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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
Key value for chemical safety assessment
Effects on fertility
Description of key information
Isovaleric acid is not considered to be reprotoxic, based on a NOAEL of 600 mg/kg bw and day in an oral rat screening study (highest tested dose), and based on a NOAEC of 10 mg 3-methylbutanol/L in OECD 414 inhalation studies with rats and rabbits under GLP conditions. 3-methylbutanol is rapidly oxidised to isovaleric acid in-vivo, i.e. the result can be transferred to isovaleric acid.
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Waiving argument: The substance is registered according to Annex VII data requirements therefore no data are required.
Justification for selection of Effect on fertility via oral route:
waiving argument: valid developmental toxicity information available
Justification for selection of Effect on fertility via inhalation route:
waiving argument: valid developmental toxicity information available
Justification for selection of Effect on fertility via dermal route:
waiving argument: valid developmental toxicity information available
Effects on developmental toxicity
Description of key information
3-methylbutanol, which may be used as surrogate because it is rapidly oxidised to isovaleric acid in-vivo, caused no developmental toxicity in GLP OECD 414 guideline inhalation studies using rats and rabbits. The NOAEL for developmental toxicity was 10 mg/L in both species.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Screening study. Similar to GLP guideline study, but only one dose level tested and using low animal number.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- screening; only one dose level tested.
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 10-15 weeks
- Weight at study initiation: 166 g (report, table IA-005)
- Fasting period before study: no data
- Housing: singly in Makrolon cages type M III
- Diet: Kliba maintenance diet mouse/rat "GLP", ad libitum):
- Water: ad libitum
- Acclimation period: from day 0 p.c. (day of supply) to day 6 p.c. (beginng of treatment)
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Isovaleric acid was topped up with olive oil in a volumentric flask and shaken to give the desired concentration of 150 mg/mL.
VEHICLE
- Justification for use and choice of vehicle (if other than water): poor water solubility of the test substance
- Concentration in vehicle: 150 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses were carried out by BASF AG; methods and results contained in a separate report
- Details on mating procedure:
- - Time-mated females rats were used
- Duration of treatment / exposure:
- Gestation day 6 through 19
- Frequency of treatment:
- one per day
- Duration of test:
- dams were sacrificed on gestation day 20
- Remarks:
- Doses / Concentrations:
600 mg/kg bw and day
Basis:
actual ingested - No. of animals per sex per dose:
- 10 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on existing information
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table IA-001 and -002 were included.
DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: if clinical signs require examination
BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 1, 3, 6, 8, 10, 13, 15, 17, 19, and 20
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: gross pathological examnation; weight of unopened uterus; number of corpora lutea, implantations, resorptions, site of implantation in uterus; lungs (histopathology) - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: site of implantation - Fetal examinations:
- - Weighing: Yes: all per litter
- Sex determiantion: Yes: all per litter
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes:half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No - Statistics:
- DUNNETT's test (food consumption, body weight data including fetuses, live fetuses, corpora lutea, uetrus data); FISHER's exact test (number of pregnant animals at the end of the study, mortality rate of dams, number of litters with foetal findings); WILCOXON test (proportion of fetuses with findings per litter); KRUSKAL-WALLIS and WILCOXON test (pathology; weight parameters))
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
no effects except salivation in all dams after treatment - Dose descriptor:
- NOAEL
- Effect level:
- 600 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 600 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
- Dose descriptor:
- NOAEL
- Effect level:
- 600 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- Isovaleric acid was not reprotoxic (development, teratogenicity) in a rat screening study. The NOAEL for both maternal and developmental toxicity was 600 mg/kg bw, the only tested dose.
- Executive summary:
The developmental toxicity of isovaleric acid (and related substances, see below) was determined in a GLP screening study that basically followed OECD 414, but using less animals (10 time-mated control and treated rats) and only one concentration (600 mg isovaleric acid/kg bw; in olive oil, oral gavage, gestation days 6-19). Dams were sacrificed on GD 20; examinations included maternal body weights, reproduction data, and pathology. Fetuses were sexed and weighed, and examined for external, soft tissue and skeletal malformations and variations.
There were no signs of maternal toxicity nor effects on prenatal development, hence the NOAEL was 600 mg/kg bw and day for maternal toxicity, developmental toxicity, and teratogenicity under the conditions of this study (BASF, 2008).
