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EC number: 207-975-3 | CAS number: 503-74-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well-documented publication which meets basic scientific principles. Screening test method, accepted scientific standards, sufficiently documented, acceptable for assessment.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Method: other: see Method
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:
- Age at study initiation: 4 weeks
- Weight at study initiation: 90 g
- Housing: in groups of 5 or 6
- Diet: ad libitum (30% dextrose, 20% cormmeal; 20% soybeanmeal, 10% casein, 9% corn starch, 5% corn oil, 4% salt mixture, 2% mixture of vitamins in dextrose) - Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Details on oral exposure:
- DIET PREPARATION
no data - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 14 d (pilot study) and 90 d (main study)
- Frequency of treatment:
- continuous
- Remarks:
- Doses / Concentrations:
5 % [= 50000 ppm)
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
approx. 5000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 5 to 6 males
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Post-exposure period: no
- Clinical signs:
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- weight gain 6.2g/day; identical to controls
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- 14g/day
- Haematological findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- no findings; 35 organs examined
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- no findings; 35 organs examined
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 50 000 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: 5% in feed = 50,000 ppm in feed
- Dose descriptor:
- NOAEL
- Effect level:
- 5 other: %
- Dose descriptor:
- NOAEL
- Effect level:
- 5 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Calculated, assuming a food uptake of 100g/kg bw and day
- Critical effects observed:
- not specified
- Conclusions:
- Despite the low number of animals it can be concluded that in light of the high dose applied the prolonged uptake of the TS is not associated with toxic effects in rats.
- Executive summary:
In a rat feeding study, neutralised isovaleric acid was fed to a group of 5 to 6 male SD rats for 90 days at 5% (50,000 ppm) in the diet. In a pilot study with 10%, the food intake was significantly reduced, rats lost significantly weight, and one rat dies. No effects were seen in the main study In the main study, the parameters examined (food consumption, bodyweight development, organ weights, haematology, blood chemistry, urinalysis, and histopathology of 35 organs) did not significantly differ from controls with the exception of a more basic urine in treated rats compared to controls (pH 8.4 versus 7.2). Based on the above the authors concluded that the NOAEL was 5% in diet or 5000 mg/kg bw/day in this study (Amoore et al, 1978).
The protocol of this pre-guideline, pre-GLP study is not fully comparable to current guideline studies since the animal number was low, only male rats were used, and because the documentation is brief. On the other hand side the study clearly showed that ingestion of even large amounts of isovaleric acid with the feed over a 3-months period did not cause local or systemic adverse effects. The study is therefore considered to be valid and suitable for assessment.
NOAEL of 5000 mg/kg for sodium isovalerate corresponds to an NOAEL of 4100 mg/kg for the free isovaleric acid.
Reference
Range-finding study:
At
10-% TS, food consumption was markedly reduced, associated with substantial
weight loss.
Definitive
study:
At 5 % [approx. 5000 mg/(kg bw and day)], no adverse effects were noted
with respect to body weight development and organ weights, histology,
and blood parameters. No local effects (irritation) were observed at
that dose level.
The mean urinary pH value was 8.4 in animals ingesting isovaleric acid salt,
compared with 7.2 for the control animals (Amoore et al, 1978).
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 4 100 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- sufficient
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
In a rat feeding study, neutralised isovaleric acid was fed to a group of 5 to 6 male SD rats for 90 days at 5% (50,000 ppm) in the diet. In a pilot study with 10%, the food intake was significantly reduced, rats lost significantly weight, and one rat dies. No effects were seen in the main study In the main study, the parameters examined (food consumption, bodyweight development, organ weights, haematology, blood chemistry, urinalysis, and histopathology of 35 organs) did not significantly differ from controls with the exception of a more basic urine in treated rats compared to controls (pH 8.4 versus 7.2). Based on the above the authors concluded that the NOAEL was 5% in diet or 5000 mg/kg bw/day in this study (Amoore et al, 1978).
The protocol of this pre-guideline, pre-GLP study is not fully comparable to current guideline studies since the animal number was low, only male rats were used, and because the documentation is brief. On the other hand side the study clearly showed that ingestion of even large amounts of isovaleric acid with the feed over a 3-months period did not cause local or systemic adverse effects. The study is therefore considered to be valid and suitable for assessment.
3-methylbutanol can be used for Read Across to isovaleric acid for the following reason: 3-methylbutanol was shown to be rapidly oxidised to isovaleric acid via isovaleric aldehyde and only minor quantities were excreted unchanged with the breath and urine. 9% of the dose was found in the urine as the glucuronide of tri-acetyl-isoamylmethylester at 24 hours post dose, hence conversion of the alcohol to isovaleric acid was approx. 90% (BG Chemie, 1997). Thus isovaleric acid is rapidly, but not exclusively, formed following dosing with 3-methylbutanol.
With the alcohol no systemic effects (e.g. neurological effects), that would not be expected for the acid were reported. Also the local effects of the acid, i.e. irritation, are not relevant for the repeated dose toxicity endpoint.
The repeated dose toxicity of the supporting substance, 3-methylbutanol, was determined in a subchronic drinking water study using rats (Wistar, 10 animals per dose and sex) according to OECD 408 and under GLP conditions. The administration of 3-Methylbutanol to male and female Wistar rats via the drinking water at dose levels of 0, 1000, 4000, and 16000 ppm over 3 months did not cause clear signs of toxicity at any dose level. In top dose males, statistically significant changes in red blood cell count, volume, and haemoglobin content was noted, but these changes were not considered to be of toxicological relevance, or adverse. Concentrations higher than 16000 ppm could not be administered. Hence, the NOAEL was 16000 ppm in drinking water, i.e. 1068 mg/kg bw and day in males and 1431 mg/kg bw and day in females (BASF; 1990).
Overall, the BASF study supports the findings made by Amoore et al. (1978) with isovalerate itself because no adverse effect was noted up to and including the top dose of 16,000 ppm of 3-methylbutanol in drinking water. Higher concentrations were not tolerated by the animals, a higher NOAEL was therefore not achievable with the supporting substance. Therefore the NOAEL of 5000 mg isovaleric acid/kg bw and day obtained by Amoore is considered to be suitable for any further considerations.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Subchronic high dose study using isovaleric acid salt (sodium isovalerate). The NOAEL is calculated for the free acid.
Justification for classification or non-classification
No adverse effects observed
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