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Toxicological information

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
Study period:
1978-11-13, end date not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was well documented and performed similar to OECD 414. No information on GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
There were few details about the test compound.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: low viscosity liquid hydrocarbon
Details on test material:
- Name of test material (as cited in study report): Diesel fuel, CAS No. 68334-30-5, API 79-6
- Substance type: Diesel fuel
- Physical state: Liquid
- Analytical purity: Not reported
- Lot/batch No.:Not reported
- Stability under test conditions: Not reported
- Storage condition of test material: Not reported

Test animals

Species:
rat
Strain:
other: CRL:COBS CD (SD)BR
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, Massachusetts
- Age at study initiation: 11 weeks old
- Weight at study initiation: Not reported
- Housing: Individually except during mating
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum, acidified (pH 2.5) water
- Acclimation period: 13 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not reported
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light


IN-LIFE DATES: From:1978-11-13 To: Not reported

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Warm glass wool filled flask with compressed air
- Method of holding animals in test chamber: Stainless steel and plexiglass containers
- Source and rate of air: Compressed air at an unspecified rate
- Method of conditioning air: Not reported
- Temperature, humidity, pressure in air chamber: Under negative pressure at the following temperatures: control=26.7+/-1.04 degrees Celsius; 100 ppm=25.5+/-1.30 degrees Celsius; 400 ppm=26.8+/-1.00 degrees Celsius
- Air flow rate: 28.3 litres per minute
- Air change rate: Not reported
- Method of particle size determination: Not determined
- Treatment of exhaust air: Not reported

TEST ATMOSPHERE
- Brief description of analytical method used: Scott Model 216 Hydrocarbon Analyzer
- Samples taken from breathing zone: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber concentrations were monitored hourly using a Scott Model 216 Hydrocarbon Analyzer calibrated with known concentrations of diesel fuel. Methane was used as an internal standard.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: Not reported
- Length of cohabitation: Not reported
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
10 days (gestational days 6 through 15)
Frequency of treatment:
6 hours a day
Duration of test:
14 days
No. of animals per sex per dose:
Twenty pregnant dams per dose
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Stated as selected by API.
- Rationale for animal assignment (if not random): Assigned sequentially to the dose groups

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations included general appearance, behaviour and condition.


DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: On gestational days 0, 6, 15, and 20


FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No



WATER CONSUMPTION: No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Visceral and thoracic organs
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- 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: one-third per litter
- Skeletal examinations: Yes: two-thirds per litter
- Head examinations: Yes: one-third per litter
Statistics:
Continuous parameters were analyzed with Dunnet's t-test. A 2x2 contingency table with Yates correction was used for ratio data. Discontinuous data (e.g., number of abnormal foetuses per litter) were analyzed using Wilcoxon Rank Sum test.
Indices:
Nidation index, liver and dead foetuses, implantations, pup weight, sex ratio, and abnormalities
Historical control data:
Historical data on 54 litters was provided for reproductive performance. The concurrent control was considered to be similar to the historical control.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
There were no deaths during the course of the study and all females were normal in appearance. Mean body weights indicated no significant differences between control and treated pregnant rats, although the food consumption of the high-dose group was significantly lower (p < 0.05) than the controls during treatment. Examination at necropsy revealed two high-dose females with dark, mottled lungs. One of these animals had a rough spleen but no further description was provided for this and the authors did not consider either of these effects to be treatment related.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEC
Effect level:
401.5 ppm (analytical)
Based on:
other:
Remarks:
overall effects
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Examination of the offspring revealed no visible abnormalities except for the occurrence of subcutaneous haematomas in 1/188, 4/227 and 4/188 in the control, low-, and high-dose groups, respectively. All litters appeared normal and the sex ratio did not differ significantly between treated and control groups. Some unusual skeletal variations related to retarded bone ossification were observed, including reduced ossification of the parietal bones and the frontal bones, and wavy ribs. These changes were noted in 7 and 17 pups from 3 and 8 litters of the control and low-dose animals only, and were not dose related. The authors concluded that neither the frequency nor the character of these changes indicated an adverse effect on foetal growth and development or a teratogenic potential. Other skeletal variations were considered to be common to animals of this strain.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEC
Effect level:
401.5 ppm (analytical)
Based on:
other:
Remarks:
overall effects
Basis for effect level:
other: developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Exposure of pregnant rats to diesel fuel (vapour) did not result in compound-induced maternal toxicity, teratology, variation in sex ratio, embryo toxicity or inhibition of foetal growth and development. Therefore the NOAEC was 2,110 mg/m3, the highest concentration tested.
Executive summary:

The teratology of diesel fuel was examined by whole body exposure of pregnant female (CRL: COBS CD (SD) BR) rats to graded measured airborne (vapour) of 0, 101.8, or 401.5 ppm (equivalent to 0, 530, and 2110 mg/m3, respectively) on days 6 through to 15 of gestation. The pregnant female rats were approximately 11 weeks of age at the time of the first dose and were assigned sequentially to treatment groups of 20 animals each. They were exposed to diesel fuel for 6 hours/day in 0.25 m3 stainless steel and plexiglass chambers operated under negative pressure. The animals were assessed daily for body weight changes, food consumption, and clinical observations.

There were no deaths during the course of the study and all females were normal in appearance. Mean body weights indicated no significant differences between control and treated pregnant rats, although the food consumption of the high-dose group was significantly lower (p < 0.05) than the controls during treatment.

On day 20 of gestation, the study was terminated and the rats were anaesthetised with chloroform. Following anaesthesia, gross examination of the organs, examination of the uterus (number of implantation sites, live/dead foetuses, number of resorption sites) and foetal examinations (soft tissue and skeletal) were performed.

Examination at necropsy revealed two high-dose females with dark, mottled lungs. One of these animals had a rough spleen but no further description was provided for this and the authors did not consider either of these effects to be treatment related.

Diesel fuel did not appear to have any effect on the uterus and examination of the offspring revealed no visible abnormalities except for the occurrence of subcutaneous haematomas in 1/188, 4/227 and 4/188 in the control, low-, and high-dose groups, respectively. All litters appeared normal and the sex ratio did not differ significantly between treated and control groups. Some unusual skeletal variations related to retarded bone ossification were observed, including reduced ossification of the parietal bones and the frontal bones, and wavy ribs. These changes were noted in 7 and 17 pups from 3 and 8 litters of the control and low-dose animals only, and were not dose related. The authors concluded that neither the frequency nor the character of these changes indicated an adverse effect on foetal growth and development or a teratogenic potential. Other skeletal variations were considered to be common to animals of this strain.

 

The authors concluded that exposure of ratsto diesel fuel (vapour) did not result in compound-induced terata, variation in sex ratio, embryo toxicity or inhibition of foetal growth and development. Therefore the NOAEC was 2,110 mg/m3 (401.5 ppm), the highest concentration tested.

This study received a Klimisch score of 2 and is classified as reliable with restrictions because the study is well-documented and generally followed OECD 414 guidelines. No information was available on GLP.