3-hydroxy-2-naphthoic acid

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:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: All information on this study, including the reliability grade, is derived from OECD SIDS 3-hydroxy-2-naphthoic acid CAS: 92-70-6 dated 2004-11-23, as the complete study report is not at hand. The testing laboratory report no. is HRI 10-1636.

Data source

Reference

Reference Type:

secondary source

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-hydroxy-2-naphthoic acid

EC Number:

202-180-8

EC Name:

3-hydroxy-2-naphthoic acid

Cas Number:

92-70-6

Molecular formula:

C11H8O3

IUPAC Name:

3-hydroxynaphthalene-2-carboxylic acid

Details on test material:

- Name of test material (as cited in OECD SIDS): 3-Hydroxy-2-naphtoic acid

Test material purity 99.2%,
impurity: 2-naphthol, 0.1%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% sodium CMC (carboxymethyl cellulose) solution

Details on mating procedure:

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

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

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.
Explanatory note (not specified in the OECD SIDS): Based on the biology of the laboratory rat the female exposure period was as follows:
treatment prior to mating = 2 weeks
mating period = 0-3 weeks
gestation/pregnancy = 3 weeks
lactation period = 3 weeks
total treatment period females = 8 to 11 weeks

Frequency of treatment:

daily (once per day)

Details on study schedule:

Age at initiation: 5 weeks (males), 10 weeks (females).
Males were sacrificed 1 week after the mating period.
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.

Doses / concentrations

Remarks:

Doses / Concentrations:
0 (vehicle control); 12.5; 50; 200 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

25 per sex per dose group (parental animals)

Control animals:

yes, concurrent vehicle

Positive control:

Not reported in OECD SIDS

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

Males:

1 animal of the control group died from malocclusion. Each one animal in the low- and mid-dose group was killed in a moribund state or died from myelogenous leukemia which was considered as not related to treatment by the study authors.

200 mg/kg bw: transient salivation and nasal discharge were observed after dosing. Body weight gain was significantly decreased (- 35-40% vs control) in the terminal study period (days 85-99).

12.5 and 50 mg/kg bw had no effects on general condition, body weight gain and food consumption.

No abnormalities were found at the hematological examination at necropsy with the exception of a slight, but statistically significant increase in the red blood cell count in the mid- and high dose group (+6%, +8% vs control). At necropsy, thickening of the mucosa of the forestomach was observed in 6 animals of the high-dose group.

Histopathological examination revealed hyperplasia of the forestomach squamous epithelium in the animals of the midand high-dose groups. Three animals of the high dose group showed enlarged livers without histopathological changes. No histopathological changes were found in bone marrow, spleen, adrenals, pituitary glands, testes, epididymides, coagulating glands, seminal vesicles and prostates. 12.5 mg/kg bw caused neither macroscopic nor microscopic changes.


Females:

Neither deaths nor moribund condition were observed in any group.

200 mg/kg bw: transient salivation was observed after dosing. Body weight gain was significantly decreased in the early study phase (days 1-8 of treatment: - 60% vs control), as well as in the terminal period of pregnancy (- 12%) to day 4 of lactation (-70%). 200 mg/kg bw had no influence on food consumption.

12.5 and 50 mg/kg bw had no effects on general condition, body weight gain and food consumption.

At necropsy, one female of the high-dose group showed thickening of the forestomach mucosa, and had squamous epithelial hyperplasia of the forestomach. No changes were found in adrenals, pituitary glands, ovaries, uterus, cervix and vagina. 50 and 12.5 mg/kg bw did not cause any macroscopic or microscopic changes. There was no significant difference in the number of implants between treated and control groups.


Reproductive Performance:

All females showed normal estrous cycle, and all animals performed fertile copulation. No adverse effect of the test substance was observed on pairing days until conception and number of vaginal estrous during the mating period. Furthermore, no abnormality was found in delivery and nursing conditions, and no adverse effects of the test substance on gestation index and gestation length were found. According to the authors of the study, 200 mg/kg bw could however suppress lactation, since the body weight of the offspring in this group was decreased.

