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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles

Data source

Referenceopen allclose all

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
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-methoxypropan-2-ol
EC Number:
203-539-1
EC Name:
1-methoxypropan-2-ol
Cas Number:
107-98-2
Molecular formula:
C4H10O2
IUPAC Name:
1-methoxypropan-2-ol
Details on test material:
- Name of test material (as cited in study report): Propylene Glycol Monomethyl Ether (PGME)
- Physical state: colorless liquid
- Analytical purity: 98.68%
- Composition of test material, percentage of components: as described below
- Isomers composition: 98.68%: 1-methoxy-2-propanol and 1.32%: 2-methoxy-1-propanol isomer

Test animals

Species:
rat
Strain:
Fischer 344
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Mich. USA
- Weight at study initiation: approximately 175-220 g at breeding
- Housing: group housed in wire-bottomed cages
- Diet: Certified Laboratory Animal Chow provided ad libitum, except during exposure
- Water: Municipal tap water provided ad libitum, except during exposure
- Acclimation period: at least two weeks prior to breeding

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approximately 22 °C
- Humidity (%): approximately 50%
- Photoperiod (hrs dark / hrs light): 12:12 hours (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: 4.3 m³ Rochester type stainless steel and glass inhalation chambers
- Source and rate of air: filtered air
- Temperature, humidity in air chamber: The mean daily temperatures within the exposure chambers were 23±2°C, 23±3°C, 23±3°C, 24±3°C, and relative humidity values were 46±5%, 49±3%, 52±3%, 50±8% for the 0-, 500, 1500, and 3000 ppm groups, respecitively.
- Air flow rate: under dynamic airflow conditions at approximately 750 liters/minute
- Vapors were generated using the glass J-tube method of Miller et al. (1980)

TEST ATMOSPHERE
- Brief description of analytical method used: 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.

Miller, R. R., Letts, R. L., Potts, W. J., and McKenna, M. J. (1980). Improved methodology for generating controlled test atmospheres. Amer. Ind. Hyg. Assoc. J. 41, 844-846.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber concentrations were measured 1-2 times per hour using a Miran I infrared spectrophotometer with a variable path-length gas cell at a wavelength of 3.5 µm. Mean time-weighted average (TWA) analytical concentrations were within ±10% of target concentraions for each seperate exposure level. Close agreement between mean daily nominal concentrations (calculated on the basis of the weight of test material used and the total chamber airflow in a 6-hr period) and the TWA analytical concentrations indicated minimal loss occurred in the vapor-generating and exposure system.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1 (male:female)
- Verification of same strain and source of both sexes: no
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
days 6-15 of gestation
Frequency of treatment:
6 hours/day
Duration of test:
21 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
500 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
1500 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
3000 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
Test groups: 31-33 females
Control group: 32 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for animal assignment: Test animals were randomized and grouped according to the day 0 of gestation using computer generated tables of random numbers.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights for rats were recorded on gestation days 6, 9, 12, 16 and 21

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Food consumption were recorded for each rat at 3-day intervals starting on day 6 of gestation

WATER CONSUMPTION: Yes
- Time schedule for examinations: Water consumption were recorded for each rat at 3-day intervals starting on day 6 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: liver, uterine horns
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
- Number of live and dead fetuses: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
Statistics:
Statistical evaluation of the frequency of alterations and of resorptions among litters and the fetal population was made by the modified Wilcoxon test. Analysis of the percentage of pregnancy and other incidence data was made by the Fisher exact probability test. Fetal sex ratio was analyzed using 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. Statistical outliers (a=0.02) for food and water consumption were deleted from the calculation of the mean values.
Historical control data:
The overall incidence of fetal malformations among historical control Fischer 344 rats is approximately 1%, and individual control groups have had malformation rates a high as 2% of the fetuses in somes studies.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
In essentially all rats, exposure to 3000 ppm of PGME resulted in lethargy and moderated ataxia; postexposure recovery was rapid. These signs were most evident following the first 4-5 exposure days, with a greater of accommodation occurring with each successive exposure. Concomitant with this slight CNS depression were statistically significant decreases in food consumption and maternal body weight gain during the intial days of exposure (table 1). Overall body weight gain during the exposure period (days 6-15) of the 3000 ppm group was also significantly lower than among controls. Rats exposed to 3000 ppm of PGME also exhibited slight-to-moderate chromodacryorrhea during the initial 4-5 days of exposure. There were no changes observed among maternal rats exposed to 500 or 1500 ppm of PGME, and no effects on liver weights were seen at any exposure level. There were no differences in pregnancy rates, litter size or resorption rates among any of the groups exposed to PGME (table 2).

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:yes

Details on embryotoxic / teratogenic effects:
There were no statistically identified differences in the fetal body weight and length in any of the groups exposed to PGME when compared to controls. The incidence of major malformations observed externally, viscerally and at skeletal examination were not statistically different from the control incidence. The only statistically significant difference from the control value was an increase in the incidence of delayed sternebral ossification observed at 3000 ppm was considered as an indication of slight fetotoxicity.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 500 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

Results are found as attachment:

Table 1: Maternal Measurements in rats

Table 2: Reproductive Parameters in rats

Table 3: Fetal alterations among rats

Applicant's summary and conclusion

Conclusions:
In conclusion, PGME was not considered teratogenic in rats at exposures up to 3000 ppm, though slight fetotoxicity was observed in rats exposed to 3000 ppm. Based on the results, the NOAEL for maternal and fetotoxicity was considered to be 1500 ppm.
Executive summary:

In this study, Fischer 344 rats were exposed by inhalation to Propylene Glycol Monomethyl Ether (PGME) during pregnancy (GD6 -GD15) at doses of 0, 500, 1500 and 3000 ppm. 

Maternal toxicity (mild transient CNS depression, decreased food consumption and body weight gain) were observed in animals at 3000 ppm. There were no statistically identified differences in the number of pregnancies, litter size, resorption rate, fetal body weight and length in any of the groups exposed to PGME when compared to controls. Slight fetotoxicity (delayed sternebral ossification) was observed in rats exposed to 3000 ppm. There were no effects observed among rats exposed to 500 and 1500ppm.

In conclusion, PGME was not considered teratogenic in rats at exposures up to 3000 ppm, though slight fetotoxicity was observed in rats exposed to 3000 ppm. Based on the results, the NOAEL for maternal and fetotoxicity was considered to be 1500 ppm.