MK1 Diesel Fuel

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

most likely 8008-20-6

IUPAC Name:

most likely 8008-20-6

Constituent 2

Reference substance name:

JP-8 jet fuel

IUPAC Name:

JP-8 jet fuel

Test material form:

other: low viscosity liquid hydrocarbon

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 or test system 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)

1

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

2

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)

1

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: embryotoxicity

2

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 ± 6.1^a	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 ± 0.11^b*
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. It can be concluded that the test substance is not toxic to development.

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 dosed 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. It can be concluded that the test substance is not toxic to development.

 

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.