2-naphthol

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: A well documented study according to OECD and GLP guidelines. In the OECD SIDS on 2-Naphthol (2002) a similar reliability was assigned.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Report date:

2000

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-naphthol

EC Number:

205-182-7

EC Name:

2-naphthol

Cas Number:

135-19-3

Molecular formula:

C10H8O

IUPAC Name:

2-naphthol

Details on test material:

purity 99.6 wt %

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Age at study initiation: 5 weeks (males), 10 weeks (females)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% sodium carboxymethylcellulose solution

Duration of treatment / exposure:

Exposure period: males: for 10 weeks prior to mating, during the mating period and until the day before necropsy (98 days); females: for 2 weeks prior to mating, during mating and gestation and until day 20 of lactation.
Premating exposure period: Male : 10 weeks / Female : 2 weeks

Frequency of treatment:

Daily

Details on study schedule:

Mating period: max 3 weeks (1:1, until pregnancy or until three weeks had elapsed).

Doses / concentrations

Remarks:

Doses / Concentrations:
0; 10; 40; 160 mg/kg bw
Basis:

No. of animals per sex per dose:

25 per sex per dose group.

Control animals:

yes, concurrent vehicle

Details on study design:

Pregnant females were allowed to deliver spontaneously and were sacrificed on day 21 of lactation together with their offspring. Test substance was applied until the day before sacrifice.

Examinations

Parental animals: Observations and examinations:

Principal organs, pituitary gland, stomach, adrenal glands, testes, epididymides, coagulating glands, seminal vesicles and prostate were isolated and examined. The organs from the control and the high-dose group and all organs with macroscopic abnormalities were processed for histopathological examinations.
Pregnant females were allowed to deliver spontaneously and were sacrificed on day 21 of lactation together with their offspring. Test substance was applied until the day before sacrifice. At necropsy, all females were examined for abnormalities of the principal organs, the uteri were isolated and the number of implantations counted. In addition, pituitary gland, stomach, adrenal glands, ovaries, cervix and vagina were examined. All organs with macroscopic abnormalities were processed for histopathological examinations.

Litter observations:

The parent animals were observed for general condition and for changes in body weight and food consumption as well as reproductive ability including parturition and lactation. Each litter was examined for number of pups born (live and dead newborns); live newborns were examined for presence of gross anomalies. All dead pups were examined by necropsy. The offspring were also observed for development up to weaning. On day 4 after birth, the size of each litter was
adjusted to 8 pups (four males and four females, in principle). Adjustment was not performed for litters of less than eight pups. Eliminated pups were examined for abnormalities by gross necropsy and fixed in formalin. Live pups were individually weighed on days 0,4,7,14 and 21 after birth, and mean pup weight in each litter was calculated by sex. On day 21 after birth, all live pups were sacrificed and examined for abnormalities by gross necropsy. Organs with abnormalities were fixed in formalin solution.

Statistics:

Frequency/length of estrous cycle, copulation and fertility indices and frequency of offspring with morphological abnormalities were analyzed by Fisher's exact probability test. Differences in histopathological findings, the graded data and total numbers of postitives were analyzed by Mann-Whitney`s U-test and one-tailed Fisher's exact probability test, respectively. Individual data or mean values of each litter were treated as a single sample, and homogeneity of variance of these samples among groups was analyzed using Bartlett's test. When homogeneity of variance was confirmed, one-way analysis of variance was applied to detect significance between groups. If a significant difference was detected, the Dunnett's test was applied for multiple comparisons. When variance was not
homogenous or zero, the Kruskal-Wallis analysis of ranks was applied, and, if significance was detected, the Dunnett's test applied for multiple comparisons.
Significance levels: p=0.01 and 0.05

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

No death or moribund conditions in the male and female rats at any dose level.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No effects on body weight in male and female groups but decrease in food consumption was observed at the beginning of the gestation period in the mid- and high-dose in female groups.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No effects on body weight in male and female groups but decrease in food consumption was observed at the beginning of the gestation period in the mid- and high-dose in female groups.

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histopathological examination revealed squamous hyperplasia of the forestomach in male group but no effects in female group.

