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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
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 is an acceptable and well-documented study report.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report Date:
2000

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
This was a reproductive study performed in two parts. Haematology, clinical chemistry, and histopathology in males were reported in Mattie et al. 1995 and were not repeated as part of this study design. In the first part, males were treated for 70 to 90 days with 0 (1mL of distilled water), 750, 1500, or 3000 mg/kg/day of undiluted JP-8 jet fuel, then mated to untreated females (one female at a time). In the second part of the study, female rats were administered the test compound at doses of 0 (1mL of distilled water), 375, 750, or 1500 mg/kg/day undiluted JP-8 jet fuel for 90 -day prior to mating, through mating, gestation, delivery, and lactation for a total of 21 weeks.
GLP compliance:
yes

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): JP-8 jet fuel
- Other: The fuel met the requirements of Military Specification MIL-T-83133A.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Labs, Kingston, New York
- Weight at study initiation: 180 to 220 grams
- Housing: Individually, except during cohabitation (1 male with 1 female)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 25 °C
- Humidity (%): Not reported
- 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)
Duration of treatment / exposure:
Males were treated for 70 to 90 days. Females were treated for 21 weeks.
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
Males: 750, 1500, or 3000 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
Females: 325, 750, or 1500 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
A minimum of 20 male rats per dose were used to test male fertility and a minimum of 35 female rats were used to test effects on female fertility.
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Doses were based on a previous 90-day study.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Not reported
- Cage side observations examined were not reported.


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations:Daily


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


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


OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At study termination
- Anaesthetic used for blood collection: No
- Animals fasted: No data
- How many animals: A maximum of 10 females per treatment group
- Parameters checked in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At study termination
- Animals fasted: No data
- How many animals: A maximum of 10 females per treatment group
- Parameters checked in table 2 were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: At weaning, 24 hours prior to sacrifice
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters checked in table 3 were examined.


NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Males: fertility and sperm analysis; Females: in the same rats used for haematology and clinical chemistry, the brain, kidneys, liver, spleen, and ovaries were weighed; reproduction indices
Sacrifice and pathology:
GROSS PATHOLOGY: No data
HISTOPATHOLOGY: Yes (see table 4)
Other examinations:
Fertility parameters were measured in both males and females.
Statistics:
General toxicity data: an ANOVA with or without multiple comparisons
Reproductive measures: a one- or two-factor ANOVA and a post-hoc comparison of dose using two-tailed t-test with pooled error was used for continuous data; a Chi-square test of proportions followed by a Fischer's Exact test was used for categorical data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no changes in clinical signs or mortality.


BODY WEIGHT AND WEIGHT GAIN: Body weights in male rats were decreased in a dose-dependent manner. Terminal body weights were approximately 545 grams, 520 grams, 475 grams, and 315 grams in the control, 750, 1500, and 3000 mg/kg/day, respectively (results were approximated from a figure). In females, body weight was only significantly reduced in the high-dose group, but the differences were not significant at terminal sacrifice. The body weight in females at 20 weeks (1 week before sacrifice) was approximately 400 grams, 385 grams, 382 grams, and 335 grams in the control, 375, 750, and 1500 mg/kg/day, respectively.


HAEMATOLOGY: Haematology was not measured in the males and no effects were noted in the females.


CLINICAL CHEMISTRY: Clinical chemistry was not measured in the males and no effects were noted in the females.


URINALYSIS: Urinalysis was not measured in the males and no effects were noted in the females.


ORGAN WEIGHTS: Absolute and relative liver weights were increased in mid- and high-dose females (Table 1).


HISTOPATHOLOGY: The test compound caused perianal dermatitis (high-dose only) and stomach hyperplasia (mid- and high-dose) in the female rats (Table 2).

OTHER FINDINGS: There were no treatment-related effects on reproduction or sperm parameters in males. There were no effects on reproduction, gestation, or litter size in females. There was a dose-related decrease in pup weight that was significant in the 750 mg/kg/day group on postnatal day 4 only and in the 1500 mg/kg/day group from postnatal day 4 through postnatal day 21 but had recovered by postnatal day 90.

Effect levels

Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: body weight

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The decreased body weight in males was probably related to nephropathy that is typically produced in male rats exposed to hydrocarbon fuels. Although there were changes in liver weight in the females, this was not accompanied by any changes in clinical chemistry or liver histopathology so is likely not of biological significance.