Effect levels (P0)

1

Dose descriptor:

NOEL

Remarks:

for systemic toxicity

Effect level:

12.5

Sex:

male

Basis for effect level:

other: Systemic toxicity / NOEL = 12.5 mg/kg bw/day, because of forestomach lesions at 50 mg/kg/day

2

Dose descriptor:

NOEL

Remarks:

for systemic toxicity

Effect level:

50

Sex:

female

Basis for effect level:

other: Systemic toxicity / NOEL = 50 mg/kg bw/day, because of forestomach lesions and adverse effects on bodyweight gain at 200 mg/kg/day.

3

Dose descriptor:

NOEL

Remarks:

for reproductive toxicity

Effect level:

200 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: Reproductive toxicity / NOEL = highest dose tested

4

Dose descriptor:

NOEL

Remarks:

for reproductive toxicity

Effect level:

50

Sex:

female

Basis for effect level:

other: Reproductive toxicity / NOEL = 50 mg/kg bw/day. Growth retardation of pups possibly related to suppressed lactation at 200 mg/kg/day.

Results: F1 generation

Details on results (F1)

Offspring:

Administration of the test substance did not affect viability and general condition, including behaviour of the offpring. There was no effect on the number of stillbirth, number of live pups, delivery index, birth index, sex ratio, viability index and weaning index.

Decreased body weights were found in the pups of both sexes in the high-dose group from birth (-15%), until day 21 (-9%).

No effects on body weight were seen in the low- and mid-dose groups.

There was an increase in the incidence of offspring with external malformations, such as kinked tail (n=1), brachyury (5), brachyury with kink (1) or microphthalmus (1, dead offspring) in the high-dose group (offspring from 2 out of 25 dams; no pup in the control showed morphological changes). In addition, there were two dead offspring of two dams with visceral malformations in this group, such as undescended testes, hypoplasia of the spleen or diaphragmatic hernia. Although all these malformatins were found only in offspring of few limited litters, teratogenicity of the compound could not be ruled out from the present results according to the authors of the study.

Effect levels (F1)

Dose descriptor:

NOEL

Generation:

F1

Effect level:

50 other: mg/kg bw/day (actual dose received by parental animals P)

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The no-observed-effect-level (NOEL) for systemic toxicity in parental male animals was 12.5 mg/kg/day, because of forestomach lesions at 50 mg/kg/day. In parental females, the NOEL was 50 mg/kg/day, because of forestomach lesions and adverse effects on bodyweight gain at 200 mg/kg/day.
Reproductive performance was not adversely affected by treatment with the test substance. Therefore, the NOEL for reproductive toxicity was set at the highest administered dose level of 200 mg/kg/day for male animals. For female animals and their offspring, it was set at 50 mg/kg/day, because of growth retardation (bodyweight of pups lower than concurrent controls) and malformations (e.g. brachyury, kinked tail, microphthalmus in pups from a limited number of litters) at 200 mg/kg/day. The growth retardation of these pups may have been related to suppressed lactation suggested by the authors of this study. Slightly deviating from this interpretation from the OECD SIDS IUCLID DATA SET of 2004, the respective SIDS Initial Assessment Report for SIAM 19 (3-hydroxy-2-naphthoic acid) set the NOEL for reproductive toxicity at 200 mg/kg/day for both sexes, and only that for toxicity to the offspring at 50 mg/kg/day.

Executive summary:

In a one-generation study, 3-hydroxy-2-naphthoic acid was tested for its reproductive toxicity at dose levels of 0, 12.5, 50 or 200 mg/kg bodyweight/day administered by oral gavage. The study was conducted according to OECD Guideline 415 and in compliance with GLP. Male rats (25/dose group) were treated for 10 weeks prior to mating, during the mating period and until the day before necropsy (total of 14 weeks), female rats (25/dose group) were treated for two weeks prior to mating, during mating and gestation and until day 20 of lactation (total of 8 - 11 weeks) followed by necropsy on the day afterwards (lactation day 21). The pregnant females were allowed to deliver spontaneously.