This study is considered to be a valid screening study. It could be noted that closely related acids were also included in this study, using the same method:
Dose
(mg/kg bw and day)NOAEL maternal toxicity
(mg/kg bw and day)NOAEL prenatal development
(mg/kg bw and day)Valeric acid
600
600
600
Isovaleric acid
600
600
600
2-methylvaleric acid
1000
1000
1000
3,5,5-trimethylhexanoic acid
300
< 300
300
Local irritation of the larynx and the upper and lower respiratory tract was seen with all tested acids. The effects were more significant –although still not severe – with valeric and isovaleric acid, and minimal with 3,5,5-trimethylhexanoic acid.
The above results provide evidence that the NOAEL of isovaleric acid is above 600 mg/kg bw and day in the rat following oral gavage.
- Endpoint:
- developmental toxicity
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study Readacross is justified due to the toxicokinetic arguments described within the Endpoint Summary.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- - Source: Dr. K. Thomae GmbH, D-7950 Biberach/Riss, FRG). The animals were free from any clinically evident signs prior to the beginning of the study.
- Age at study initiation: approx. 11 weeks
- Weight at study initiation: approx. 216 g
- Housing: singly in wire cages
- Diet: KLIBA rat/mouse laboratory diet 24-343-4 10 mm pellets, Klingentalmühle AG, CH-4303 Kaiseraugst, Switzerland; during the exposure-free observation period ad libitum
- Water: tap water ad libitum; during the exposure-free observation period
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- air
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: the animals were exposed singly in wire cages in the whole-body inhalation chambers (volumes ca. 1100 L (test group 1, 2 and 3), and ca. 1600 L (test group 0 and parts of the test groups during the pre-flow period).
- Method of holding animals in test chamber: animals were expose din the wire cages
- Source and rate of air: the test substance was supplied by means of two continuously driven metering pumps to a vaporizer heated with a circulating thermostat. The evaporation temperature was 50-70°C. A measured stream of fresh air took up the vapours and was mixed with another stream of fresh air. After passing through a mixing device, this mixture of vapours and air was supplied to the exposure chamber.
- Temperature, humidity, pressure in air chamber: temperature and pressure in the inhalation chamber was measured continuously (generally 3 times/exposure). The relative humidity was measured at least daily.
- Air flow rate: all air flows, supply air and exhaust air were adjusted by means of flowmeters for all test groups and recorded, as a rule, 6 times/exposure.
TEST ATMOSPHERE
- Brief description of analytical method used: The concentrations of the test groups were analyzed by gas chromatography after absorption of 3-methylbutanol in 2-propanol. The gas chromatograph was calibrated with the test substance.
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Gas chromatography
- Details on mating procedure:
- - Impregnation procedure:cohoused
- If cohoused:
- M/F ratio per cage: 1:4
- Length of cohabitation: over night
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Gestation days 6 - 15; 6 hours/day
- Frequency of treatment:
- daily
- Duration of test:
- 20 days
- Remarks:
- Doses / Concentrations:
0.5, 2.5 and 10 mg/L
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
0.51±0.02, 2.50±0.17,and 9.8±0.66 mg/L
Basis:
analytical conc.
GC - No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on the results of a pilot study. Doses up to 5 mg/L caused no toxicity in females.
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least daily
BODY WEIGHT: Yes
- Time schedule for examinations: on gestation days 0, 3, 6, 9, 12, 15, 18, and 20
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20.
- Organs examined: uterus, ovaries, placenta - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: - Statistics:
- DUNNETT's test, Fisher's exact test
- Indices:
- The folowing indices were calculated:
- conception rate ( %;): (number of pregnant animals/ number of fertilized animals)*100
- preimplantation loss (%): (number of corpora lutea - number of implantations/number of corpora lutea)*100
- postimplantation loss (%): (number of implantations - number of live fetuses/number of implantations)*100 - Historical control data:
- yes
- Details on maternal toxic effects:
- Maternal toxic effects:yes. Remark: marginal body weight retardation at 10 mg/L
Details on maternal toxic effects:
Transient marginal body weight reduction at 10 mg/L at beginning of the study - Dose descriptor:
- NOAEC
- Effect level:
- 2.5 mg/L air (analytical)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEC
- Effect level:
- 10 mg/m³ air (analytical)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects. Remark: at any dose level
- Dose descriptor:
- NOAEC
- Effect level:
- 10 mg/L air (analytical)
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- In an OECD 414 study (inhalation, rats) , 3-methylbutanol caused marginal maternal toxicity but no toxicity to reproduction (development, teratogneicity).
- Executive summary:
The toxicity of 3-methylbutanol to reproduction was examined in Wistar rats (25 females per dose; whole body inhalation exposure at 0, 0.5, 2.5, and 10 mg/L; gestation days 6-15, 6 hours per day) according to OECD 414 and under GLP conditions. No maternal or developmental toxicity was noted in a pre-test at 5 mg/L.
