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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report similar or equivalent to OECD 414. GLP.

Data source

Reference Type:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:

Test material

Constituent 1
Reference substance name:
unleaded gasoline vapor condensate
unleaded gasoline vapor condensate
Constituent 2
Reference substance name:
API 94-02
API 94-02
Details on test material:
- Name of test material (as cited in study report): unleaded gasoline vapor condensate
- Other: Density = 0.65

Test animals

Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories, Portage, MI
- Age at study initiation: 71 days
- Weight at study initiation: 261-264 g
- Housing: Individually housed in suspended stainless-steel cages with wire mesh floors and fronts
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days

- Temperature (°C): 20-24
- Humidity (%): 38-74
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
other: 99.98% Nitrogen
Details on exposure:
- System of generating particulates/aerosols: Charging a glass-lined Pfaulder kettle (closed system) with 6746 lbs of unleaded gasoline. The sample was slowly heated and stirred as the liquid temperature was raised to 150 F, resulting in a vapor temperature of 130 F. The vapor was condensed by passing through a series of two receiving vessels chilled with cold water and dry ice, then through additional vapor traps chilled in dry ice/ isopropyl alcohol. The vapor condensate collected by this method represented 10.4% of the initial sample weight. The chilled condensate was uniformly mixed, transferred to 5-gallon containers, and shipped to the testing laboratory where it was stored at ambient temperature in a solvent storage building until use.
- Exposure apparatus: 1000-L glass and stainless steel exposure chamber (Wahlmann Mfg. Co., Timonium, MD)
- Source and rate of air: Test material was pumped directly from the storage container, refrigerated to minimize volatilization during transfer, into a countercurrent volatilization chamber
- Method of conditioning air: Gasoline vapor laden nitrogen flowed through the top of the volatilization chamber into the turret of the 1000 L exposure chamber, where it mixed with room air to the appropriate exposure concentration as it was drawn into the chamber.
- Temperature and humidity in air chamber: 20-25 °C, 34-70 %; monitored every 1/2 hour
- Air flow rate: 200 L/min
- Air change rate: 5 min
- Method of particle size determination: TSI Aerodynamic Particle Sizer at least once during every exposure
- Treatment of exhaust air: Chambers were exhausted through a system of a coarse filter, a HEPA filter, and a charcoal filter
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
One sample per chamber per week was collected by syringe grab sampling and analyzed by gas chromatography (Hewlett Packard 5890II with flame ionization detector) to characterize 12 major components of the test atmosphere to demostrate stability of test vapor over the course of the study. Composition and stability of the test material were evaluated by characterizing the liquid unleaded gasoline vapor condensate and comparing the major components with the generated atmospheres throughout the study.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: nightly
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Frequency of treatment:
once daily, 6 h
Duration of test:
Through day 20 of gestation
Doses / concentrationsopen allclose all
Doses / Concentrations:
2653 mg/m3
analytical conc.
Doses / Concentrations:
7960 mg/m3
analytical conc.
Doses / Concentrations:
23900 mg/m3
analytical conc.
No. of animals per sex per dose:
24 females/dose
Control animals:
yes, sham-exposed


Maternal examinations:
- Time schedule: Twice daily; during days 6 through 19, animals were evaluated pre- and post- exposure when animals were removed from the inhalation chambers

- Time schedule: Days 0 and 6 through 20

- Time schedule for examinations: days 0, 3, 6, 9, 12, 15, 18, and 20 of gestation

- Sacrifice on gestation day 20
- Organs examined: uterus and ovaries

- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
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: Where no uterine implants were grossly apparent, the uterus was stained with ammonium sulfide to visualize any uterine foci.
Fetal examinations:
- External examinations, weighed and sexed: Yes: [all per litter]
- Soft tissue examinations: Yes: [ half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]
Conducted where appropriate
No data provided
Historical control data:
No data provided

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
All mated females survived to scheduled sacrifice. Physical examinations performed pre- and post-exposure did not indicate any adverse effect from exposure to unleaded gasoline vapor condensate. Mean maternal body weight and weight gain during gestation were not adversely affected by treatment.

Effect levels (maternal animals)

Dose descriptor:
Effect level:
23 900 mg/m³ air (analytical)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Pregnancy rates in treated groups were statistically indistinguishable from the sham treated control group. No adverse effects of treatment were evident from uterine implantation data. There were no aborted pregnancies or premature deliveries in any group. No macroscopic abnormalities related to test material exposre were observed in postmortem examination of maternal animals. No external malformations or variations were recorded among fetuses from control or treated groups.

Effect levels (fetuses)

Dose descriptor:
Effect level:
23 900 mg/m³ air (analytical)
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

The maternal NOAEL and developmental NOAEL for unleaded gasoline vapor condensate were 23900 mg/m3. Under the conditions of this study, unleaded gasoline vapors did not produce evidence of developmental toxicity. These findings do not warrant classification of the test material as a developmental hazard under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

Unleaded gasoline vapor condensate was administered once daily to pregnant rats on gestation days 6-19 via vapor inhalation at doses of 0, 2653, 7960, or 23900 mg/m3 (24 rats/dose) to assess for developmental toxicity.  Maternal parameters (food consumption, body weight gain) monitored throughout gestation and at study termination (clinical chemistry, grossly visible abnormalities) were not adversely affected by treatment.  Reproductive parameters (number of implants, resorptions, or viable fetuses) were not adversely affected by administration of the test material at any of the dose levels tested.  No evidence of abnormal development was observed during external, skeletal, or visceral examinations of fetuses from pregnant dams exposed. Thus, unleaded gasoline vapor condensate did not produce any maternal toxicity, fetal toxicity, or developmental effects in rats.  Based on the study results, the maternal and developmental NOAELs were both 23900 mg/m3.  These findings do not warrant the classification of the test material as a developmental hazard under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.