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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:
May 3, 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to EPA TSCA Guidelines and in accordance with principles of GLP.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1989
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990
Reference Type:
publication
Title:
Dipropylene glycol monomethyl ether (DPGME): Inhalation teratology study in F344 rats.
Author:
Breslin WJ et al.
Year:
1990
Bibliographic source:
Summarized in: Toxicologist 10:39 abstract 154.

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OTS 798.4350 (Inhalation Developmental Toxicity Screen)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Dipropylene Glycol Monomethyl Ether (DPGME)
- Physical state: colourless liquid
- Analytical purity: approximately 100% (GC and GC/MS analyses)
- Impurities (identity and concentrations): No impurities at a level equal to or above 0.1%, with the exception of water, were identified. The water content of the samples was 0.23% (Lot no.-880913) and 0.018% (Lot no.-881220), determined by Karl Fischer titration analyses.
- Composition of test material, percentage of components: Both lots of the test material were analysed by infrared spectroscopy and the infrared spectrum were consistent with the structure of DPGME. GC and GC/MS analyses indicated the test material to be approximately 100% DPGME.
- Lot/batch No.: 880913 and 881220
- Expiration date of the lot/batch: not specified in the report
- Stability under test conditions: not specified in the report
- Storage condition of test material: not specified in the report

Test animals

Species:
rat
Strain:
Fischer 344
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory
- Age at study initiation: not specified in the report
- Weight at study initiation: 165-200 grams (at initiation of breeding)
- Fasting period before study: not specified in the report
- Housing: individually housed
- Diet (e.g. ad libitum): ad libitum, except during exposure
- Water (e.g. ad libitum): ad libitum, except during exposure
- Acclimation period: 2 weeks prior to breeding


ENVIRONMENTAL CONDITIONS
- Temperature (°C): standard conditions
- Humidity (%): standard conditions
- Air changes (per hr): standard conditions
- Photoperiod (hrs dark / hrs light): standard conditions

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: four cubic meter stainless steel and glass Rochester-type inhalation chambers
- Method of holding animals in test chamber: whole body exposure
- Source and rate of air: ambient
- Method of conditioning air: not specified in the report
- System of generating vapors: Vapors of the test material were generated by metering the test material into a glass J-tube or modifed distillation column. Compressed air was passed through the J-tube/distillation coulmn simultaneously to vaporize the test material. The air was heated with a heat gun to help vaporize the material.
- Temperature, humidity, pressure in air chamber: 22°C and 50% RH
- Air flow rate: 800 liters/minute
- Air change rate: not specified in the report
- Treatment of exhaust air: not specified in the report


TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of the test material was determined approximately ten times/exposure period by infrared spectroscopy. The analytical equipment was calibrated with vapor standards of known concentrations and was checked prior to each exposure with at least one standard. The nominal concentration was calculated daily for each chamber. DPGME vapor distribution was determined prior to the start of the study and once during the exposure period with animals in chambers. Four points were compared to the primary sampling line (reference line) in each chamber in which DPGME was introduced.
- 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:
The average concentration of DPGME relative to the reference line in the 50, 150 and 300 ppm exposure chambers were 98 ± 5%, 101 ± 3% and 106 ± 1%, respectively for the pretest determinations and 93 ± 3%, 100 ± 1% and 110 ± 2%, respectively for the test period determinations. Refer to Table 1 for more details
Details on mating procedure:
- Impregnation procedure: [cohoused]
- If cohoused:
- M/F ratio per cage: 1:1 (male:female)
- Length of cohabitation: as per guidelines
- Further matings after two unsuccessful attempts: [not specifed in the report]
- Verification of same strain and source of both sexes: [not specifed in the report]
- Proof of pregnancy: [sperm in vaginal smear] referred to as [day 0] of pregnancy
- Any other deviations from standard protocol: not specified in the report
Duration of treatment / exposure:
days 6-15 of gestation
Frequency of treatment:
6 hours/day (daily from days 6-15 of gestation)
Duration of test:
days 6-15 of gestation (dosing)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
50 ppm
Basis:
nominal conc.
51 ppm (average analytical concentration)
Remarks:
Doses / Concentrations:
150 ppm
Basis:
nominal conc.
154 ppm (average analytical concentration)
Remarks:
Doses / Concentrations:
300 ppm
Basis:
nominal conc.
285 ppm (average analytical concentration)
No. of animals per sex per dose:
Numbers bred -
G1 - 32
G2 - 33
G3 - 37
G4 - 32
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on range finding study (HET K-005533-017, listed under reference section)
- Rationale for animal assignment: Animals were randomized on 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: Days 0, 3, 6, 9, 12, 16 and 21 of gestation