 

In parental animals, clinical signs, bodyweight gain, food consumption, and in dams reproductive ability including parturition and lactation were recorded, and blood was collected for haematology examinations prior to necropsy. All animals were subjected to gross necropsy. In addition, histopathology was performed on the principal organs,pituitary gland, stomach, adrenal glands, testes, epididymides, coagulating glands, seminal vesicles, prostate, ovaries, cervix and vagina of the parental control and the high-dose groups and on all gross lesions. Uteri of dams were isolated and the number of implantations was recorded.

 

For each litter, its general condition and size, as well as viability, behaviour, gross anomalies and live-bodyweight of each pup were recorded at regular intervals. Litters larger than 8 pups were adjusted to 8 (in general, four males and four females) on day 4 after birth. Stillbirths/dead pups, eliminated pups and, by lactation day 21 the remaining pups, were examined for abnormalities by gross necropsy.

 

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 positives 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`t 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 was applied for multiple comparisons. Significance levels were p=0.01 and 0.05.

 

 

Parental Toxicity:

At 12.5 mg/kg/day adverse effects attributable to treatment with the test substance were not evident in parental animals.

 

At 50 mg/kg/day the red blood cell count was slightly, statistically significantly, higher in male animals (+ 6%) than in concurrent controls and histopathology revealed hyperplasia of the forestomach squamous epithelium in males. The general condition, bodyweight gain and food consumption were unaffected in parental animals at 12.5 and 50 mg/kg/day.

 

At 200 mg/kg/day, transient salivation in both sexes and nasal discharge in males were seen after dosing, and bodyweight gain was significantly lower than in concurrent controls in males towards the end of the treatment period (–35 - –40%) and in females during the first treatment week (–60%), as well as at the end of pregnancy (–12%) until lactation day 4 (–70%). Food consumption was unaffected at 200 mg/kg/day. In addition, the red blood cell count was slightly, statistically significantly, higher (+ 8%) in males than in concurrent controls and histopathology revealed hyperplasia of the forestomach squamous epithelium. The latter was consistent with the necropsy finding of thickening of the forestomach mucosa in 6 males and one female of this group. The macroscopic finding of enlarged livers in three high dose males had no histopathological correlate. The number of implants did not distinguish treated groups from the concurrent control group. No histopathological changes were found in bone marrow, spleen, adrenals, pituitary glands, testes, epididymides, coagulating glands, seminal vesicles, prostates, ovaries, uterus, cervix and vagina.

 

Reproductive Performance:

Reproductive performance was not adversely affected by treatment with the test substance. All females showed normal estrous cycle, and all animals performed fertile copulation. No adverse effect of the test substance was observed on pairing days until conception and on number of vaginal estrous during the mating period. Furthermore, no abnormality was found in delivery and nursing conditions, and no adverse effects of the test substance on gestation index and gestation length were evident. According to the authors of the study, 200 mg/kg bodyweight could, however, suppress lactation, since the body weight of the offspring in this group was decreased.

 

Offspring:

The number of stillbirth, number of live pups, delivery index, birth index, sex ratio, viability index and weaning index were unaffected by treatment with the test substance. Viability and general condition, including behaviour of the offspring were also unaffected. Bodyweight was unaffected in pups of the low and mid dose groups (12.5 and 50 mg/kg/day, respectively), but in both sexes of the high-dose group (200 mg/kg/day) it was lower than concurrent controls from birth (-15%) until day 21 (-9%).

 

Teratogenic effects were not evident in the low and mid dose groups. In the high dose group an increase in the incidence of offspring with external malformations, such as kinked tail (n=1), brachyury (5), brachyury with kink (1) or microphthalmus (1, dead offspring) was recorded (offspring from 2 of 25 dams), whilst there were no morphological changes in any pups of the concurrent control group. In addition, two dams of the high dose group had a dead offspring with visceral malformations, such as undescended testes, hypoplasia of the spleen or diaphragmatic hernia. Although all these malformations were evident in offspring from a limited number of litters, the authors of the study inferred that teratogenicity of the test substance could not be ruled out.