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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: fertility
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to OECD guideline 422, acceptable with restrictions (only 8 weeks exposure instead of 70 days, only a summary of the results available)

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:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
only 8 weeks (56 days) exposure instead of 70 days, only a summary of the results available
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
Sex:
male/female
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
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 7 days
- Proof of pregnancy: sperm in vaginal smear day 0 of pregnancy
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
Duration of treatment / exposure:
8 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Details on study schedule:
- Parental animals (P) were mated until 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.
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

Examinations

Parental animals: Observations and 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
Oestrous cyclicity (parental animals):
not performed
Sperm parameters (parental animals):
Parameters examined in [P] male parental generations: sperm count, sperm motility and abnormalities (8 males/dose level)
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
- Clinical observations / mortality: daily
- Body weights: immediately after birth and at 4 and 21 days old
- Sex: immediately after birth and on day 4 and 21 post partum
Number of male pups examined were 6, 1-2, 0 and 1 at 0, 30, 100 and 200 ppm, respectively; females examined were 6, 9-10, 10 and 9 at 0, 30, 100 and 200 pp, respectively.
Postmortem examinations (parental animals):
GROSS NECROPSY
- Gross necropsy was performed according to standard protocol (not further specified)

HISTOPATHOLOGY / ORGAN WEIGHTS: not performed
Postmortem examinations (offspring):
GROSS NECROPSY
- Macroscopic observations: checked for external abnormalities (not further specified; 9 foetuses/2 litters at 30 ppm and 8 foetuses/1 litter at 200 ppm examined)

HISTOPATHOLOGY / ORGAN WEIGTHS: not performed
Statistics:
Dunnett's test (Dunnett, 1980), Fisher exact test

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
not specified
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): two males at 200 ppm died (time of death not indicated). Clinical signs are not indicated.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): 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).

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): no significant effects were seen on motility or the number of sperms. The percentage of abnormal sperms present at 200 ppm was statistically significant increased (1.11 to 0.64% in the control). Males were killed 13-14 days after the last exposure to the test substance and sperm were counted and examined for motility and for abnormalities. Therefore, reversible effects on sperm cells might have disappeared.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
- Mating rate (copulation detected): no effect was observed
- 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)
- Duration of gestation: no effect was observed
- Implantation sites/dam (day 19 of gestation):
Exposed males with control females: 15.0, 5.7 and 5.2 at 0, 30 and 100 ppm, respectively;
Control males with exposed females: no effect observed
- No. of litters (on day 19 of gestation or within 24 hours after birth):
Exposed males with control females: 15, 9, 4 and 1 at 0, 30, 100 and 200 ppm;
Control males with exposed females: 15, 19, 19 and 17 at 0, 30, 100 and 200 ppm, respectively

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEC
Remarks:
toxicity
Effect level:
140 mg/m³ air
Sex:
male
Basis for effect level:
other: decreased body weight gain at 467 mg/m3
Dose descriptor:
NOAEC
Remarks:
fertility
Effect level:
< 140 mg/m³ air
Sex:
male
Basis for effect level:
other: decreased pregnant females and the lower pups viability index

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING): pup mortality occurred during the first 4 days after birth.
- Percentage survival on day 4 (exposed males with control females): 77 and 33 at 0 and 30 ppm, respectively (the litters were too small by 100 and 200 ppm to calculate a viability index);
- Percentage survival on day 4 (control males with exposed females): no effect observed.
- Pups alive on day 21 per pups alive on day 4: no effects observed
- Litter size (exposed males with control females): 14, 6, 5 and 8 at 0, 30, 100 and 200 ppm, respectively;
- Litter size (control males with exposed females): 14, 13, 13 and 12 at 0, 30, 100 and 200 ppm, respectively

BODY WEIGHT (OFFSPRING): no effect was observed

SEXUAL MATURATION (OFFSPRING)
- Sex ratio: no effect observed

GROSS PATHOLOGY (OFFSPRING)
- External abnormalities: no treatment-related effects observed

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Summary of reproductive performance of rats after inhalation exposure for eight weeks to Allyl Glycidyl Ether

Conc. (ppm)

Results when males were exposed (a)

Results when females were exposed (b)

Copulations detected (c)

No. of females impregnated

No. of litters (d)

Total pups/ litter (e)

Copulations detected (c)

No. of females impregnated

No. of litters (d)

Total pups/ litter (e)

0

15/20

15

15

13.8±2.2

15/20

15

15

13.8±2.2

30

18/20

9

9

5.9±4.9

17/20

19

19

13.0±2.1

100

17/20

4

4

5.3±4.9

19/20

20

19

12.7±2.4

200

14/18

1

1

8.0

15/20

17

17

12.1±1.5

(a) Data from control females mated with exposed males

(b) Data from exposed females mated with control males

(c) Number of copulations detected/number of females

(d) Litters examined at d 19 of gestation or within 24 h after birth

(e) Mean ± standard deviation

 

Reproductive status of maternal rats and postnatal survival of offspring of rats exposed for eight weeks (before mating) to Allyl Glycidyl Ether by inhalation

Parameters examined

control

30 ppm

100 ppm

200 ppm

No.(a)

Mean(b)

No.(a)

Mean(b)

No.(a)

Mean(b)

No.(a)

Mean(b)

Results when males were exposed (c)

Length of gestation (days)

7

23.1±0.9

3

23.7±0.6

0

-

1

23.0

Implantation sites per dam

7

14.0±4.6

5

6.4±5.7*

0

-

1

10.0

Pups alive on day 1

7

11.6±5.5

3

6.3±4.0

0

-

1

8.0

Pups alive on day 4

7

8.9±4.7

3

0.7±1.2

0

-

1

8.0

Pups alive on day 21

7

8.9±4.7

3

0.7±1.2

0

-

1

8.0

Results when females were exposed (c)

Length of gestation (days)

7

23.1±0.9

8

22.6±0.7

9

22.8±0.4

7

22.7±0.5

Implantation sites per dam

7

14.0±4.6

10

15.0±1.9

10

14.4±1.7

9

13.6±1.1

Pups alive on day 1

7

11.6±5.5

10

12.4±2.1

10

12.7±2.7

9

12.1±1.4

Pups alive on day 4

7

8.9±4.7

10

11.3±4.1

10

11.1±4.0

9

11.9±1.5

Pups alive on day 21

7

8.9±4.7

10

11.2±4.2

10

1.1±4.0

9

11.9±1.5

(a) Number of dams or litters

(b) Mean ± standard deviation

(c) Control female rats were mated with exposed male rats.

(d) Exposed female rats were mated with control male rats.

*P<0.05 vs. the controls by Dunnett’s test

Applicant's summary and conclusion