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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Fertility and teratogenic studies of diethylene glycol monobutyl ether in rats and rabbits
Author:
Nolen GA, Gibson WB, Benedict JH, Briggs DW, Schardein JL
Year:
1985
Bibliographic source:
Fund appl. Toxicol. 5, 1137.

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(2-butoxyethoxy)ethanol
EC Number:
203-961-6
EC Name:
2-(2-butoxyethoxy)ethanol
Cas Number:
112-34-5
Molecular formula:
C8H18O3
IUPAC Name:
2-(2-butoxyethoxy)ethanol
Details on test material:
- Name of test material (as cited in study report): diethylene glycol monobutyl ether.
- Analytical purity: 95% +/-2% as determined by gas chromatography. IR spectrum was identical to a 98.5% pure reference standard.
- Other: supplied by Union Carbide Company.

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Langshaw Farms Inc, Augusta, MI
- Age at study initiation: 5 months
- Housing: individually in suspended wire cages
- Diet ad libitum: Purina certified rabbit chow 5322
- Water: tap, ad libitum
- Acclimation period: 72 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 20-70 with an occasional fluctuation to 78.
- Photoperiod (hrs dark / hrs light): 12/12. Received 30mg/USgal of 12.5% sodium sulphamethazine in drinking water for 7 days 6 weeks before study commenced.

Administration / exposure

Route of administration:
dermal
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: 10x20cm
- Type of wrap if used: no data. Not occluded, no wrap
- Time intervals for shavings or clipplings: prior to initial treatment and then weekly clipped.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes, warm water then dried by towel.
- Time after start of exposure: 4 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 3ml/kg
- Concentration (if solution): no data
- Constant volume or concentration used: yes, 3ml/kg

VEHICLE
- Amount(s) applied (volume or weight with unit): 3ml/kg
- Concentration (if solution): no data

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, collars during exposure period
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: artificial insemination. 3 weeks prior to insemination, does superovulated by injection of 50 USP of chorionic gonadotropin. 10 male rabbits used as semen donors - ejaculated using artificial vaginas. Ejaculate checked to ensure >60% motile before use. Equal numbers of does inseminated from each buck. After insemination, does given 100DUS of chorionic gonadotropin to ensure ovulation.
- Proof of pregnancy: Day of insemination taken as GD0
Duration of treatment / exposure:
days 8 to 19 of gestation
Frequency of treatment:
4 hours/day
Duration of test:
to GD 19
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for animal assignment (if not random): Animals distributed amongst test groups by weight to ensure mean body weights within 2.9SD of means.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: every 3 days beginning GD0

FOOD CONSUMPTION: Yes, daily

POST-MORTEM EXAMINATIONS: No data
- Sacrifice on gestation day 29 by sodium pentobarbital
- Organs examined: no data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- other: number of vialble and non viable fetuses.
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes: by the method of Staples RE (Teratol, 9, A37-8, 1974)
- Skeletal examinations: Yes: by Alizarin red S (Dawson AB, Stain Technol 1, 123-4 (1926)
- Head examinations: No data
Other: weighed, sexed. Fetal findings classified as malformations or variations.
Statistics:
Comparison of treated to control groups. Feed consumption, corpora lutea, implants, resorptions, viable fetuses fetal and, body weights by ANOVA with Bartlett's test for homogeneity and appropriate t-test for variance equality. Regression analysis on dose levels. Fetal abnormalities by Fisher's exact test. Significance set at p<0.05.
Indices:
not reported
Historical control data:
not reported

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Control: No effects
100mg/kgbw/day: No effects.
300mg/kgbw/day:  6/20 slight erythema, 5/20 desquamation.
1000mg/kgbw/day: All animals showed moderate irritation (edema, fissuring, coriaceousness)
All effects began about one week after treatment and persisted until the end of the study.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
All treated dams showed reduced weight gain but only the mid dose group reached statistical significance and there was clearly no dose respose relationship. The standard deviations of the treated animals were >50% of the means. These effects were not thought to be related to the amount of dose absorbed.
Food consumption and compound intake (if feeding study):
no effects observed
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:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
One abortion in high dose group, not attributed to treatment.
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
effects observed, non-treatment-related
Description (incidence and severity):
One early delivery in mid dose group, not attributed to treatment
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 early delivery in mid dose group, not attributed to treatment
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw (total dose)
Based on:
test mat.
Basis for effect level:
dermal irritation
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
all other effects

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
5 dead fetuses were seen in group dosed with 100mg/kgbw.
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
2-(2-butoxyethoxy)ethanol is not teratogenic by the dermal route of exposure
Executive summary:

In a well conducted and reported teratology study in rabbits which conformed to the basic OECD guideline requirements, 2 -(2 -butoxyethoxy)ethanol (DEGBE) produced no signs of developmental toxicity when tested at doses up to 1000mg/kg applied by the dermal route. The only finding that was clearly attributed to treatment was significant irritation at the site of application manifest at doses from 300mg/kg upwards. There was some evidence for a reduction in maternal body weight gain, but this was only significant in the mid dose animals and there was no clear dose response relationship.