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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Well documented publication which meets basic scientific principles. Glycol ether acetates are rapidly hydrolysed in vivo to the parent glycol ethers by plasma esterases and will show the same systemic toxicity profile as the parent glycol ether. Data here reported here is for developmental toxicity of 2-butoxyethanol. Full details of the justification for the use of an analogue for this end point are included in the document appended to chapter 13 of this dossier.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Teratogenic evaluation of ethylene glycol monobutyl ether in Fischer 344 rats and new zealand white rabbits following inhalation exposure.
Author:
Tyl RW, Millicovsky G, Dodd DE, Pritts I, France KA and Fisher LC
Year:
1984
Bibliographic source:
Env. Health Perspect., 57, p47-68.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):
- Source: Union Carbide Corporation
- Lot #45-235
- Analytical purity: 99.6 %, verified.

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazelton Dutchland Labs, Denver
- Weight at study initiation: 4kg approx
- Housing: individually in stainless steel wire mesh cages
- Diet (ad libitum except during exposure): Big red rabbit food, Agway Inc
- Water (ad libitum except during exposure): tap
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature, Humidity, Photoperiod (hrs dark / hrs light): Controlled and monitored but not specified.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass and stainless steel 2.1x1x2.1(h)m, volume 4350l.
- Method of holding animals in test chamber: no restraint
- Air change rate: 14/hr
- Temperature, humidity, pressure in air chamber: measured 4x per exposure: temp 75.7-80.9F, humidity 33.9-49%
- System of generating vapour: Liquid metered from a piston pump into a heated glass evaporator. Temperature maintained at minimum required to vapourise liquid. Vapour carried to exposure chamber by conditioned air. Expected chamber concentration reached within 20mins of start of experiment.
- Treatment of exhaust air: filtered.

TEST ATMOSPHERE
- Brief description of analytical method used: GC with FID calibrated over expected concentration range. Sampling once per hour.
- Samples taken from breathing zone: yes. Vapour concentrations in breathing zone found variation of 1%
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC with FID calibrated over expected concentration range. Sampling once per hour.
Details on mating procedure:
Bred using in house breeding colony males. Date of copulation designated GD0
Duration of treatment / exposure:
6hr/day on GD 6-18 (GD0 = day of copulation)
Frequency of treatment:
6hrs/day
Duration of test:
to GD 29
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 25, 50, 100 or 200 ppm (0, 121, 242, 483 or 966 mg/m3)
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 24-26, 49-51, 96-100, 195-207ppm
Basis:
analytical conc.
No. of animals per sex per dose:
24 per dose group.
Control animals:
yes, sham-exposed
Details on study design:
no further information

Examinations

Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes daily

BODY WEIGHT: Yes, days GD 0, 9, 12, 15, 18, 21, 29

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29 (eleven days after the last exposure).
- Organs examined: liver, kidney, thymus, spleen, uterus.
- haematologic analysis also carried out for erythrocyte count, haemoglobin and hematocrit.

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- other: dead and live fetuses. Non-gravid animals also examined for signs of resorptions.
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
Statistics:
For continuous variables: comparison with control by Levene's test for equal variances, ANOVA and t test with Bonferroni probabilities. Non-parametric data compared using Kruskal-Wallis test followed by Mann-Whitney U test when appropriate. Incidence data compared using Fisher's exact test. Significance level of 0.05 used for all assessments.
Indices:
no data
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Clinical observations included periocular wetness, perinasal wetness and discharge, red fluid on trays under age and stained fur. At 200 ppm four females died or were sacrificed by the third day after the onset of dosing and four aborted. All were pregnant. There was no effect on pregnancy rate across treatment groups. Maternal body weight loss was observed in all groups including controls during exposure, but the difference was greatest at 200 ppm and, by GD15, the actual body weight at 200 ppm was significantly lower. Exposure to 200 ppm produced a significant reduction in maternal body weight (8%), gravid uterine weight (22%) and number of total implants and viable implants.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 ppm
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
100 ppm
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
There was a signficant reduction in the number of total and viable implants at 200ppm, but no effects on number of non-viable implants, pre-implantation loss, percent live fetuses, sex ration or male and female body weight per litter. There was no statistically significant increase in the number of fetuses or litters with one or more affected fetuses with pooled external, visceral, skeletal or total malformations in any treatment group relative to controls. For individual malformations, there was a significant increase relative to controls in the number of litters at 100 ppm with one or more foetuses exhibiting fusion of papillary muscles in the left ventricle. Five foetuses from 4/19 litters were affected. However, since this malformation was not observed at the higher or other concentrations it was considered by the authors, the reviewers and the rapporteur as coincidental and not treatment-related. The incidences of skeletal variations did not indicate an adverse treatment effect on ossification. There were significant decreases in the incidences of litters at 200 ppm with unossified sternebra 6 and with rudimentary ribs on lumbar vertebra 1. However the former observation was indicative of better ossification and the latter observation was because more ribs at 200 ppm were full (extra) rather than rudimentary and there were actually no intergroup differences in supernumerary rib numbers. No other variations were observed. Rudimentary rib or extra rib was seen across all groups at relatively high frequency with no apparent exposure related incidence.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

No adverse reproductive effects were observed in animals exposed to 25 ppm or 50 ppm. At 200 ppm four females died or were sacrificed by the third day after the onset of dosing and four aborted. The blood samples taken at necropsy on GD29 (eleven days after the last exposure) showed increased haemoglobin concentration and haematocrit at 100 and 200 ppm, but statistical significance was only evident at 100 ppm. There were no significant increases in the number of foetuses or litters with one or more affected foetuses with pooled external, visceral, skeletal (total) malformations in any treatment group.

Applicant's summary and conclusion

Conclusions:
Exposure of rabbits to 2-butoxyethanol by vapour during pregnancy results in both maternal toxicity and developmental toxicity at concentrations of 200ppm.
Executive summary:

In a GLP developmental toxicity study, pregnant rabbits were exposed to 2 -butoxyethanol vapour at concentrations up to 200ppm during GD6 -18. The results indicated that exposures of up to 100ppm were without effect but exposures of 200ppm produced both maternal toxicity, manifest as reduced body weight and gravid uterine weight, and toxicity to the conceptus (embryotoxicity), manifest as as fewer viable implants. There was no evidence of teratogenicity. This result can be extrapolated to the acetate ester of this substance.

Synopsis

NOAEC (maternal) =100ppm

NOAEC (developmental) =100ppm

Similar values would apply for butoxyethyl acetate.