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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented publication, acceptable with restrictions (Exposure was only before mating and not according to a standard developmental study protocol).

Data source

Reference
Reference Type:
publication
Title:
Toxicology and carcinogenesis studies of Allyl Glycidyl Ether (CAS No. 106-92-3) in Osborne-Mendel rats and B6C3F1 Mice (inhalation studies).
Author:
National Toxicology Program (NTP)
Year:
1990
Bibliographic source:
NTP Technical Report 376, NIH Publication No. 90-2831, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Four groups of rats (20/sex/dose) were exposed to vapor of Allyl Glycidyl Ether at concentrations of 0, 140, 467 and 934 mg/m3 (0, 30, 100 and 200 ppm; 6 hours/day, 5 days/week) for 8 weeks (pre-mating). Mating (1:1) begun 2 days after the end of the 8 week exposure period: control animals with control animals, exposed males with control females and control males with exposed females. Half of the pregnant females were used for fetal examinations (killed on day 19 of pregnancy); the remainders were used for postnatal examinations (up to day 21 post-partum).
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Allyl Glycidyl Ether
- Physical state: clear colorless liquid
- Analytical purity: 99 %
- Lot/batch No.: E337MO

Test animals

Species:
rat
Strain:
Osborne-Mendel
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: CAMM Research Institute (Wayne, NJ)
- Age at study initiation: 8 weeks
- Weight at study initiation (mean weight): male 234-269 g, females 177-187 g
- Diet (e.g. ad libitum): NIH 07 Rat and Mouse Ration (Zeigler Bros., Inc., Gardners, PA)
- Water (e.g. ad libitum): Automatic watering system
- Acclimation period: 21 days

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
not specified
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Vapor Generation System: No additional preparation of the liquid allyl glycidyl ether (AGE) was necessary before introduction into the vapor generation system. The liquid was pumped from a stainless steel reservoir to a vaporizer by a stable micrometering pump with adjustable pump rates.
- Temperature, humidity in air chamber: 20.6-26.7 °C, 32-75%

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography with a flame ionization detector
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Actual concentrations: Not indicated; in most instances, the vapor concentrations were within 10 % of the nominal concentrations
- Stability: No significant decomposition was observed
- Homogeneity: homogeneous distribution of the vapor
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Mating begun 2 days after the end of the 8 week exposure period: control animals with control animals, exposed males with control females and control males with exposed females.
- Length of cohabitation: 7 days
- Proof of pregnancy: sperm in vaginal smear day 0 of pregnancy
Duration of treatment / exposure:
8 weeks (premating)
Frequency of treatment:
6 hours/day; 5 days/week
Duration of test:
males 10 weeks, females 11-14 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 100 and 200 ppm (equivalent to 0, 140, 467, 934 mg/m3)
Basis:

No. of animals per sex per dose:
20
Control animals:
yes, sham-exposed
Details on study design:
- Post exposure period: male 2 weeks; females 3 weeks (until day 19 of gestation)

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked: clinical signs / mortality

BODY WEIGHT: Yes
- Time schedule for examinations: animal weights were recorded before the studies, once per week, and at necropsy.

FOOD CONSUMPTION: no

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day: Females in which copulation was detected were separated into two groups:
Foetal examination group (10F): killed on day 19 of pregnancy (to study developmental effects)
Pup examination group (10F): killed along with their pups on day 21 post-partum
- Organs examined: not reported

OTHER: uterus, ovaries were weighed
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes, males exposed: 8, 6, 4 and 0 females examined at 0, 30, 100 and 200 ppm, respectively; females exposed: 8, 9, 10 and 8 examined at 0, 30, 100 and 200 ppm, respectively.
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes, shape of head, limbs, and number of digits and gross external malformations and cleft palate in all foetuses.
- Foetal weight: all foetuses, placenta separately
- Foetal sex: determined
Statistics:
Dunnett's test (Dunnett, 1980)

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
- Mortality: no effect observed
- Clinical signs: not reported
- Body weight: A decrease body weight gain was seen in males (82 and 70% of control) and females (92 and 86% of control) at 100 and 200 ppm at the end of exposure. At termination female body weight had recovered, while male body weights were still reduced at all dose levels (90, 89 and 84% of control at 30, 100 and 200 ppm, respectively).
- Organ weight: No effect was seen on placenta weight either when the males or the females were exposed previous to mating. No effect was seen on gravid uterus weight when the female rats were exposed. However, a statistically significant decrease in gravid uterus weight was observed when males were exposed to the test substance (45 and 40% of control at 30 and 100 ppm, respectively), due to the lower number of implantation.

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Effect level:
ca. 467 mg/m³ air
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
- External findings including malformations and anomalies:
Control males with exposed females: no treatment-related findings;
Exposed males with control females: due to effects on number of pups from 30 ppm and higher, no accurate evaluation can be done.
- Fetal weight:
Control males with exposed females: no treatment-related findings;
Exposed males with control females: due to effects on number of pups from 30 ppm and higher, no accurate evaluation can be done.
- Sex ratio
Control males with exposed females: no treatment-related findings;
Exposed males with control females: due to effects on number of pups from 30 ppm and higher, no accurate evaluation can be done.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

REPRODUCTION DATA:

- Number of females impregnated:

Exposed males with control females: decreased at 30, 100 and 200 ppm (15/20, 9/20, 4/20 and 1/18 at 0, 30, 100 and 200 ppm, respectively);

Control males with exposed females: no effect was observed (15/20, 19/20, 20/20 and 17/20 at 0, 30, 100 and 200 ppm)

- Number of corpora lutea/female:

Exposed males with control females: 16.6, 17.4, 15.8 and 0 at 0, 30, 100 and 200 ppm, respectively;

Control males with exposed females: 16.6, 16.6, 15 and 13.5 at 0, 30, 100 and 200 ppm, respectively (statistically significantly reduced at 200 ppm)

- No. of implantations/female:

Exposed males with control females: 15, 5.7, 5.2 and 0 at 0, 30, 100 and 200 ppm, respectively (statistically significantly reduced at 100 and 200 ppm);

Control males with exposed females: 15, 15, 13.5 and 12.6 at 0, 30, 100 and 200 ppm, respectively (statistically significantly reduced at 200 ppm)

- No. of resorptions/female:

Exposed males with control females: 1.0, 0, 0 and 0, at 0, 30, 100 and 200 ppm, respectively;

Control males with exposed females: 1.0, 1.33, 2.1 and 0.5 at 0, 30, 100 and 200 ppm, respectively.

- Live foetuses/litter:

Exposed males with control females: 14.0, 5.7, 5.2 and 0 at 0, 30, 100 and 200 ppm, respectively (statistically significantly reduced at 30 and 100 ppm);

Control males with exposed females: 14.0, 13.7, 12.8 and 12.1 at 0, 30, 100 and 200 ppm, respectively.

- Dead foetuses/litter: no effect observed

Applicant's summary and conclusion