were statistically equivalent across treatment groups. No apparent trends (nonstatistically significant reductians) were observed at any exposure level. There were no treatment-related differences in maternal terminal body weight.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption during gestation expressed as grams/dam/day was statistically equivalent among groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Water consumption was equivalent among groups.
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:
effects observed, treatment-related
Description (incidence and severity):
While not statistically significant, gravid uterine weight appeared reduced at 5.0 and 10.0 mL/kg/day. Corrected terminal body weight (body weight at sacrifice minus gravid uterine weight), corrected body weight change (gestational weight gain minus gravid uterine weight), liver weight (absolute and relative to corrected body weight) and absolute kidney weight were unaffected by treatment. Relative kidney weight was significantly increased at 10.0 mL/kg/day.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related necropsy findings of the dams at scheduled sacrifice on g.d. 18. At 0.5 (but not 5.0 and 10.0) mL/kg/day dams exhibited a statistically increased incidence of cystic ovaries. Findings at 10.0 mL/kg/day involved 2 dams, one exhibiting small kidneys and one exhibiting clotted blood and colour change in a single amniotic sac. These findings were not considered to be treatment-related
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Microscopic evaluation of maternal kidneys from the 0.0 and 10.0 mL/kg/day groups revealed no treatment-related histological changes.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Percent preimplantation and postimplantation losses were equivalent across groups.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): effects observed, non-treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): One female each at 0.0, 1.0 and 10.0 mL/kg/day and 2 females at 5.0 mL/kg/d contained only non-viable implants (early or late resorptions or dead fetuses) at scheduled sacrifice. A total of 25 - 28 litters containing one or more live fetuses were examined in each group.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Pregnancy rate was equivalent for all dose groups, ranging from 90.0 - 96.7%.
Other effects:
no effects observed
Details on maternal toxic effects:
There was no effect of treatment on the number of ovarian corpora lutea, total, viable or non-viable (early and late resorptions and dead fetuses) implantations per litter or on sex ratio (percent males).

Effect levels (maternal animals)

Key result
Dose descriptor:
NOEL
Effect level:
5 other: mL/kg bw/day
Based on:
test mat.
Basis for effect level:
organ weights and organ / body weight ratios

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fetal body weights (all fetuses, male or female) per litter were significantly reduced at 5.0 and 10.0 mL/kg/day. Fetal body weights per litter at 0.5 mL/kg/day were equivalent to control values.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Fetal body weights (all fetuses, male or female) per litter were significantly reduced at 5.0 and 10.0 mL/kg/day. Fetal body weights per litter at 0.5 mL/kg/day were equivalent to control values.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There no effect on sex ratio (percent males).
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no statistical differences in the incidences of any individual malformations. A total of 78 different types of individual fetal skeletal variations were observed. Of these, six findings, cervical centra #1, #2, #3 and/or #4 poorly ossified, reduced number of caudal segments, poorly ossified frontal bone, poorly ossified supraoccipital bone, some proximal phalanges of the hindlimb poorly ossified and some proximal phalanges of the hindlimb unossified, exhibited significantly increased incidences at 10.0 mL/kg/day when compared to the control group. There was also a statistically significant increase in the incidence of poorly ossified supraoccipital and frontal at 5.0 mL/kg/day. There were no statistically increased individual skeletal variations at 0.5 mL/kg/day. There were no treatment-related increases in the incidence of variations by category (external, visceral or skeletal) or of total variations.
Visceral malformations:
no effects observed
Other effects:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Effect level:
0.5 other: mL/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
0.5 other: mL/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

Any other information on results incl. tables

Summary of effects seen by daily gavage of mice with undiluted TEG over the period of organogenesis:

 Effect

 Dosage (ml/kg)         
   0.0 = water control  0.5 ml/kg  5.0 ml/kg  10.0 ml/kg
 Gestational body weight change, dys 0 - 18 (g)*  30.90 +/- 7.47  29.63 +/- 6.58  28.35 +/- 8.44  27.59 +/- 6.94
 Maternal relative kidney weight (%)*  1.297 +/- 0.109  1.319 +/- 0.1290  1.353 +/- 0.1032  1.384 +/- 0.1435**
 Gravid uterine weight (g)*  20.729 +/- 6.056  20.303 +/- 4.900  19.631 +/- 6.057  18.562 +/- 4.980
 All fetuses  1.429 +/- 0.115  1.416 +/- 0.997  1.350 +/- 0.066**  1.303 +/- 0.098***
 - males  1.463 +/- 0.114  1.442 +/- 0.116  1.384 +/- 0.074**  1.332 +/- 0.106***
 - females  1.391 +/- 0.118  1.395 +/- 0.092  1.321 +/- 0.066**  1.271 +/- 0.102***

* results as mean +/- SD

** p<0.05 (compared to controls)

*** p<0.01 (compared to controls)

Applicant's summary and conclusion