Isovaleric acid

Endpoint summary

Description of key information

Isovaleric acid is a relatively strong acid (pKa=4.7; cf. section 4.21) wich is corrosive to the skin. The acute toxicity is, however moderate (oral LD50, rat approx. 2500 mg/kg bw; dermal LD50, rabbit >2000 mg/kg bw; inhalation, rat LC50 >2060 mg/m³).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given: comparable to guideline studies

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: males 184 g ; females 162 g (means)
- Fasting period before study: 15-20 hr

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5% and 1-2 drops of Chremophore El.

Details on oral exposure:

VEHICLE
- Concentration in vehicle:6.8 - 50%
- Amount of vehicle (if gavage): dose volume: 10 mL/kg bw
- Justification for choice of vehicle: aqueous solution of 0.5% CMC

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

681, 1000, 1470, 2150, 2610, 3160, 3830, and 5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

other: not needed

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations: daily; weighing: on days 0, 2-4, 7, and 13
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 2 500 mg/kg bw

Based on:

test mat.

Mortality:

see table below

Clinical signs:

other: Dyspnea, apathy, unkempt fur, and poor condition was seen at 1000 mg/kg bw and above. Cyanosis, atony, unsteady gait was seen at 1470 mg/kg bw and above; narcosis, impaired pain reflexes, trembling, exsiccation and exophthalmia was seen at 2610 mg/kg bw a

Gross pathology:

Dead animals: heart: hyperaemic congesting; glandular stomach: haemorrhage, gastritis; intestine: reddened mucosa, injected vessels.
Surviving animals: forestomach: button formation (in groups 1470-3160 mg/kg bw; wall thickened in animals at 215ß-3160 mg/kg bw. No changes in animals at 681-1000 mg/kg bw

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The LD50 of isovaleric acid was approx. 2500 mg/kg bw in male and female rats

Executive summary:

The acute oral toxicity of isovaleric acid was determined in male and female Sprague-Dawley similar to OECD 401 (5 rats/sex; oral gavage; test substance at 681, 1000, 1470, 2150, 2610, 3160, 3830, and 5000 mg/kg bw in 0.5% CMC; observation period 14 days). Signs of toxicity were seen at 1000 mg/kg bw and above in a dose-dependent manner. No deaths occurred at doses up to and including 2150 mg/kg bw, with a steep increase of mortality at higher doses. The LD₅₀was ca. 2500 mg/kg bw for male and female rats. Necropsy revealed lesions in the stomach and intestine that are attributable to the irritating property of the isovaleric acid (BASF, 1980).

The study is considered to be valid and suitable for assessment.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 500 mg/kg bw

Quality of whole database:

suitable for assessment

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Similar to guideline study. Documentation scarce, but raw data are available upon request

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Principles of method if other than guideline:

Inhalation risk test

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Route of administration:

inhalation: vapour

Type of inhalation exposure:

not specified

Vehicle:

air

Details on inhalation exposure:

Air was guided through a 5-cm layer of test material contained in a wash bottle to generate a saturated vapour atmosphere

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

7 h

Concentrations:

saturated atmosphere

No. of animals per sex per dose:

12 animals

Dose descriptor:

LC0

Effect level:

2 060 mg/m³ air

Exp. duration:

7 h

Remarks on result:

other: Exposure to saturated atmosphere in Inhalation Risk Test. Effect level (2060 mg/m³) calculated.

Mortality:

rats survived inhalation exposure at saturation, exposure period 7 hours

Conclusions:

The LC0 was 2060 mg/m³ in this study. All rats (n=12) survived inhalation exposure at saturation, exposure period 7 hours. Slight respiratory tract irritation was noted.

Executive summary:

Inhalation risk test; similar to guideline (saturation exposure without analytical measurement). The saturation concentration can be calculated (using data from GESTIS: molecular weight 102.13; vapour pressure 0.5 mbar at 20°C; 1 ppm = 3.53 mg/m³). Result: the saturation concentration is 2060 mg/m³, i.e. 584 ppm. All rats (n=12) survived a 7-hr exposure period at the maximum attainable concentration, i.e. the LC0 -value was 2060 mg/m³.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

2 060 mg/m³ air

Quality of whole database:

suitable for assessment

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Equivalent to guideline study.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

