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EC number: 221-975-0 | CAS number: 3302-10-1
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP Guideline Study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 3,5,5-trimethylhexanoic acid
- EC Number:
- 221-975-0
- EC Name:
- 3,5,5-trimethylhexanoic acid
- Cas Number:
- 3302-10-1
- Molecular formula:
- C9H18O2
- IUPAC Name:
- 3,5,5-trimethylhexanoic acid
- Test material form:
- liquid
- Details on test material:
- - Name of test material (as cited in study report): i-Nonanoic Acid
- Physical state: liquid, colorless, clear
- Analytical purity: 99.9 area-% (AT-1000) or 98.6 area-% (DB-1)
- Lot/batch No.: B52 19.09.2012
- Expiration date of the lot/batch: 19.09.2014
- Stability under test conditions: Stability guaranteed by sponsor
- Storage condition of test material: Room temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 10-13 weeks
- Weight at study initiation:
- Housing: 1 rat per cage
- Diet: Ground Kliba maintenance diet ad libitum
- Water : filtered tap water ad libitum
- Acclimation period: From GD 0 (day of supply) to the beginning of administration (GD6), the animals were accustomed to the environmental conditions and to the diet
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): 15 airchanges per hour
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- 4 mL/kg body weight; for test substance preparation, the specific amount of test substance will be weighed, topped up with corn oil in a calibrated beaker and intensely mixed with a magnetic stirrer; during administration, the preparations were kept homogenous with a magnetic stirrer; preparations are stored at room temperature
- Analytical verification of doses or concentrations:
- yes
- Details on mating procedure:
- Animals paired by the breeder (time-mated animals) were supplied at noon on the day of evidence of mating; this day is referred to as GD0
- Duration of treatment / exposure:
- Animals are treated once daily from GD6-GD19
- Frequency of treatment:
- Once daily
- Duration of test:
- Dams are sacrificed on day 20
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 20 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 60 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25 females per dose
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily, abnormalities and changes are documented
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Bw is recorded on day 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consuption is recoreded from GD0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19, 19-20
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination:
Examinations included:
- Gross-pathological examination
- Weight of the unopened uterus
- Number of corpora lutea
- Number of implantations
- Number of early resorptions
- Site of implantations in the uterus - Fetal examinations:
- After removal of fetuses from the uterus, the following examinations have been made:
- weight of each fetus
- sex
- weight of placentas
- gross pathological examination of fetuses after dissection from uterus
- half of the fetuses of each dam is skined, fixed in ethyl alcohol and the skeleton and cartilage stained (method by Kimmel and Trammell)
- the other half of the fetuses is fixed in Harrisons fluid and soft tissues examined - Statistics:
- Dunnett's test, Fishers exact test and Wilcoxon test
- Historical control data:
- Results were compared to historical control data for Wistar rats that were available in the test facility
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 200 mg/kg bw/day group: 2 dams died shortly before term
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 200 mg/kg bw/day group: Decreased net body weights (8% below control) at the end of gestation, distinctly reduced net body weight gain during treatment (47% below control)
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 200 mg/kg bw/day group: Decreased food consumption towards the end of gestation (13-23% below control)
- Food efficiency:
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 200 mg/kg bw/day group: Increased red blood cell (RBC) counts, hemoglobin and hematocrit values, decreased relative reticulocyte counts, increased absolute and relative monocyte and large unstained cell (LUC) counts
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased urea levels, decreased total protein, albumin, globulin, cholesterol, triglyceride and calcium levels
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- 200 mg/kg bw/day group: Increase in liver weight (absolute +13%, relative +23%)
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 60 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no effects observed
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 200 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- haematology
- mortality
- organ weights and organ / body weight ratios
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 200 mg/kg bw/day group: Reduced fetal weights (14% below control), at 60 mg/kg bw/day: only minimal weight reduction (5% below control), not considered as adverse: there was no no effects on the degree of fetal maturity and the reduction was within the historical control range
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- 200 mg/kg bw/day group: Morphological changes indicating a delay or disturbance of development, such as increased
incidences of supernumerary ribs (73.9 % affected fetuses per litter) and wavy
ribs (14.4%), incompletely ossified Skulls 43.7%, unossified sternebra (31.5%), incomplete
ossification of metacarpal (7.3%), incomplete ossification of pubis (4.7%), incomplete
ossification of ischium (3.3%)
Increased incidence of severely altered rib cages (multiple rib findings like wavy, bent or
knobby) in 9.4% fetuses per litter, resulting in a skeletal malformation rate of 11.1% affected
fetuses per litter
60 mg/kg bw/day group: skull ossification was decreased in mid-dose animals; however, these decreases were still within historical control data - Visceral malformations:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- A yellow discoloration of fetal livers was noted in almost all high-dose litters (200 mg/kg bw/day) and approximately half of the mid-dose litters (60 mg/kg bw/day). The rate of affected fetuses per litter was about 60 and 20%, respectively. The dose-relationship suggests an association to the treatment, but the cause of this discoloration is not known. The shape and size of those livers were completely unchanged. As there is no frank morphological change observable, the level of concern for this finding is rather low. It is not considered as evidence for an adverse effect.
