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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was carried out in a method equivalent/similar to OECD TG 414.

Data source

Reference
Reference Type:
publication
Title:
Developmental toxicity of JP-8 jet fuel in the rat
Author:
Cooper, J.R., Mattie, D.R.
Year:
1996
Bibliographic source:
Journal of Applied Toxicology 16(3):197-200

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): JP-8 jet fuel
- Substance type: Kerosine
- Physical state: Liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, New York
- Age at study initiation: Not reported (rats were time mated and were purchased on day 4 of pregnancy)
- Weight at study initiation: Not reported
- Housing: In shoe-box cages, presumably individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): Not reported
- Acclimation period: 2 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 23
- Humidity (%): 45 to 55%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:
10 days
Frequency of treatment:
daily
Duration of test:
Gestational days 6 to 15
Doses / concentrations
Remarks:
Doses / Concentrations:
500, 1000, 1500, or 2000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
Thirty
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Not reported
- Other: Volume of JP-8 varied from 1.1 to 7.3 millilitres in order to obtain the desired dose and the dam's body weight. Controls received sterile water.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked for toxicity with no specific details provided.


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: Not reported


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Liver, kidney, gravid uterus weights; no details on gross examinations


OTHER:
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: Only specified that resorption sites were recorded and that non-gravid uteri were examined for early resorptions.
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
Body weight (maternal and pups) were analyzed using Bartlett's test for homogeneity followed by a one-way analysis of variance and Bonferroni's test. Non-parametric data were analyzed using the Kruskal-Wallis test followed by the Mann-Whitney U test when appropriate. The incidence of foetal malformations/variations per litter were compared using Fisher's exact test.
Indices:
Maternal weight gain, maternal organ weight, male foetal weight, female foetal weight, mortality, number of gravid and non-gravid rats, corpora lutea/dam, implantation sites/dam, number of dams with resorptions only, resorptions/dam, number of dams with live young, live foetuses/dam, dead foetuses/dam, male to female foetus ratio, variations observed, and malformations observed

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
There was a significant decrease in maternal weight gain with doses of 1000 mg/kg/day or greater (table 1). Maternal necropsy weight was significantly different than the control in the 1500 and 2000 mg/kg/day groups. There were no apparent clinical signs of toxicity. There were no differences in the reproductive endpoints examined.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
There was a significant decrease in foetal weight in both male and female foetuses with 1500 and 2000 mg/kg/day (table 1). The test compound did not significantly increase the incidence of malformations or variations compared to the control nor was the sex ratio altered.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: embryotoxicity
Dose descriptor:
LOAEL
Effect level:
1 500 mg/kg bw/day (actual dose received)
Basis for effect level:
other: embryotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Thirteen females (one 1000 mg/kg/day; three 1500 mg/kg/day, and nine 2000 mg/kg/day) were found dead. Although there appears to be a dose-dependent increase in the mortality, necropsy found the cause of death to be related to the presence of the test compound in the lungs indicating dosing into the lungs instead of the gastrointestinal tract.

Table 1

Maternal and foetal weights of rats treated with JP-8

 

Control

500 mg/kg/day

 1000 mg/kg/day

1500 mg/kg/day

2000 mg/kg/day

Dams pregnant

26

23

27

27

20

Maternal weight gain (grams)

133 ± 6.1a

120 ± 6.5

91.9 ± 6.5 *

39.5 ± 6.1 *

19.7 ± 7.1 *

Male foetal weight

4.08 ± 0.07

4.12 ± 0.08

3.92 ± 0.075

3.46 ± 0.05 *

3.10 ± 0.11b*

Female foetal weight

3.95 ± 0.07

4.01 ± 0.09

3.72 ± 0.05

3.45 ± 0.05 *

3.01 ± 0.10 *

aMean ± standard error of the mean (SEM)

bThis is reported as 3.10 ± 11 in the report, it is assumed that this is an error and that the decimal point was left out.

* p<0.05

Applicant's summary and conclusion

Conclusions:
JP-8 jet fuel administered orally to pregnant dams affected the body weights of both the pregnant dams and the foetuses. The maternal LOAEL is 1000 mg/kg/day, based on reduced body weight gain. The maternal NOAEL is 500 mg/kg/day. The foetal LOAEL is 1500 mg/kg/day, based on reduced body weight. The foetal NOAEL is 1000 mg/kg/day.
Executive summary:

In a developmental toxicity study, undiluted JP-8 jet fuel was administered to 30 Sprague-Dawley (Crl:CD) rats/dose by gavage at various volumes to achieve dose levels of 0 (sterile water), 500, 1000, 1500, or 2000 mg/kg bw/day from days 6 through 15 of gestation.

 

There was a significant decrease in maternal weight gain with doses of 1000 mg/kg/day or greater. Maternal necropsy weight was significantly different than the control in the 1500 and 2000 mg/kg/day groups. There were no apparent clinical signs of toxicity. Reproductive endpoints were not assessed in this study because females were pregnant prior to treatment and did not deliver, so only developmental endpoints can be assessed. Thirteen females (one 1000 mg/kg/day; three 1500 mg/kg/day, and nine 2000 mg/kg/day) were found dead. Although there appears to be a dose-dependent increase in the mortality, necropsy found the cause of death to be related to the presence of the test compound in the lungs indicating dosing into the lungs instead of the gastrointestinal tract. The maternal LOAEL is 1000 mg/kg/day, based on reduced body weight gain. The maternal NOAEL is 500 mg/kg/day.

 

There was a significant decrease in foetal weight in both male and female foetuses with 1500 and 2000 mg/kg/day. The test compound did not significantly increase the incidence of malformations or variations compared to the control nor was the sex ratio altered. The developmental LOAEL is 1500 mg/kg/day, based on reduced foetal weight. The developmental NOAEL is 1000 mg/kg/day.

 

This study received a Klimisch score of 1 and is classified as reliable without restrictions because it was carried out in a method equivalent/similar to OECD TG 414.