6-hydroxy-2-naphthoic acid

Developmental toxicity / teratogenicity

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: Study conducted in accordance with US GLP regulations.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

OECD-recommended limit dose of 1000 mg/kg bw/day not reached. Number of animals per group was less than 20.

GLP compliance:

yes

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

6-hydroxy-2-naphthoic acid

EC Number:

240-759-7

EC Name:

6-hydroxy-2-naphthoic acid

Cas Number:

16712-64-4

Molecular formula:

C11H8O3

IUPAC Name:

6-hydroxynaphthalene-2-carboxylic acid

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): C-195
- Substance type: Solid
- Physical state: Powder
- Analytical purity: Test article form states that sponsor has information
- Impurities (identity and concentrations): Test article form states that sponsor has information
- Composition of test material, percentage of components: Test article form states that sponsor has information
- Isomers composition: Test article form states that sponsor has information
- Purity test date: Test article form states that sponsor has information
- Lot/batch No.: Test article form states that sponsor has information
- Expiration date of the lot/batch: Material stated to have shelf-life of 1 year, when stored at room temp.
- Stability under test conditions: Not stated
- Storage condition of test material: Room Temperature

Test animals

Species:

rat

Strain:

other: Charles River COBS(R) CD(R)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan
- Age at study initiation: Approximately 12 weeks
- Weight at study initiation: 229 - 257 grams at Gestation Day 0
- Housing: Individually housed in suspended wire-mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Animals were acclimated for 13 days prior to study initiation

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hour dark / 12 hours light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5% high viscosity carboxymethyl cellulose

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test article was prepared fresh daily as a suspension in 0.5% high viscosity carboxymethyl cellulose. Concentration was adjusted to allow a fixed volume of 10 mL/kg per animal to yield the final dose of 250 mg/kg bw/day. A magnetic stir plate was used to keep test article in suspension during the dosing period.

VEHICLE
- Justification for use and choice of vehicle (if other than water): rationale not given in report.
- Concentration in vehicle: Concentration was adjusted to allow for a constant volume of 10 mL/kg per animal to yield the final dose of 150 mg/kg bw/day.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused: Occurence of copulation was determined daily by inspection for a copulatory plug.
- M/F ratio per cage: 1M/1F
- Length of cohabitation: Until verification of copulation
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy

Duration of treatment / exposure:

Single daily dose on days 6 through 15 of gestation.

Frequency of treatment:

Single Daily Dose

Duration of test:

Terminal sacrifice of females at Gestation Day 20.

Doses / concentrations

Remarks:

Doses / Concentrations:
250 mg/kg bw/day
Basis:
nominal conc.

No. of animals per sex per dose:

13 females

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observed daily prior to treatment, and then observed daily on days 6 through 20 of gestation.
- Cage side observations were reported in text.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Gestation days 0, 6, 9, 12, 16 and 20

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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: Immediately following sacrifice, the number and location of viable and non-viable fetuses, early and late resorptions and the number of total implantations and corpora lutea were recorded. The abdominal and thoracic cavities and organs of the females were examined for grossly evident morphological changes and the carcasses discarded. Uteri from females that appeared non-gravid were opened and placed in 10% ammonium sulfide solution for confirmation of pregnancy status.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Uteri from females that appeared non-gravid were opened and placed in 10% ammonium sulfide solution for confirmation of pregnancy status.

Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No data

Statistics:

- Male to Female sex distribution and the number of litters with malformations were compared using the Chi-square test criterion with Yates' correction for 2x2 contingency tables and/or Fisher's exact probability test.
- The number of early and late resporptions and postimplantation losses were compared by the Mann-Whitney U-Test.
- The mean number of viable fetuses, total implantations, corpora lutea and mean fetal body weights were compared by analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances).

Historical control data:

Provided as Appendix III of the report.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Survival was 100% in the test article-treated group and the control group. There were no biologically meaningful differences in any endpoint observation when compared to controls. Incidental antemortem observations noted in both treated and control groups were hair loss and soft stool. There was no treatment-related effect on maternal body weights relative to controls.

Effect levels (maternal animals)

Dose descriptor:

NOEL

Effect level:

> 250 mg/kg bw/day

Based on:

other: Expert Opinion

Basis for effect level:

other: other:

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
A statistically significant decrease in mean fetal body weight (P<0.05) occurred in the treated group when compared to controls. This mean value was slightly reduced when compared to the mean historical control value, and may be attributable to the increase in total implantations in this group (which was also statistically significant, with p<0.05, and the increase in number of viable fetuses. The mean values for viable fetuses and total implantationsin the control group were slightly reduced when compared to the respective mean historical control, and may account for the statistical significance obeserved in the treated group. There were no biologically meaningful differences in the mean numbers of corpora lutea, postimplantation loss, viable fetuses and the fetal sex distribution when compared to the control group. There were no malformations observed in any fetus in the treated group.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Survival was 100% in the treated group and in the control. There were no treatment-related effects observed with regard to appearance, behavior, mean maternal body weight gain during gestation, postmortem examination at sacrifice, Cesarian section values or the number of litters with malformations and genetic and developmental variations.

Treatment with test article did not produce a teratogenic response when administered orally by gavage to pregnant Charles River COBS(R) CD(R) rats at a dosage level of 250 mg/kg/day.

Executive summary:

Survival was 100% in the treated group and in the control. There were no treatment-related effects observed with regard to appearance, behavior, mean maternal body weight gain during gestation, postmortem examination at sacrifice, Cesarian section values or the number of litters with malformations and genetic and developmental variations.

Treatment with test article did not produce a teratogenic response when administered orally by gavage to pregnant Charles River COBS(R) CD(R) rats at a dosage level of 250 mg/kg/day