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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:
weight of evidence
Study period:
1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study report which meets basic scientific principles.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Cross-reference
Reason / purpose:
read-across: supporting information
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study report which meets basic scientific principles.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Time-mated Sprague-Dawley rats were dosed orally with JP-8 at 0, 500, 1000, 1500 and 2000 mg/kg/day on days 6-15 of pregnancy.
GLP compliance:
not specified
Species:
rat
Strain:
Crj: CD(SD)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Age at study initiation: One hundred and fifty time-mated virus antibody-free rats were purchased on day 4 of pregnancy.
- Weight at study initiation: all groups contained dams of approximately equivalent body weight at the beginning of the study
- Diet (e.g. ad libitum): Purina Lab Chow, ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71-73°F
- Humidity (%): 45-55% relative humidity
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
On days 6-15 of pregnancy the animals assigned to each treatment group were administered one of the following doses of JP-8 by oral gavage: 500, 1000, 1500 and 2000mg/kg/day. The volume of JP-8 administered ranged from 1.1 to 7.3 ml daily, depending on the dam's body weight and dose group. Control animals received 1 ml of sterile water daily in order to emulate any stress that may have been associated with the dosing process. Animals were examined daily for evidence of toxicity. On day 20 of pregnancy all animals were euthanized with carbon dioxide.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
GD 6-15
Frequency of treatment:
daily
Duration of test:
GD 6-15
Remarks:
Doses / Concentrations:
0, 500, 1000, 1500 and 2000mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
30 females
Control animals:
yes, sham-exposed
Maternal examinations:
Animals were examined daily for evidence of toxicity.
Ovaries and uterine content:
The dam's body weight and the liver, kidney and gravid uterus weights were recorded. The total number of corpora lutea, live fetuses, dead fetuses and resorption sites were also recorded for each dam. Uteri that appeared to be non-gravid were placed in a 10% ammonium sulfate solution for 10 min and then reevaluated for the presence of early resorptions.
Fetal examinations:
Viable fetuses were sexed, weighed and examined for gross abnormalities. One-half of the fetuses were evaluations using the technique of Wilson. The remaining fetuses were placed in ethanol for later examination of skeletal anomalies using the procedure of Staples and Schnell.
Statistics:
Maternal body weight and average pup weights per litter were first analyzed using Bartlett's test for homogeneity of variance followed by one-way analysis of variance (ANOVA) procedures. Bonferoni's test was used to compare the body weights of maternal and fetal control animals with those of animals in the treatment groups. Non-parametric data (i.e. corpora lutea counts, number of live fetuses and the number of dead fetuses) were analyzed using the Kruskal- Wallis test followed by the Mann-Whitney U test when appropriate. The incidence of fetal malformations/variations per litter were compared using Fisher's exact test. In all cases P <= 0.05 was used as the level of significance.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Significant maternal toxicity was evidenced by a reduction in maternal body weight gain in the 1000, 1500 and 2000 mg/kg/day dose groups. Maternal necropsy weight (maternal body weight minus pregnant uterus's weight) was also significantly different from that of the control animals at doses of 1500 and 2000 mg/kg/day. No clinically apparent maternal toxicity was noted during the course of the study. Thirteen animals were found dead in their cage at various times during the dosing period and each was submitted to necropsy. In all cases the cause of death was found to be related to the presence of JP-8 in the lungs. Maternal observations at necropsy, including the number of females pregnant, number of corpora lutea per female, number of fetuses per female and post-implantation loss, were within the normal range for all treatment groups.
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The average body weight of male and female fetuses was significantly reduced in the 1500 and 2000 mg/kg/day dose groups. A detailed examination of the fetal tissues revealed no significant increase in the incidence of malformations or variations in treated versus control animals. The sex ratio of male and female fetuses was also similar among the control and dose groups.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The maternal NOAEL was determined to be 500 mg/kg/day based on reduced maternal body weight. The fetotoxicity NOAEL was determined to be 1000 mg/kg/day based on reduced fetal weight. There were no developmental or teratogenic effects noted (aside from body weight reduction) in any dose tested.
Executive summary:

Time-mated Sprague-Dawley rats were dosed orally with JP-8 at 0, 500, 1000, 1500 and 2000 mg/kg/day on days 6-15 of pregnancy. The maternal NOAEL was determined to be 500 mg/kg/day based on reduced maternal body weight. The fetotoxicity NOAEL was determined to be 1000 mg/kg/day based on reduced fetal weight. There were no developmental or teratogenic effects noted (aside from body weight reduction) in any dose tested.

