6-hydroxy-2-naphthoic acid

Endpoint summary

Description of key information

Two acute oral toxicity studies are available for the read-across substance, 3-hydroxy-2-naphthoic acid.  The effect level for oral toxicity was using the most conservative (lowest LD50) value from the female animals of the Key Study.  In the Acute Inhalation study of the substance of record, 6-hydroxy-2-naphthoic acid, no systemic effects were observed.  The only observed effect was slight reversible irritation of the oral and respiratory mucous membranes consistent with mechanical irritation.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

1983-09-27 - 1983-12-2

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline conforming study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

of 1981

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG breeding colony
- Weight at study initiation: male 197 g (mean); female 191 g (mean)
- Fasting period before study: 16h
- Housing: makrolon cage, groups of 5
- 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 +/- 2
- Humidity (%): 55 +/- 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

2% aqueous carboxymethyl cellulose (CMC)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 25%
- Amount of vehicle (if gavage): 1.25ml/kg bw in the lowest dose group and 5.0 ml/kg bw in the highest dose group

Doses:

male: 800, 1000, 1250 mg/kg bw
female: 315, 500, 800, 1000, 1250 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
weighth was determined: 0, 7, 14 days post application,
clinical signes were observed: 10, 30, 60 min; 2, 4, 6 h, 1, 2, 3, 4-14 d post application

- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

Probit analysis

Sex:

male/female

Dose descriptor:

LD50

Effect level:

823 mg/kg bw

95% CL:

>= 581 - <= 1 070

Sex:

male

Dose descriptor:

LD50

Effect level:

869 mg/kg bw

95% CL:

>= 394 - <= 1 350

Sex:

female

Dose descriptor:

LD50

Effect level:

795 mg/kg bw

95% CL:

>= 485 - <= 1 320

Mortality:

315 mg/kg bw : 0/5 (f)
500 mg/kg bw: 2/5 (f)
800 mg/kg bw: 1/5 (m), 2/5 (f)
1000 mg/kg bw: 3/5 (m), 3/5 (f)
1250 mg/kg bw: 5/5 (m), 4/5 (f)
all deaths occured 35 - 200 min. post application

Clinical signs:

other: Similar clinical signs were observed in both sexes. Clinical signes included reduced activity, accelerated breathing, closure of eyes and diarrhea (occurring 30-60 min post application).

Gross pathology:

Surviving animals were free of pathological changes at the end of the observation period (14 d). Gastrointestinal irritation and dark or mottled livers were observed in the dead animals.

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information REGULATION (EC) No 1272/2008 Criteria used for interpretation of results: EU

Conclusions:

LD50 male/female: 823 mg/kg bw
LD50 male: 869 mg/kg bw
LD50 female: 795 mg/kg bw

Executive summary:

3-Hydroxy-2-naphthoic acid was tested for its acute toxicity in the rat according to OECD Guideline 401 and in compliance with GLP. An oral LD₅₀ of 823 mg/kg bw was determined for both sexes, 869 mg/kg for males and 795 mg/kg for females. Mortality occurred within 35 -200 minutes after dosing. Principal clinical signs were reduced spontaneous activity, ventral and lateral recumbency and crawling in all dose groups, in addition to closure of eyes, hunched posture and accelarated breathing in several dose groups starting at approximately 10 to 30 min post administration. In addition, diarrhea was noted in several dose groups starting mainly at approximately 30 to 60 min post administration. As from the day after the administration all surviving animals were free from clinical signs. Bodyweight was unaffected by treatment with the test substance. No macroscopic pathology findings were evident in animals which survived the 14-day post-dosing observation period, whilst dark or mottled livers and signs of gastrointestinal irritation were evident in decedent animals. There was no indication of relevant sex-related differences in toxicity of the substance after single oral administration.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

795 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No GLP statement; However, is a well-conducted, well-documented study.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Sprague-Dawley derived CD
- Source: Charles River Breeding Laboratories, Wilmington, MA, USA
- Date received: 29 July 1980
- Age at study initiation: Not given
- Weight at study initiation: Males, 290-300 grams; Females, 210-249 grams
- Fasting period before study: Not stated.
- Housing: Not stated.
- Diet (e.g. ad libitum): Not stated.
- Water (e.g. ad libitum): Not stated.
- Acclimation period: Not stated.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): mean temperature was 21 degrees C during exposure.
- Humidity (%): mean relative humidity was 74% during exposure.
- Air changes (per hr): Not given. Study report gives air flow rate of "15 liters per minute" and states that "test material was delivered in a total volume of 3600 L of air".
- Photoperiod (hrs dark / hrs light): Not stated.