Table 5

Body weight and liver weights in female rats

 

Control

325 mg/kg/day

750 mg/kg/day

1500 mg/kg/day

 

n=10

n=7

n=8

n=8

Terminal Body weight

351.0 ± 12.6

354.3 ± 9.0

357.5 ± 6.5

348.8 ± 16.3

Absolute liver weight

14.8 ± 0.8

15.7 ± 0.6

17.8 ± 0.7 *

19.1 ± 0.7 **

Liver to body weight

4.2 ± 0.1

4.4 ± 0.1

5.0 ± 0.2 **

5.5 ± 0.1 **

Liver to brain weight

754.9 ±38.9

823.6 ± 39.8

903.1 ± 31.8 *

993.6 ± 46.3 **

* p<0.05

** p<0.01

Table 6

Incidence and severity significant histopathological findings in female rats

 

Control

325 mg/kg/day

750 mg/kg/day

1500 mg/kg/day

 

n=8

n=4

n=5

n=6

Perianal dermatitis

0

0

0

83% (1.2) *

Anal hyperplasia

0

0

0

50% (0.7)

Stomach gastritis

0

50% (0.5)

20% (0.2)

0

Stomach hyperplasia

0

75% (0.8)

100% (1.6) *

100% (1.7) *

* p<0.05

Applicant's summary and conclusion

Conclusions:
The study LOAEL for systemic effects is 1500 mg/kg/day and the NOAEL for systemic effects is 750 mg/kg/day, based on reduced body weight in dams and in pups. The LOAEL for adult males rats exposed to JP-8 orally was 750 mg/kg/day due to changes in clinical pathology, body weight, organ weights and the same irritation seen in female rats. The reproduction NOAEL was 3000 and 1500 mg/kg/day in males and females, respectively.
Executive summary:

This was a reproductive study performed in two parts. In the first part, males were treated for 70 to 90 days with 0 (1mL of distilled water), 750, 1500, or 3000 mg/kg/day of undiluted JP-8 jet fuel, then mated to untreated females (one female at a time). Males were gavaged throughout the cohabitation period and were returned to their individual cage after successful mating. In the second part of the study, female rats were administered the test compound at doses of 0 (1mL of distilled water), 375, 750, or 1500 mg/kg/day undiluted JP-8 jet fuel for 90 -day prior to mating, through mating, gestation, delivery, and lactation for a total of 21 week. During mating, they were housed with untreated males. Litters were standardized to 4 male pups and 4 female pups on postnatal day 5. Although those pups were used for neurobehavioral tests, the data was not provided in the study report.

There were no effects on clinical signs or mortality in either sex. Haematology, clinical chemistry, and urinalysis were measured only in females without any effects noted. Body weights in male rats were decreased in a dose-dependent manner and was likely related to nephropathy that is specific in male rats treated with hydrocarbons. In females, body weight was only significantly reduced in the high-dose group. Absolute and relative liver weights were increased in mid- and high-dose females, but were not likely biologically significant due to the lack of changes in clinical chemistry or histopathology in the liver. The test compound caused perianal dermatitis (high-dose only) and stomach hyperplasia (mid- and high-dose) in the female rats (histopathology was not conducted on the males for this study because previous studies have indicated nephropathy). There were no treatment-related effects on reproduction or sperm parameters in males. There were no effects on reproduction, gestation, or litter size in females. There was a dose-related decrease in pup weight that was significant in the 750 mg/kg/day group on postnatal day 4 only and in the 1500 mg/kg/day group from postnatal day 4 through postnatal day 21 but had recovered by postnatal day 90.

The study LOAEL for systemic effects is 1500 mg/kg/day and the NOAEL for systemic effects is 750 mg/kg/day, based on reduced body weight in dams and in pups. The LOAEL for adult males rats exposed to JP-8 orally was 750 mg/kg/day due to changes in clinical pathology, body weight, organ weights and the same irritation seen in female rats.Changes in male rats may be complicated by the male rat-specific nephropathy produced after exposure to hydrocarbon fuels such as JP-4 and JP-8. The reproduction NOAEL was 3000 and 1500 mg/kg/day in males and females, respectively.

This study received a Klimisch score of 1 and is classified as reliable without restrictions because it is an acceptable and well-documented study report.