Data source

Reference
Reference Type:
publication
Title:
Developmental Toxicity of JP-8 Jet Fuel in the Rat
Author:
Cooper JR, Mattie MR
Year:
1996
Bibliographic source:
JOURNAL OF APPLIED TOXICOLOGY, VOL. 16(3), 197-200 (1996)

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Time-mated Sprague-Dawley rats were dosed orally with JP-8 at 0, 500, 1000, 1500 and 2000 mg/kg/day on days 6-15 of pregnancy.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
JP-8 is a kerosene-based jet fuel presently in use by the Air Force.

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Age at study initiation: One hundred and fifty time-mated virus antibody-free rats were purchased on day 4 of pregnancy.
- Weight at study initiation: all groups contained dams of approximately equivalent body weight at the beginning of the study
- Diet (e.g. ad libitum): Purina Lab Chow, ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71-73°F
- Humidity (%): 45-55% relative humidity
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
On days 6-15 of pregnancy the animals assigned to each treatment group were administered one of the following doses of JP-8 by oral gavage: 500, 1000, 1500 and 2000mg/kg/day. The volume of JP-8 administered ranged from 1.1 to 7.3 ml daily, depending on the dam's body weight and dose group. Control animals received 1 ml of sterile water daily in order to emulate any stress that may have been associated with the dosing process. Animals were examined daily for evidence of toxicity. On day 20 of pregnancy all animals were euthanized with carbon dioxide.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
GD 6-15
Frequency of treatment:
daily
Duration of test:
GD 6-15
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 500, 1000, 1500 and 2000mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
30 females
Control animals:
yes, sham-exposed

Examinations

Maternal examinations:
Animals were examined daily for evidence of toxicity.
Ovaries and uterine content:
The dam's body weight and the liver, kidney and gravid uterus weights were recorded. The total number of corpora lutea, live fetuses, dead fetuses and resorption sites were also recorded for each dam. Uteri that appeared to be non-gravid were placed in a 10% ammonium sulfate solution for 10 min and then reevaluated for the presence of early resorptions.
Fetal examinations:
Viable fetuses were sexed, weighed and examined for gross abnormalities. One-half of the fetuses were evaluations using the technique of Wilson. The remaining fetuses were placed in ethanol for later examination of skeletal anomalies using the procedure of Staples and Schnell.
Statistics:
Maternal body weight and average pup weights per litter were first analyzed using Bartlett's test for homogeneity of variance followed by one-way analysis of variance (ANOVA) procedures. Bonferoni's test was used to compare the body weights of maternal and fetal control animals with those of animals in the treatment groups. Non-parametric data (i.e. corpora lutea counts, number of live fetuses and the number of dead fetuses) were analyzed using the Kruskal- Wallis test followed by the Mann-Whitney U test when appropriate. The incidence of fetal malformations/variations per litter were compared using Fisher's exact test. In all cases P <= 0.05 was used as the level of significance.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Significant maternal toxicity was evidenced by a reduction in maternal body weight gain in the 1000, 1500 and 2000 mg/kg/day dose groups. Maternal necropsy weight (maternal body weight minus pregnant uterus's weight) was also significantly different from that of the control animals at doses of 1500 and 2000 mg/kg/day. No clinically apparent maternal toxicity was noted during the course of the study. Thirteen animals were found dead in their cage at various times during the dosing period and each was submitted to necropsy. In all cases the cause of death was found to be related to the presence of JP-8 in the lungs. Maternal observations at necropsy, including the number of females pregnant, number of corpora lutea per female, number of fetuses per female and post-implantation loss, were within the normal range for all treatment groups.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
The average body weight of male and female fetuses was significantly reduced in the 1500 and 2000 mg/kg/day dose groups. A detailed examination of the fetal tissues revealed no significant increase in the incidence of malformations or variations in treated versus control animals. The sex ratio of male and female fetuses was also similar among the control and dose groups.

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: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day (actual dose received)
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:
The maternal NOAEL was determined to be 500 mg/kg/day based on reduced maternal body weight. The fetotoxicity NOAEL was determined to be 1000 mg/kg/day based on reduced fetal weight. There were no developmental or teratogenic effects noted (aside from body weight reduction) in any dose tested.
Executive summary:

Time-mated Sprague-Dawley rats were dosed orally with JP-8 at 0, 500, 1000, 1500 and 2000 mg/kg/day on days 6-15 of pregnancy. The maternal NOAEL was determined to be 500 mg/kg/day based on reduced maternal body weight. The fetotoxicity NOAEL was determined to be 1000 mg/kg/day based on reduced fetal weight. There were no developmental or teratogenic effects noted (aside from body weight reduction) in any dose tested.