Vienna White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Gauckler. D-6050 Offebach
- Weight at study initiation: 2-3 kg
- Fasting period before study: no data
- Housing: in stainles steel cages
- Diet: approx. 130 g/animal and day
- Water: approx. 250 mL/animal and day
- Acclimation period: at least 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

vegetable oil

Details on dermal exposure:

TEST SITE
- Area of exposure: 300 cm²
- Type of wrap if used: semiocclusive

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied: 5 mL/kg bw
- Concentration (if solution): 40%
- Constant volume or concentration used: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): 5 mL/kg bw
- Concentration (if solution): 60%
- Purity: olive oil, DAB 9

Duration of exposure:

24 hrs

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations: at least once per day; weighing: weekly
- Necropsy of survivors performed: yes
- Other examinations performed: histopathology of treated skin

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 1/6 animals died within 24 hours

Mortality:

One male died during day 1. Necropsy revealed dilatation of the heart and moderate lung edema

Clinical signs:

other: none

Other findings:

One male died during day 1. Necropsy revealed dilatation of the heart and moderate lung edema.

Sacrificed animals: skin: full thickness necrosis; organs: no pathological findings

Conclusions:

The dermal LD50 was >2000 mg/kg bw in male and female rabbits.

Executive summary:

The acute dermal toxicity of isovaleric acid was determined in White Vienna rabbits (3 per sex; semi-occlusive dressing, exposure period 24 hours; dose 2000 mg/kg bw; vehicle: olive oil) using a protocol that was equivalent to OECD 402. The observation period was 14 days. One male died on day 1, all other animals survived without clinical signs of toxicity. At termination, histopathology revealed full thickness necrosis at all treated sites, moderate lung oedema and heart dilatation in the animal that died, no findings in animals that were sacrificed. Hence, the dermal LD50 was >2000 mg/kg bw in rabbits (BASF, 1990).  

The study is considered to be valid and suitable for assessment.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

suitable for assessment. Local effects on skin described.

Additional information

The acute oral toxicity of isovaleric acid was determined in male and female Sprague-Dawley similar to OECD 401 (5 rats/sex; oral gavage; test substance at 681, 1000, 1470, 2150, 2610, 3160, 3830, and 5000 mg/kg bw in 0.5% CMC; observation period 14 days). Signs of toxicity were seen at 1000 mg/kg bw and above in a dose-dependent manner. No deaths occurred at doses up to and including 2150 mg/kg bw, with a steep increase of mortality at higher doses. The LD₅₀was ca. 2500 mg/kg bw for male and female rats. Necropsy revealed lesions in the stomach and intestine that are attributable to the irritating property of the isovaleric acid (BASF, 1980).

Rats survived inhalation a 7-hour exposure period at saturation (calculated: 2060 mg/m³ or 584 ppm), indicating a low inhalation hazard. A slight respiratory tract irritation was noted (BASF, 1980).

The acute dermal toxicity of isovaleric acid was determined in White Vienna rabbits (3 per sex; semi-occlusive dressing, exposure period 24 hours; dose 2000 mg/kg bw; vehicle: olive oil) using a protocol that was equivalent to OECD 402. The observation period was 14 days. One male died on day 1, all other animals survived without clinical signs of toxicity. At termination, histopathology revealed full thickness necrosis at all treated sites, moderate lung oedema and heart dilatation in the animal that died, no findings in animals that were sacrificed. Hence, the dermal LD50 was >2000 mg/kg bw in rabbits (BASF, 1990). 

Justification for selection of acute toxicity – oral endpoint
Rat study similar to guideline; vehicle: water

Justification for selection of acute toxicity – inhalation endpoint
Inhalation risk test; similar to guideline (saturation exposure without analytical measurement). The saturation concentration can be calculated (using data from GESTIS: molecular weight 102.13; vapour pressure 0.5 mbar at 20°C; 1 ppm = 3.53 mg/m³). Result: the saturation concentration is 2060 mg/m³, i.e. 584 ppm. All rats (n=12) survived a 7-hr exposure period the maximum attainable concentration, i.e. LC0 was 2060 mg/m³.

Justification for selection of acute toxicity – dermal endpoint
Rabbit study similar to guideline. Limit dose: 2000 mg/kg bw

Justification for classification or non-classification

According to regulation EC/1272/2008 no classification is required for the acute oral, inhalation, or dermal toxicity.