IN-LIFE DATES: Not stated.

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglass Exposure Chamber
- Exposure chamber volume: 100 L
- Method of holding animals in test chamber: Closed Chamber
- Source and rate of air: Source not stated, rate given as 15 liters per minute.
- Method of conditioning air: Described only as "dry air".

- System of generating particulates/aerosols: Test material was press-packed into a Wright Dust Feed cylinder using a Carver Hydraulic Press at a pressure of 1500 psi. The Wright Dust Feed mechanism, set at a gear ratio of 1.5 to 1 was arranged to feed into the exposure chamber. Dry air at a flow rate of 15 liters per minute was passed through the dust feed mechanisms to generate the dust, which was directed undiluted into the exposure chamber.

- Method of particle size determination: Particle size distribution samples were taken at half-hour intervals using a Casella cascade impactor. The distribution was calculated based on the amount of material collected on the impactor stages.

- Treatment of exhaust air: Not stated.
- Temperature, humidity, pressure in air chamber: mean chamber temperature of 21 degrees C, and relative humidity of 74% during exposure.

TEST ATMOSPHERE
- Brief description of analytical method used:
- Samples taken from breathing zone: yes/no

VEHICLE
- Composition of vehicle (if applicable): Air
- Concentration of test material in vehicle (if applicable): mean airborne test material concentration given as 0.51 mg/Liter air.
- Justification of choice of vehicle: Most relevant vehicle for this route of administration.
- Lot/batch no. (if required): Not applicable.
- Purity: Not given.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Not given.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Aerodynamic Mass Median Diameter of 3.61 micron, with Geometric Standard Deviation Range of 2.21 to 6.55.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Total airborne concentration measured hourly.

Duration of exposure:

4 h

Concentrations:

Nominal concentration of 3.8 mg/Liter.

No. of animals per sex per dose:

5 animals per sex, only one dose level evaluated.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: Animals were observed for abnormal signs before exposure, every 15 minutes during the first hour of exposure, hourly through the rest of the exposure period, hourly for four hours post-exposure, and daily thereafter for 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed:

Sex:

male/female

Dose descriptor:

other: slight reversible irritation of the oral and respiratory mucous membranes.

Effect level:

3.8 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No animals died during the exposure period, or the during the subsequent 14-day observation period.

Clinical signs:

other: During exposure, animals were noted to be "huddled together in the chamber." In addition, some animals were observed to be rubbing their eyes, and some were noted to have labored breathing and wet and/or matted fur. After removal from the chamber, most

Body weight:

Although small, transient weight losses were observed in most rats, body weights recovered to pre-exposure values in Males by Day 7, and in females by Day 14.

Gross pathology:

At necropsy, 4 males and 3 females showed foci of lung discoloration. However, these were determined to be common pathological entities in this particular strain of rats, and was deemed to not be related to the test material.

Interpretation of results:

relatively harmless

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

A four-hour acute inhalation exposure to a dust of test material at a nominal concentration of 3.8 mg/L with an aerodynamic mass median diameter of 3.61 microns and geometric standard deviation range of 2.21 to 6.55 did not produce mortality, but caused a slight reversible irritation of the oral and respiratory mucous membranes. Also observed was slight neuro-muscular impairment during the 4 hour post-exposure observation period.

Executive summary:

A four-hour acute inhalation exposure to a dust of test material at a nominal concentration of 3.8 mg/L with an aerodynamic mass median diameter of 3.61 microns and geometric standard deviation range of 2.21 to 6.55 did not produce mortality, but caused a slight reversible irritation of the oral and respiratory mucous membranes. Also observed was slight neuro-muscular impairment during the 4 hour post-exposure observation period.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

The acute inhalation toxicity of the substance of record, 6 -hydroxy-2 -naphthoic acid (6 -HNA) was determined. As there were no mortalities, and the only observed effects were consistent with mechanical irritation attributed to the inhalation of particulate matter, no inhalation effect level could be established. Regarding oral toxicity, two separate studies on the read-across substance, 3 -hydroxy-2 -naphthoic acid (3 -HNA) consistently gave LD₅₀ values which would place it (and structurally-related substances) into Toxicity Category IV, according to Regulation (EC) No 1272/2008.

Justification for selection of acute toxicity – oral endpoint
Two Acute Oral Toxicity studies are available for the read-across substance, 3-hydroxy-2 naphthoic acid. The lowest LD50 value for either males or females across both studies was 795 mg/kg body weight.

Justification for classification or non-classification

Classification as Oral Toxicity Category IV is based on the absence of inhalation effects, and oral LD₅₀ values for the read-across substance, which fell consistently in the Toxicity Category IV group.