In the main study, maternal toxicity was limited to a transient marginal body weight retardation at the start of the exposure period. Reproduction parameters were not affected at any dose. There was no effect regarding viability, development and malformations noted in the fetuses. The NOAEC for maternal toxicity was 2.5 mg/L, the NOAEC for developmental toxicity and teratogenicity was 10 mg/L, the highest tested dose (Klimisch, 1990).
Since 3-methylbutanol is rapidly oxidised to isovaleric acid, this result can be transferred to isovaleric acid. In this context it could be further noted that the same result (NOAEC 2.5 mg/L for the maternal organism and 10 mg/L for the foetal organism) was obtained in a GLP OECD 414 inhalation study with white Himalayan rabbits (15 dams/group; 0.5, 2.5, and 10 mg/L; gestation days 6-19, 6 hours/day; Klimisch and Hellwig, 1990). These results are suitable for the assessment of isovaleric acid.
Referenceopen allclose all
Isovaleric acid: Summary of reproduction data, dams (report, tables IA-010 – IA-012)
|
|
Olive oil |
Isovaleric acid |
Pregnant at terminal sacrifice, N |
|
9 |
9 |
Resorptions (mean %) |
total |
2.6 |
0.6 |
early |
1.4 |
0.6 |
|
late |
0.1 |
0.0 |
|
Dead fetuses, N |
|
2 |
1 |
Live fetuses |
Total, N |
69 |
81 |
total |
94.6 |
92.9 |
|
females |
46.6 |
40.2 |
|
males |
48.0 |
52.8 |
|
Per cent live females |
|
49.3 |
43.2 |
Per cent live males |
|
50.7 |
56.8 |
Isovaleric acid: Summary of reproduction data, fetuses (report, table IB-001)
|
|
Olive oil |
Isovaleric acid |
Mean placental weights of all viable fetuses (g) (N) |
|
0.46 (9) |
0.46 (9) |
Mean foetal weights (g) |
total |
3.6 |
3.5 |
male |
3.7 |
3.6 |
|
female |
3.4 |
3.4 |
Isovaleric acid: Summary of all foetal external, soft tissue, and skeletal observations (table IB-025)
|
|
Olive oil |
Isovaleric acid |
Litters evaluated, N |
N |
9 |
9 |
Fetuses evaluated, N |
total |
71 |
82 |
Live |
69 |
81 |
|
dead |
2 |
1 |
|
Total malformations (means, %) |
Foetal incidence, % |
0.0 |
0.0 |
Litter incidence, % |
0 |
0 |
|
Affected fetuses per litter, % |
0.0 |
0.0 |
|
Total variations (means, %)
|
Foetal incidence, % |
56 |
57 |
Litter incidence, % |
100 |
100 |
|
Affected fetuses per litter, % |
57.1 |
57.7 |
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Good. The negative result on isovaleric acid is supported by negative results on
valeric acid, 2-methylvaleric acid, 3,5,5-trimethylvaleric acid (BASF, 2008), and on
3-methylhexanoic acid, and 2-methylpentanoic acid (Narotsky, 1994).
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 11 586 mg/m³
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Good. The NOAEC was 10 mg/L in two GLP guideline studies using species (rat and rabbit). 10,000 mg 3-methylbutanol (MW 88.15) correspond to 11586 mg isovaleric acid (MW 102.13), i.e. the Effect level value given above corresponds to isovaleric acid.
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
No fertility study was located for isovaleric acid. However,Waiving according to the REACH regulation ANNEX VIII, column 2, a fertility study is not required if valid developmental toxicity information is available. This is here the case as outlined below.
Oral exposure
The developmental toxicity of isovaleric acid (and several related substances, see below) was determined in a GLP screening study that basically followed OECD 414, but using less animals (10 time-mated control and treated rats) and only one concentration (600 mg isovaleric acid/kg bw; in olive oil, oral gavage, gestation days 6-19). Dams were sacrificed on GD 20; examinations included maternal body weights, reproduction data, and pathology. Fetuses were sexed and weighed, and examined for external, soft tissue and skeletal malformations and variations.
There were no signs of maternal toxicity nor effects on prenatal development, hence the NOAEL was 600 mg/kg bw and day for maternal toxicity, developmental toxicity, and teratogenicity under the conditions of this study (BASF, 2008).
