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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:
1983
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study equivalent to OECD guideline 414.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report Date:
1983
Reference Type:
publication
Title:
Teratologic Evaluation of Inhaled Propylene Glycol Monomethyl Ether in rats and rabbits
Author:
Hanley et al.
Year:
1984
Bibliographic source:
Fund Appl Toxicol, 4,784-794
Reference Type:
publication
Title:
Ethylene Glycol Monomethyl Ether (EGME) and Propylene Glycol Monomethyl Ether (PGME): Inhalation Fertility and Teratogenicity Studies in rats, mice and rabbits
Author:
Hanley et al.
Year:
1984
Bibliographic source:
Env. Health Persp. 57, 7-12

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Method: other
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Propylene Glycol Monomethyl Ether
- Physical state: colorless liquid
- Analytical purity: 98.68%
- Impurities (identity and concentrations): not specifed in the report
- Composition of test material, percentage of components: as described below
- Isomers composition: 98.68 ± 0.22% 1-methoxy-2-propanol and 1.32 ± 0.22% 2-methoxy-1-propanol isomer
- Purity test date: not specifed in the report
- Lot/batch No.: QP 810310-25
- Expiration date of the lot/batch: not specifed in the report
- Stability under test conditions: not specifed in the report
- Storage condition of test material: not specifed in the report

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: adullt females
- Weight at study initiation: 3.5-4.5 kg
- Fasting period before study: not required
- Housing: individually housed in wire-bottomed cages
- Diet (e.g. ad libitum): Certified Laboratory Animal Chow, except during exposure
- Water (e.g. ad libitum): Municipal water except during exposure
- Acclimation period: two weeks prior to breeding


ENVIRONMENTAL CONDITIONS
- Temperature (°C): approximately 22 °C
- Humidity (%): approximately 50%
- Air changes (per hr): not specified in the report
- Photoperiod (hrs dark / hrs light): 12:12 (light:dark cycle)

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Rochester type stainless steel and glass inhalation chambers
- Method of holding animals in test chamber: not specified in the report
- Source and rate of air: filtered air
- Method of conditioning air: not specified in the report
- Temperature, humidity, pressure in air chamber: approximately 21 °C and 50% RH
- Air flow rate: 750 liters/minute
- Air change rate: not specified in the report
- Treatment of exhaust air: not specified in the report
- Vapors were generated by metering the liquid test substance at calculated rates into glass vaporization tubes which were swept into the chamber inlet ducts with compressed air with compressed air where there was further mixing and dilution with incoming air by turbulence. The compressed air was preheated to the minimum extent required for complete vaporization, using a compressed air flameless heat torch. Total chamber airflow was maintained at approximately 750 liters/minute.

TEST ATMOSPHERE
- Brief description of analytical method used: The nominal concentration (ratio of the amount of PGME vaporized to the total amount of air through the chamber) was calculated for each chamber on a daily basis. The actual concentration of PGME in each exposure chamber was measured 1-2 times/hour by infrared spectroscopy using a MIRAN I infrared gas analyser at a wave-length of ~ 3.5 µm.
- Samples taken from breathing zone: not specified in the report

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Target concentrations - 0, 500, 1500 and 3000 ppm
Analytical concentrations - 0, 505 ± 10, 1506 ± 15 and 3009 ± 23 ppm
Refer to Attachment 1 for further details
Details on mating procedure:
- Impregnation procedure: [artificial insemination]
- If cohoused: not applicable
- Verification of same strain and source of both sexes: [no]
- Proof of pregnancy: the day of artificial insemination referred to as [day 0 ] of pregnancy
Duration of treatment / exposure:
days 6-18 of gestation
Frequency of treatment:
6 hours/day
Duration of test:
29 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 ppm (nominal)
Basis:
analytical conc.
0 ppm
Remarks:
Doses / Concentrations:
500 ppm (nominal)
Basis:
analytical conc.
505 ± 10 ppm
Remarks:
Doses / Concentrations:
1500 ppm (nominal)
Basis:
analytical conc.
1506 ± 15 ppm
Remarks:
Doses / Concentrations:
3000 ppm (nominal)
Basis:
analytical conc.
3009 ± 23 ppm
No. of animals per sex per dose:
31-33 inseminated rabbits
Control animals:
yes, concurrent vehicle
Details on study design:
Sex: female
Duration of test: 29 days
- Dose selection rationale: Based on range finding (probe) study, refer to HET K-005539-014, listed under reference
- Rationale for animal assignment: Randomization of test animals was done on day 0 of gestation, using computer-generated tables of random numbers