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Details on results (P0)

Males:
2-Naphthol did not cause death or moribund conditions in the male rats at any dose level. Transient salivation was observed after dosing in all treatment groups given 2-naphthol. A decrease in locomotor activity was observed after dosing 40 mg/kg or more. The animals in the 40 mg/kg group also showed transient incomplete or complete closure of the eye and nasal discharge. In the group given 160 mg/kg, the animals showed transient lacrimation after dosing.
2-Napththol did not affect body weight gain and food consumption. At necropsy, thickened forestomach mucosa was observed in the animals of the mid- and high-dose groups. Histopathological examination revealed squamous hyperplasia of the forestomach in these animals. No micro- or macroscopic changes were found in the pituitary gland, testes, epididymides, coagulating gland, seminal vesicle and prostate. 10 mg/kg bw caused neither macroscopic nor microscopic changes.

Females:
Neither deaths nor moribund condition were observed in any group. 40 mg/kg caused a transient decrease in locomotor activity and salivation in the early study period. In the animals of the high-dose group, these transient effects were observed after dosing throughout the whole study period. In mid- and high-dose animals nasal discharge, leaning and prone position and reduced activity were also observed after dosing.
While body weight gain was not clearly suppressed, a decrease in food consumption was observed at the beginning of the gestation period in the mid- and high-dose groups.
Food consumption was also decreased after day 4 of lactation in the animals of the high-dose group. No abnormalities were found at gross necropsy and at microscopic examinations including pituitary gland, stomach, ovaries, uterus, cervix and vagina.

Effect levels (P0)

1

Dose descriptor:

NOEL

Effect level:

160 other: mg/kg bw

Sex:

male

Basis for effect level:

other: Reproductive toxicity

2

Dose descriptor:

NOEL

Effect level:

40 other: mg/kg bw

Sex:

female

Basis for effect level:

other: Reproductive toxicity

3

Dose descriptor:

LOEL

Effect level:

10 other: mg/kg bw

Sex:

male

Basis for effect level:

other: Systemic toxicity (salivation)

4

Dose descriptor:

NOEL

Effect level:

10 other: mg/kg bw

Sex:

female

Basis for effect level:

other: Systemic toxicity (reduced food consumption and decreased locomotor activity at 40 mg/kg bw).

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Description (incidence and severity):

Administration of the test substance did not affect general condition, including behaviour of the offpring.

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

The viability index was slightly reduced at day 4 after birth in the high dose group.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreased body weights in female groups (14.5%) and less pronouced effects in male groups for the high-dose group. No effects in the low- and mid-dose groups.

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Details on results (F1)

Offspring:
Administration of the test substance did not affect general condition, including behaviour of the offpring. Birth index in the high-dose group was decreased (not statistically significant). The viability index was slightly reduced at day 4 after birth in the high dose group.
There was no effect of 2-naphthol treatment on sex ratio and weaning index.
Decreased body weights were found in the female pups in the high-dose group at day 21 after birth (- 14.5 %). Similar, but less pronounced effects were found in male pups. No effects on body weight were seen in the low- and mid-dose groups. One newborn from a dam given 10 mg/kg bw/day was runt. At necropsy, offspring from 1-2 dams in each group, including the control group, showed morphological changes including anomalies and variations. As for external
changes, microphthalmia (1 pup), slight subcutaneous hematoma (1 pup) and detachment of the skin (2 pups) were observed in offspring from each one dam in the control, low-dose and high-dose group, respectively. Among these changes, microphthalmia, found in one pup of the control group, was the only change classified as malformation. As for visceral changes, dilatation of the renal pelvis (a variation) was observed in each one pup from dams given 10 or 40 mg/kg bw. Since no significant differences in the incidence of both external and visceral changes and no dose relationships were observed, these effects were judged as chance events.

Effect levels (F1)

Dose descriptor:

NOEL

Generation:

F1

Effect level:

40 other: mg/kg bw

Sex:

not specified

Basis for effect level:

other: Reduced viability was seen in the offspring at 160 mg/kg bw.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

A one-generation reproduction toxicity test on 2-naphthol was performed on Sprague-Dawley male rats. A NOAEL F1 offspring was identified at 40 mg/kg bw.