Decahydronaphthalene

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Evaluation of 60 chemicals in a preliminary developmental toxicity test

Author:

Hardin BD, Schuler RL, Burg JR, Booth GM, Hazelden KP, MacKenzie KM, Piccirillo VJ, Smith KN.

Year:

1987

Bibliographic source:

Teratogenesis, Carcinogenesis, Mutagenesis 7, 29-48

Materials and methods

Principles of method if other than guideline:

Reproduction toxicity test.
Pregnant mice were dosed during mid-pregnancy and were then allowed to deliver litters. Litter size, birth weight, and neonatal growth and survival to postnatal day 3 were recorded as indices of potential developmental toxicity

GLP compliance:

not specified

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Decahydronaphthalene

EC Number:

202-046-9

EC Name:

Decahydronaphthalene

Cas Number:

91-17-8

Molecular formula:

C10H18

IUPAC Name:

decahydronaphthalene

Details on test material:

Decahydronaphthalene, no data on purity or isomer ratio

Test animals

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Species/ Strain: mice, CD-1
- Source: Charles River Breeding Laboratories
- Age: 6-8 weeks
- Food (ad libitum): BP Nutrition Rat Mouse Breeder Diet No. 3, Purina Certified Rodent Chow
No. 5002, Wayne Lab-Blox, or Zeigler Brothers NIH-07 diet
- Water (ad libitum)
- Housing: during dose-range finding group housed (five per cage) throughout treatment, and observation periods, during main study singly housed in solid-bottom boxes. Nesting material (Bed-O-Cobs, Sani-chip, San-i-cel, or sterilized white wood shavings) was changed once weekly, but no bedding change was made later than gd 17 to avoid disturbing mice near parturition.

ENVIRONMENTAL CONDITIONS:
-12 hrs dark/ light cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

- gavage, dosing volume of 5 ml/kg body weight
- vehicle: corn oil
- control group with concurrent vehicle
- during dose-range finding: five dose levels using ten virgin female mice per group. Treatments were administered once daily for 8 consecutive days, with a dosing volume determined on the basis of body weights on the first treatment day.
- during main study: 2700 mg/ kg/ day, Treatments in the reproductive phase were administered once daily on gd 6-13, with a dosing volume determined on the basis of pretreatment body weights on gd 6. Experimental blocks consisted of 2-6 chemically treated groups with a concurrent vehicle control.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Details on mating procedure:

no data, time-mated mice were to be shipped on gd 0-2

Duration of treatment / exposure:

during dose-range finding: once daily for 8 consecutive days, during main study: administered once daily on gd 6-13,

Frequency of treatment:

once daily

Duration of test:

until gd 22 in the main study

Doses / concentrations

Dose / conc.:

2 700 mg/kg bw/day (nominal)

No. of animals per sex per dose:

48

Control animals:

other: yes, controls recived corn oil

Details on study design:

- All experiments were conducted in two phases: an initial dose-finding study, followed by a reproductive phase which employed a single dose level for the main study. In both pases, treatments were administered by gavage using as dosing volume of 5 ml/kg bw.
- For dose-finding, test item was tested at five dose levels using ten virgin female mice per group. Mice were observed twice daily during treatment, and once daily for 8 days following treatments. Body weights were recorded on the first and last (eighth) day of treatment, and on days 4 and 8 post-treatment. Signs of toxicity were recorded, and dead mice were necropsied to exclude dosing error, eg, instillation into the lungs or perforation of the esophagus, as a cause of death.

- Dose selection rationale: For the reproductive phase (main study), the LDI0 predicted on the basis of dose-finding results was the single dose used.

- Rationale for animal assignment (if not random):

- Other: Treatments in the reproductive phase were administered once daily on gd 6-13, with a dosing volume determined on the basis of pretreatment body weights on gd 6.
Experimental blocks consisted of 2-6 chemically treated groups with a concurrent vehicle control. Mice were observed twice daily during treatment, and once daily on gd 14-17. Body weights were again recorded on gd 17. At the daily observation, signs
of toxicity were recorded. Dead mice were necropsied to exclude dosing error as a cause of death. Beginning on gd 18, mice were observed twice daily for signs of parturition. When delivery was judged to be complete (postnatal day !), the number
of live pups was recorded, and live pups were weighed together as a litter, then returned to the dam. Neither live nor dead pups were systematically examined for malformations.
Two days later (postnatal day 3), live pups were again counted and weighed as a litter, and maternal body weights were recorded. Dams and litters were then discarded. Females that failed to deliver a litter by the presumed gd 22 were killed and uteri were examined.
If there was no gross evidence of a failed pregnancy, uteri were placed in 10% ammonium or sodium sulfide to reveal implantation sites as evidence of early termination of pregnancy.

Examinations

Maternal examinations:

Mortality, body weight change, viable litters

Fetal examinations:

liveborn per litter, percentage survival, birth weight, weight gain on postnatal day 3

Statistics:

Data reported by individual testing laboratories were coded into the Parklawn Computer System. and printouts were reviewed by the contractors to verify the accuracy of the data. The Statistical Analysis System (SAS Institute Inc., Cary. NC) was then used to analyze results of each experimental block. Body weights on gd 6 were analyzed by 2-tail ANOVA to verify that there were no group differences in initial body weight. Mortality (excluding death attributed to dosing error) was contrasted between pregnant and nonpregnant mice by 2-tail Fisher's exact test. Nonpregnant mice, as determined by uterine examination. were excluded from all subsequent analyses. The proponion of pregnant survivors that delivered a viablelitter (at least one liveborn pup) was compared with the concurrent vehicle control by I-tail Fishers exact test. For mice that delivered a viable litter, maternal body weight
change from gd 6 to postnatal day (pd) 3, the number of liveborn pups per litter, percent neonatal survival to pd 3, average pup weight at birth and average pupweight gain by pd 3 were analyzed by pairwise multiple comparisons of control and treated groups using a 2-tail Mann-Whitney U-test.

Historical control data:

no information

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Mortality:

mortality observed, treatment-related

Description (incidence):

7 of 48 pregant mice treated were reported dead

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

7.5 ± 2.6 g significantly higher than control: 6.1 +/-3.7 g (not toxicologically relevant, within limits of historical controls)

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes.
Remark: mortality, body weight gain

Details on maternal toxic effects:
7 of 48 pregant mice treated were reported dead
maternal body weight gain was 7.5 +/- 2.6 g, significantly higher than control: 6.1 +/-3.7 g (not toxicologically relevant, within limits of historical controls)
viable litters: 23/ 24

Effect levels (maternal animals)

1

Dose descriptor:

LOAEL

Effect level:

2 700 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

< 2 700 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

3

Dose descriptor:

NOAEL

Effect level:

> 2 700 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

live born/ litter: 9.9 +/- 2.3 (control: 9.4 +/- 2.7)

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

birth weight: 1.6 +/- 0.1 g; weight gain: 1.0 +/- 0.2 g

Changes in postnatal survival:

no effects observed

Description (incidence and severity):

percentage survival: 100

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 2 700 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: embryotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

No adverse developmental effects were noted.

Executive summary:

Pregnant mice were dosed during mid-pregnancy (gestation days 6 -13) with decahydronaphthalene by gavage at a dose level of 2700 mg/kg bw/d and were then allowed to deliver litters. Litter size, birth weight, and neonatal growth and survival to postnatal day 3 were recorded as indices of potential developmental toxicity. Seven of 48 treated dams were reported dead, body weight gain was statistically significant increased as compared to control that received corn oil but within the variation of controls. There were no adverse effects on neonatal parameters, number of liveborn per litter, survival and body weight gain to post natal day 3.