FOOD CONSUMPTION : Yes
- Time schedule for examinations: 2-4 days intervals, beginning from day 0 of gestation

WATER CONSUMPTION : Yes
- Time schedule for examinations: 2-4 days intervals, beginning from day 0 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21

OTHER: All organs examined, maternal liver and gravid uterine weights recorded. Sections of maternal iver preserved in buffered 10% formalin, but not examined microscopically.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: The uteri of apperantly non-pregnant animals were stained with a 10% solution of sodium sulfide and examined for implantation sites.
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:
Descriptive statistics (means and standard deviations were performed for feed and water consumption values. Maternal body weights, body weight gain, absolute and relative organ weights, and fetal weights were evaluated by Bartlett's test for equality of variances. Based upon the outcome of Bartlett's test, a parametric or nonparametric analysis of variance (ANOVA) was performed. If the ANOVA was significant, analysis by Dunnett's test or the Wilcoxon Rank-Sum test with Bonferroni's correction was performed, respectively. Statistical evaluation of the frequency of pre-implantation loss, resorptions and fetal alterations among litters and the fetal population was performed using a censored Wilcoxon test with Bonferroni's correction. The number of corpora lutea and implants and litter size were evaluated using a non-parametric ANOVA followed by the Wilcoxon Rank-Sum test with Bonferroni's correction. Pregnancy rate was analyzed using the Fischer exact probability test. The sex ratio was analyzed using a binomial distribution test. Statistical outliers were identified by a sequential outlier test, but, other than feed and water values, were not excluded from analyses.
Indices:
Preganancy ratio (%), pre-implantation loss (%), implanations resorbed (%), litter with resorptions (%), sex ratio
Historical control data:
Refer to Table 10

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No treatment related effects were observed on feed or water consumption, body weight, body weight gain, liver weight and reproductive and fetal parameters at the time of cesarean sections. The statistically significant lower body weights of rats in the 150 ppm group were present prior to exposure on days 0 and 6 and thus not attributed to treatment

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
300 ppm (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
>= 300 ppm (nominal)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No treatment related effects on the incidence of malformations or variations were observed at any exposure levels and were in general agreement with the historical data.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
300 ppm (nominal)
Basis for effect level:
other: teratogenicity
Dose descriptor:
LOAEL
Effect level:
>= 300 ppm (nominal)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In conclusion, inhalation exposure of pregnant rats to concentrations of dipropylene glycol methyl ether (DPGME) as high as 300 ppm on days 6 through day 15 of gestation was not maternally toxic, embryo/fetotoxic or teratogenic. Three hundred ppm was the highest concentration of DPGME that was practically attainable at normal room temperature and pressure.
Executive summary:

Groups of 32 to 37 bred Fischer 344 rats were exposed via inhalation for 6 hours/day to 0 (control filtered air), 50, 150 and 300 ppm of DPGME vapors on day 6 through 15 of gestation. In-life parameters examined included clinical observations, feed consumption, water consumption and body weight. On day 21 of gestation, all animals were euthanased prior to cesarean section. Maternal liver and gravid uterine weights, the number of corpora lutea, implantations, resorptions and live/dead fetuses were recorded. The fetuses were removed from the uterus, weighed and examined for external, visceral and skeletal alterations. No treatment-related effects were observed on any of the maternal, embryonal and fetal parameters evaluated.

In conclusion, inhalation exposure of pregnant rats to concentrations of DPGME as high as 300 ppm on days 6 through day 15 of gestation was not maternally toxic, embryo/fetotoxic or teratogenic. Three hundred ppm was the highest concentration of DPGME that was practically attainable at normal room temperature and pressure.