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily throughout the experimental period

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 6, 9, 12, 15, 19 and 29

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: all organs

OTHER: Maternal liver weights were recorded at the time of cesarean section and sections of maternal liver were preserved in 10% formalin but were not evaluated histologically
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: No
Statistics:
Statistical evaluation of the frequency of alterations and of resorptions among litters and the fetal population was made by the modified Wicoxon test. Analysis of the percentage of pregnancy and other incidence data was made by the Fisher exact probability test. The fetal sex ratio was analyzed by a binomial distribution test. Analysis of other data was done by parametric or non-parametric analysis of variance followed by either Dunnett's test or Wilcoxon's rank sum test with a Bonferroni correction, as appropriate. For food and water consumption data, statistical outliers were identified by a sequential outlier test
Indices:
Per cent pregnant, preimplantation loss, per cent implantations resorbed, per cent litters with resorptions, per cent dead fetuses, sex ratio
Historical control data:
not provided

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Signs of mild and transient CNS depression (viz. mild lethargy) were observed among approximately half of the maternal rabbits exposed to 3000 ppm of PGME for the first 1-2 days of exposure, with rapid accomodation occurring subsequently. There were six deaths among maternal rabbits during the course of study; one among the control and 500 ppm groups and four among 3000 ppm animals. Of these one death at 3000 ppm was attributed to pneumonia and the cause of death among the remaining 3 animals was not determined. There were no statistically identified difference in body weight and weight gain, absolute and relative liver weight among any of the exposure groups. There were no statistically significant differences in any of the reproductive parameters in any of the PGME exposed rabbits when compared to controls.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 500 ppm
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
The incidence of major malformations observed externally, internally or by skeletal examination, whether considered individually or collectively in each exposure group, was not statistically significantly different from the control incidence. A number of minor malformations were observed among all exposure groups, including controls and the incidence was not statistically significant when compared to controls and there was no consistent pattern indicative of any treatment related effects.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
3 000 ppm
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

Table 1: Exposure concentration and chamber conditions Table 2: Body weights and Liver weights of pregnant rabbits Table 3: Summary of Cesarean Section Data Table 4: Incidence of fetal alterations among litters of rabbits

Applicant's summary and conclusion

Conclusions:
Based on the results of the study, the NOAEL for maternal toxicity was 1500 ppm and NOAEL for teratogenicity was 3000 ppm
Executive summary:

In this study, New Zealand White rabbits were exposed by inhalation to Propylene Glycol Monomethyl Ether (PGME) during pregnancy (GD6 -GD18) at doses of 0, 500, 1500 and 3000 ppm. This test was performed according to a method similar to OECD guideline 414. 

Signs of mild and transient CNS depression (viz. mild lethargy) were observed among approximately half of the maternal rabbits exposed to 3000 ppm of PGME for the first 1-2 days of exposure, with rapid accomodation occurring subsequently. There were six deaths among maternal rabbits during the course of study; one among the control and 500 ppm groups and four among 3000 ppm animals. Of these one death at 3000 ppm was attributed to pneumonia and the cause of death among the remaining 3 animals was not determined. There were no statistically identified difference in body weight and weight gain, absolute and relative liver weight among any of the exposure groups. There were no statistically significant differences in any of the reproductive parameters in any of the PGME exposed rabbits when compared to controls.

The incidence of major malformations observed externally, internally or by skeletal examination, whether considered individually or collectively in each exposure group, was not statistically significantly different from the control incidence. A number of minor malformations were observed among all exposure groups, including controls and the incidence was not statistically significant when compared to controls and there was no consistent pattern indicative of any treatment related effects.

Based on the results of the study, the NOAEL for maternal toxicity was 1500 ppm and NOAEL for teratogenicity was 3000 ppm