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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:
other: A published study which is sufficiently well reported to be able to judge it as reliable for risk assessment purposes for this end point.
Cross-reference
Reason / purpose:
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:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Remarks:
significant deviations noted
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): 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 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 / concentrations
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
nominal in water
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: Yes / No / 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

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No deaths. For local skin effects see table 1. 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.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 100 - < 300 mg/kg bw (total dose)
Basis for effect level:
other: other:

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Occasional isolated effects in single dams across dose groups was not attributed to treatment (one abortion in high dose group, 1 early delivery in mid dose group). There were no significant differences seen in the mean  numbers of corpora lutea, implants, resorptions or viable  foetuses or in the mean foetal body weight. and incidence of skeletal  anomalies or of gross or visceral malformations.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Skin irritancy was noted as follows after approximately one week of treatment and persisted until sacrifice:

 Dose group:  Control and 100mg/kg  300mg/kg  1000mg/kg
 Findings:  No effects  6/20 slight erythema5/20 desquamation All animals showed moderate irritation (edema, fissuring, coriaceousness)


  

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 teratology study which conformed to the basic OECD guideline requirements, 2 -(2 -butoxyethoxy)ethanol produced no signs of developmental toxicity when tested at doses up to 1000mg/kg bw/day 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 bw/day 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.