This study is considered to be a valid screening study. It is further noted that that closely related acids were also included in this oral gavage study, using the same method:
|
Dose |
NOAEL maternal toxicity |
NOAEL prenatal development |
Valeric acid |
600 |
600 |
600 |
Isovaleric acid |
600 |
600 |
600 |
2-methylvaleric acid |
1000 |
1000 |
1000 |
3,5,5-trimethylhexanoic acid |
300 |
< 300 |
300 |
Local irritation of the larynx and the upper and lower respiratory tract was seen with all tested acids. The effects were more significant –although still not severe – with valeric and isovaleric acid, and minimal with 3,5,5-trimethylhexanoic acid.
Further support
comes from the results on 3-methylhexanoic and
2-methylpentanoic acid that were obtained with rats following oral
gavage in screening so-called Chernoff-Kavlock studies, using a reduced
number of test animals (20 controls, 15 treated rats per dose), two dose
levels, and reduced examinations (Clinical signs, body weight, and
pre-implantation loss in dams. Foetal weight at birth and at day 6.
Histopathology on the pups on a screening level as follows:
Dead pups: soft tissue alterations
Externally malformed pups: skeletal and/or soft tissue alterations as
indicated by the gross findings
Surviving pups: skeletal alterations in 2 pups per litter (one per sex).
In total 15 linear and branched short-chain aliphatic acids were tested (butyric, pentanoic, octanoic acid; 2-ethylbutyric, 2-methylpentanoic, bromopentanoic, 2-ethoxypentanoic, 2-ethylhexanoic, 2-propylhexanoic, 2-butylhexanoic, 2-methyloctanoic, 3-methylhexanoic, and 5-methylhexanoic acid. Positive results were only obtained with 3 substances bearing a side chain with 2 or more carbons at the 2-position (2-ethylhexanoic, 2-propylhexanoic, and 2-propylpentanoic acid), whereas 2-ethybutanoic acid was negative. The two substances that are considered to be most related to isovaleric acid, i.e. 3-methylhexanoic acid (3-MH) and 2-methylpentanoic acid (2-MP), were also no developmental toxicants is this screening study. Maternal toxicity but no developmental toxicity was noted at the highest tested doses which also represent the developmental toxicity NOAEL values of 500 mg/kg bw and day (3-MH) and 250 mg/kg bw and day (2-MP), respectively. For QSAR considerations the authors concluded that a side chain at the 2-position with two or more carbons is required for developmental toxicity (Narotsky et al., 1994).
Overall,the above results provide evidence that the NOAEL of isovaleric acid is above 600 mg/kg bw and day in the rat following oral gavage.
Inhalation exposure
Inhalation studies on 3-methylbutanol using rats and rabbits (OECD 414, GLP) were located. The substance is rapidly oxidised to isovaleric acid in-vivo, therefore the results may be used for assessment of isovaleric acid. More specifically, the toxicity of 3-methylbutanol to reproduction in Wistar rats (25 females per dose; whole body inhalation exposure at 0, 0.5, 2.5, and 10 mg/L; gestation days 6-15, 6 hours per day) was examined according to OECD 414 and under GLP conditions. No maternal or developmental toxicity was noted in a pre-test at 5 mg/L. In the main study, maternal toxicity was limited to a transient marginal body weight retardation at the start of the exposure period. Reproduction parameters were not affected at any dose. There was no effect regarding viability, development and malformations noted in the fetuses. The NOAEC for maternal toxicity was 2.5 mg/L, the NOAEC for developmental toxicity and teratogenicity was 10 mg/L, the highest tested dose (Klimisch, 1990).
Since 3-methylbutanol is rapidly oxidised to isovaleric acid, this result can be transferred to isovaleric acid. In this context it is noteworthy that the same result (NOAEC 2.5 mg/L for the maternal organism and 10 mg/L for the foetal organism) was obtained in a GLP OECD 414 inhalation study with white Himalayan rabbits (15 dams/group; 0.5, 2.5, and 10 mg/L; gestation days 6-19, 6 hours/day; Klimisch and Hellwig, 1990).
These results are suitable for the assessment of isovaleric acid. Taking default values for the rat into consideration (respiratory volume, rat: 290 L/6 hours; ECHA, Guidance Document R8, Table R.8-2), the NOAEC of 10 mg/L corresponds to 2900 mg 3-methylbutanol/kg bw and day. Taking molecular weights into consideration, this corresponds to 3360 mg isovaleric acid/kg bw and day in the rat. The use of 600 mg/kg bw and day for the derivation of DNEL values is therefore considered to be very conservative.
Justification for selection of Effect on developmental toxicity: via oral route:
Screening study on isovaleric acid (and related acids)
Justification for selection of Effect on developmental toxicity: via inhalation route:
Valid GLP guideline study on 3-methylbutanol which is rapidly oxidised in-vivo to isovaleric acid.
Justification for classification or non-classification
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.