6-hydroxy-2-naphthoic acid

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1988-10-5 - 1989-08-03

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Limited scope of clinical/organ/tissue examinations and of functional observational battery; Apart from that, well documented and reported study, conducted according to OECD 407 test guideline of 1981 and in compliance with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1989

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

of 1981

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

IUPAC Name:

3-hydroxy-2-naphthoic acid

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): BONS, Beta-Oxynaphthoesäure, 2-Naphthalenecaboxy acid,3-hydroxy
- Substance type: yellow powder
- Physical state:solid
- Analytical purity: 98.5 %
- Impurities (identity and concentrations): 1% ß-Naphthol
- Lot/batch No.: Pt. 680/88
- Storage condition of test material: at 22°C in the dark

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG breeding colony
- Age at study initiation: ca. 6 weeks
- Weight at study initiation (day -4): mean male: 101 g, female: 96 g
- Fasting period before study: none
- Housing: groups of 5, macrolon cages
- Diet (e.g. ad libitum): rat diet Altromin 1324, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/-3
- Humidity (%): 50+/- 20
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: aqueous carboxymethyl cellulose

Details on oral exposure:

The administration volume was 5 ml/kg bodyweight at all dose levels. Hence the concentration of test substance in the aqueous CMC preparation (vehicle) administered was 0.00, 0.24, 1.20 and 6.00 % (w/v) in the vehicle control, low dose, mid dose and high dose groups, respectively.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

28 applications in 29 days.

Frequency of treatment:

7days per week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 12, 60, 300 mg/kg bw/day (mf)
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Positive control:

Not available

Examinations

Observations and examinations performed and frequency:

Clinical observations: twice daily.
Functional observations (not specified), and examination of eyes, oral cavity and teeth: at weekly intervals.
Body weights: determined at beginning of the study and then twice per week.
food consumption: determined twice per week.
water consumption: determined once per week.
Haematology/Clinical chemistry/Urinalysis: at study end from all animals.

Sacrifice and pathology:

All animals were killed on day 29 after 28 consecutive days of oral (gavage) treatment.
Organ weights and organ to body weight ratios determined: heart, lung, liver, kidneys, spleen, testes, adrenals.
Organs/tissues examined at necropsy (macroscopic and microscopic): heart, lung, liver, kidneys, spleen, stomach, jejunum, colon, thymus, testes, adrenals, bone marrow.

Other examinations:

No

Statistics:

Not specified, significance level p= 0.05

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

water consumption increased at 300 mg/kg at day 7 and day 14

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Phosphate decreased , bilirubin increased at 300 mg/kg bw . Although values were within the range of historical controls they are considered to be substance related because of the distinct deviation from the concurrent control.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

bilirubin (ca 35 µmol/L) in female at 300 mg/kg bw

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

slightly increased liver weight in females at 300 mg/kg bw

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

adrenal gland findings in females at 60 and 300 mg/kg bw

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

necrosis of adrenal cortex in one female at 60 mg/kg bw and in one female at 300 mg/kg bw

Histopathological findings: neoplastic:

not specified

Effect levels

1

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Sex:

male

Basis for effect level:

other: At 300 mg/kg/day decreased serum phosphate level (toxiccological relevance of this finding is unclear), increased bilirubin concentration in serum and urine but without microscopic correlates in the liver.

2

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The administration of the test substance had no influence on body weights, food consumption and behaviour of the animals. No mortality was observed. There were no neurological impairments, no eye opacities and no pathological findings in the oral cavity or teeth. 300 mg/kg bw: an increased water consumption was observed during the first two study weeks; at the end of the study, a significant decrease in serum phosphate, and an increase in serum bilirubin levels were observed when compared to the controls (the levels were within the normal range of the historical controls). In both sexes, bilirubin was found in the urine (ca. 35 µmol/L) and serum. Females showed a slight, but statistically significant increase in liver to bodyweight ratios (without histopathological correlate)(no further details available). At histopathology, one out of five females of the high-dose and one out of five female of the mid-dose group showed adrenal necroses. Examination of the animal from the intermediate dose group revealed diffuse necrosis of the right adrenal cortex. Complete necrosis of the adrenal cortex was detected in the female of the high dose group. Liver fibrosis, and changes in the lobular structure were microscopically seen in one of the females of the low-dose group, but considered as a chance event due to the lack of a dose-response.

Applicant's summary and conclusion

Conclusions:

For male animals the no-observed-effect-level (NOEL) was set at 60 mg/kg/day, because of decreased serum phosphate levels (toxicological relevance of this finding is unclear) and increased bilirubin concentration in serum and urine (but without microscopic correlates in the liver). For female animals the no-observed-effect-level (NOEL) was set at 12 mg/kg/day, mainly because of necroses of the adrenal cortex in one female each at 60 and 300 mg/kg/day. In addition, at 300 mg/kg decreased serum phosphate levels, increased bilirubin concentration in serum and urine and slightly increased liver to bodyweight ratios (but without histopathological correlates in the liver) were evident.

Executive summary:

Rats (5 males and 5 females/dose group) were treated by oral gavage administration with 3-Hydroxy-2-naphthoic acid at dose levels of 0, 12, 60 or 300 mg/kg bodyweight/day once daily, seven days/week over 28 days. All animals were killed after 28 treatment days (day 29). At regular intervals during the study, eyes, oral cavities and teeth were examined and clinical signs, functional observations (not specified), body weights, food consumption and water consumption were recorded. In addition, at the end of the study, haematology, clinical chemistry and urinalysis examinations were performed on all animals. Organ weights were determined and macroscopic pathology and histopathology were performed on a number of organs/tissues from all animals.

Bodyweight, food consumption and animal behavior were unaffected by treatment with the test substance and mortality, neurological impairment, eye opacities and pathological findings in oral cavity or teeth were not evident at all dose levels. At 12 mg/kg/day, no signs of toxicity attributable to treatment with the test substance were evident. At 60 mg/kg/day, male animals were unaffected by treatment, whereas a relationship of necroses in the adrenal cortex in one female at 60 and one female at 300 mg/kg/day to treatment with the test item could not be entirely discounted. In addition, at 300 mg/kg/day a transient increase in water consumption, decreased serum phosphate levels and increased bilirubin concentrations in serum and urine were evident in both sexes and slightly increased liver to body weight ratios in females. Histopathological hepatic correlates were not evident.

The no-observed-effect-level (NOEL) was 60 mg/kg/day for male animals and 12 mg/kg/day for female animals.