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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to EPA TG 798.4900 and in accordance with GLP.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990
Reference Type:
publication
Title:
Unnamed
Year:
1990

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes

Test material

Constituent 1
Details on test material:
- Name of test material (as cited in study report): dipropylene glycol methyl ether (DPM) as surrogate for dipropylene glycol methyl ether acetate (DPMA)
- Molecular formula (if other than submission substance): C7H16O3
- Molecular weight (if other than submission substance): 148.2
- Analytical purity: 100%
- Impurities (identity and concentrations): No impurities at a level equal to or above 0.1% were identified in the test material
- Composition of test material, percentage of components: 100% DPGME
- Lot/batch No.: 881220
- Stability under test conditions:

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Duchland
- Weight at study initiation: 3.5-4.5 kg
- Housing: individual
- Diet (e.g. ad libitum): 4oz/day - 8 oz/day, except during exposure
- Water (e.g. ad libitum): ad libitum
- Acclimation period: three weeks


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: 4 cubic meter stainless steel and glass Rochester-type inhalation chambers (1.6 meter cube with a pyramidal top)
- Source and rate of air: compressed air
- Temperature, humidity, pressure in air chamber: 22°C, 50% RH
- Air flow rate: 800 l/min
- Vapors of test material were generated by metering the test material into a glass J-tube or modified distillation column. Compressed air was passed through the J-tube/distillation column simultaneously to vaporize the test material. The air was heated with a heat gun to help vaporize the test material.

TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of the test material was determined approximately 10 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 (ratio of test material used to the total chamber airflow through the chamber) was calculated daily for each chamber.
- Samples taken from breathing zone: Four points were compared to the primary sampling line (reference line) in each chamber in which DPGME was introduced.
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 determination and 93 ± 3%, 100 ± 1% and 110 ± 2%, respectively, for the test period.
The average analytical concentration of DPGME vapors present in the chambers during exposures were 0, 51, 152 and 282 ppm for the control, 50, 150 and 300 ppm exposure chambers, respectively.
Details on mating procedure:
- Impregnation procedure: [artificial insemination]
- Proof of pregnancy: [day of insemination] referred to as [day 0] of pregnancy
Duration of treatment / exposure:
days 7-19 of gestation
Frequency of treatment:
6 hours/day
Duration of test:
28 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
50 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
150 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
300 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
16 inseminated rabbits/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the results of a teratology probe study
- Rationale for animal assignment (if not random): random

Examinations

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

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 7, 10, 13, 16, 20 and 28 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 28
- Organs examined: maternal liver and uterine contents
- Any animal which died or demonstrated indications of early termination of preganancy was subjected to a complete necropsy examination.

OTHER: CLINICAL CHEMISTRY: Yes
- ALP, ALT, AST, CK, UN, creatinine, TP, albumin, globulin, glucose, cholesterol, triglycerides, total bilirubin and electrolytes (Na, K, P, Cl, Ca) were conducted with CentriChem automated chemistry analyser and Beckman E4A
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
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
Statistics:
Maternal body weights, weight gain, absolute and relative organ weights and fetal body weights - Bartlett's test for equality of variances, ANOVA, Dunnett's or Wilcoxon Rank-Sum Test with Bonferroni's correction
Pre-implantation loss, resorptions and fetal alterations among litters and fetal population - censored Wilcoxon Test with Bonferroni's correction
Number of corpora lutea and implants, litter size - ANOVA followed by Wilcoxon Rank-Sum Test with Bonferroni's correction
Pregnancy rate - Fisher exact probability test
Sex ratio - binomial distribution test

Indices:
Pre-implantation loss, implantations resorbed and litter with resorptions

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Effect levels (maternal animals)

Dose descriptor:
NOEL
Effect level:
>= 300 ppm (nominal)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Effect levels (fetuses)

Dose descriptor:
NOEL
Effect level:
>= 300 ppm
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 rabbits to concentrations of DPGME as high as 300 ppm (highest concentration of DPGME practically attainable at normal room temperature and pressure) on days 7 through day 19 of gestation was not maternally toxic, embryo/fetotoxic or teratologic.
Executive summary:

Groups of 16 inseminated New Zealand White rabbits were exposed via inhalation for 6 hours/day to 0 (control, filtered air), 50, 150 and 300 ppm of DPGME vapors on days 7 through 19 of gestation. In-life parameters included clinical observations and body weight. On day 28 of gestation, all animals were euthanatized prior to cesarean section. Maternal liver and gravid uterine weights, number of corpora lutea, implantations, resorptions and live/dead fetuses were recorded at cesarean section. All fetuses were then removed from the uterus, weighed and examined for external, visceral and skeletal alterations. No treatment related effects were observed on any of the maternal or embyonal/fetal parameters evaluated at any exposure level.

In conclusion, inhalation exposure of pregnant rabbits to concentrations of DPGME as high as 300 ppm (highest concentration of DPGME practically attainable at normal room temperature and pressure) on days 7 through day 19 of gestation was not maternally toxic, embryo/fetotoxic or teratologic.

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