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Test Group 3 (200 mg/kg/d)
• Reduced fetal weights (14% below control)
• Morphological changes indicating a delay or disturbance of development, such as increased incidences of supernumerary ribs (73.9 % affected fetuses per litter) and wavy ribs (14.4%), incompletely ossified Skulls 43.7%, unossified sternebra (31.5%), incomplete ossification of metacarpal (7.3%), incomplete ossification of pubis (4.7%), incomplete ossification of ischium (3.3%)
• Increased incidence of severely altered rib cages (multiple rib findings like wavy, bent or knobby) in 9.4% fetuses per litter, resulting in a skeletal malformation rate of 11.1% af-fected fetuses per litter
Test Group 2 (60 mg/kg/d)
• No test substance-related adverse effects on fetuses
Test Group 1 (20 mg/kg/d)
• No test substance-related adverse effects on fetuses
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 60 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 200 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- skeletal malformations
- other: developmental effects at maternal toxic doses
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: skull
- skeletal: sternum
- skeletal: rib
- skeletal: supernumerary rib
- skeletal: pelvic girdle
- Description (incidence and severity):
- supernumary and wavy ribs, altered rib cages, other localisations: incomplete ossification
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 200 mg/kg bw/day
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this prenatal developmental toxicity study, the oral administration of I-Nonanoic acid to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) caused evidence of maternal toxicity at a dose of 200 mg/kg bw/d, such as mortality, reduced body weights/weight gain, hematological alterations, dysregulated liver cell metabolism and dose-relatedly increased liver and adrenal weights. An increase in liver weight in the mid dose group was without histopathological correlate and hence not considered adverse. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 60 mg/kg bw/d.
Pups of the high-dose group showed signs of developmental defecets as depicted by reduced body weights, severely altered rib cages (eading to an increased malformation rate), wavy ribs, decreased ossification of skulls, sternebrae, sacral arch, metacarpal, pubis and ischium. Considering strong systemic toxicity observed in dams, these effects are most likely due to maternal toxicity and not a direct effect of the substance on development. In the mid dose-group (60 mg/kg/d), fetal body weights were statistically significantly reduced (5%). Since there were no effects on the degree of fetal maturity at 60 mg/kg bw/d, the slight weight reduction in this group is not considered to be an adverse, toxicologically relevant effect of the test substance. Moreover, the decrease in fetal body weight was within the historical control range. Accordingly, skull ossification was decreased in mid-dose animals; however, these decreases were still within historical control data, indicating that this effects is not considered adverse. A yellow discoloration of fetal livers was noted in almost all high-dose litters (200 mg/kg bw/d) and approximately half of the mid-dose litters (60 mg/kg bw/d). The rate of affected fetuses per litter was about 60 and 20%, respectively. The dose-relationship suggests an association to the treatment, but the cause of this discoloration is not known. The shape and size of those livers were completely unchanged. As there is no frank morphological change observable, the level of concern for this finding is rather low. It is not considered as evidence for an
adverse effect.
Since no effects have been noted in low-dose animals and effects observed in mid-dose rats are not considered to be an adverse, toxicologically relevant effect of the test substance, the NOAEL for developmental toxicity is set at the mid dose, i.e. 60 mg/kg/d.
Since morphological changes in offspring were only observed at 200 mg/kg bw/d, a dose level which caused distinct maternal toxicity, including mortality isononanic acid does not need to be classified with respect to teratogenic effects. - Executive summary:
i-Nonanoic acid was tested for its prenatal developmental toxicity in Wistar rats. The test substance was administered as an emulsion in corn oil to groups of 25 time-mated female Wistar rats by gavage at doses of 20, 60, and 200 mg/kg body weight/day (mg/kg bw/day) on gestation days (GD) 6 through 19. The control group, consisting of 25 females, was dosed with the vehicle (corn oil) in parallel. A standard dose volume of 4 mL/kg body weight was used for each test group.
The following test substance-related adverse effects/findings were noted:
Test group 3 (200 mg/kg bw/day):
Dams
Mortality in 2 dams shortly before term
Decreased food consumption towards the end of gestation (13-23% below control)
Decreased net body weights (8% below control) at the end of gestation, distinctly reduced net body weight gain during treatment (47% below control)
Increased red blood cell (RBC) counts, hemoglobin and hematocrit values
Decreased relative reticulocyte counts
Increased absolute and relative monocyte and large unstained cell (LUC) counts
Increased urea levels
Decreased total protein, albumin, globulin, cholesterol, triglyceride and calcium levels
Increase in liver weight of absolute +13% and relative +23%
Fetuses
Reduced fetal weights (14% below control)
Morphological changes indicating a delay or disturbance of development, such as increased incidences of supernumerary ribs (73.9 % affected fetuses per litter) and wavy ribs (14.4%), incompletely ossified Skulls 43.7%, unossified sternebra (31.5%), incomplete ossification of metacarpal (7.3%), incomplete ossification of pubis (4.7%), incomplete ossification of ischium (3.3%)
Increased incidence of severely altered rib cages (multiple rib findings like wavy, bent or knobby) in 9.4% fetuses per litter, resulting in a skeletal malformation rate of 11.1% affected fetuses per litter
Test group 2 (60 mg/kg bw/day):
No test substance-related adverse effects on dams, gestational parameters or fetuses
Test group 1 (20 mg/kg bw/day):
No test substance-related adverse effects on dams, gestational parameters or fetuses
In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 60 mg/kg bw/day.
The no observed adverse effect level (NOAEL) for prenatal developmental toxicity is 60 mg/kg bw/day, based on reduced fetal weights, as well as a delay of development and a slightly increased malformation rate at 200 mg/kg bw/day.
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