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EC number: 817-668-1 | CAS number: 667899-24-3
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Atsugi breeding center
- Age at study initiation: (P) 10 wks
- Weight at study initiation: (P) Males: 330.8-420.4 g; Females: 207.2-245.0 g
- Housing: 2 animals per cage at mating
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0-25.0
- Humidity (%): 40.0-75.0
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Doses were based on a 14 d range-finding study.
DIET PREPARATION
- Rate of preparation of diet (frequency): Prepared up to 8 days before dosing
- Storage temperature of food: Room temperature and shade
VEHICLE
- Justification for use and choice of vehicle (if other than water): For solubility
- Concentration in vehicle: 5, 15, 50% w/v
- Lot/batch no. (if required): V2P1825 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentration of test substance was analyzed by GC method
- Duration of treatment / exposure:
- 42 days for males and 42-54 days for females
- Frequency of treatment:
- Daily once
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 12 animals (5 animals for satelite groups)
- Control animals:
- yes, concurrent vehicle
- Positive control:
- Not applicable
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily during breeding period and recovery period, twice daily during dosing
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a week
Functional behavior: Day 42 in all groups and Day 14 of recovery for satellite groups
BODY WEIGHT: Yes
- Time schedule for examinations: for males weekly and at necropsy, for females weekly during dosing and on Days 0, 7, 14 and 20 of gestation and on Days 0 and 4 of lactation and at necropsy
FOOD CONSUMPTION: weekly
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy
- Anaesthetic used for blood collection: No
- Animals fasted: No data
- How many animals: 5 animals/sex/dose including the satellite groups
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: No data
- How many animals: 5 animals/sex/dose including the satellite groups
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- Fisher’s exact test (significance level: 5%) was performed on the function test results. Among the histopathological findings in the test substance treatment groups, the graded data was tested for significance in relation to the control group using Mann-Whitney U-testing (significance level: 5%), while the total values for positive grades were tested for significance with the control group using Fisher’s exact one-sided testing (significance level: 5%). For the other data, the values obtained for each individual or the mean values for each litter were used as single samples, and these samples were compared with the values within the satellite group or within the other groups. Where two groups were used in the analysis, F-testing was performed first, followed by Student t-testing if no significant differences were observed. If a significant difference was observed in the F-testing, Aspin-Welch testing was performed. When three or more groups were used in the analysis, the Bartlett method was used first in order to test for uniformity of variance in each group (significance level: 5%).If the variance was uniform, one-way analysis of variance (significance level: 5%) was performed. If a significant difference was observed between groups, the Dunnett method was used to perform a multiple comparison (significance level: 5%). On the other hand, if the variance in any of the groups was 0 and if the variance was not uniform, Kruskal-Wallis rank testing (significance level: 5%) was performed. If a significant difference was observed between groups, the Dunnett testing method was used to perform a multiple comparison (significance level: 5%).
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- A statistically significant increase in haemoglobin and haematocrit in females at 100 mg/kg bw/day and increased prothrombin time in females at 100 mg/kg bw/day were not considered to be treatment related as no effects at higher doses were noted. No effects were observed at the end of the recovery period.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No effects in males or females in main group; statistically significant increase in urea nitrogen (121% of control) in females at 1000 mg/kg bw/day at the end of the recovery period; no effects in males at the end of the recovery period.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Statistically significant increase in absolute brain weight of females at 300 mg/kg bw/day was not considered to be treatment related as no effect at 1000 mg/kg bw/day was noted. A statistically significant increase of relative liver weight (105% of control) in females at 1000 mg/kg bw/day at the end of recovery, was not considered to be treatment related as it was only seen at the end of recovery, the increase was slight and no histopathological effect was found. No effects in males during main test or at end of recovery were noted.
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Testes: focal seminiferous tubule atrophy: 3/12 M at 100 and 1/12 M at 300 mg/kg bw/day; no findings at 1000 mg/kg bw/day and no findings at the end of the recovery period; therefore not treatment related.
Kidney: very slight basophilic tubules in cortex in 2/5 control males and 4/5 males at 1000 mg/kg bw/day and in 1/5 female at 1000 mg/kg bw/day; no findings at end of recovery period.
Ovary: follicle cysts and increased number of follicles in closed state and a corresponding marked reduction in corpus luteum in 1/12 female at 1000 mg/kg bw/day; at end of recovery follicle cysts in 1/5 female at 1000 mg/kg bw/day. Other findings were comparable to the control group in incidence and severeness. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: There were no effects related to test substance treatment.
- Key result
- Critical effects observed:
- no
- Conclusions:
- Under the study conditions, the systemic NOAEL of the substance in rats was determined to be greater than 1000 mg/kg bw/day.
- Executive summary:
A study was conducted to determine the repeated dose toxicity of the substance in rats according to OECD Guideline 422, in compliance with GLP. A combined repeated dose-reproductive developmental screening study was conducted in rats in which the test substance was administered to groups of 12 animals per sex via oral gavage at dose levels of 100, 300 and 1000 mg/kg bw/day for 42 days (males) or 42 -54 days (for females). Mortality, clinical signs, food consumption and body weight measurements were performed on a regular basis during the dosing period. Hematological and clinical chemistry examinations were performed before scheduled necropsy. Terminal body weight and organ weights were determined after the necropsy along with gross pathological and histopathological examinations of the major organs. Apart from few non-treatment related effects, no adverse effects were observed in any of the treated groups. Under the study conditions, the systemic NOAEL of the substance in rats was determined to be greater than 1000 mg/kg bw/day (MHLW, 2005).
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 005
- Report date:
- 2005
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- 2,2-bis[[(2-ethyl-1-oxohexyl)oxy]methyl]propane-1,3-diyl bis(2-ethylhexanoate)
- EC Number:
- 230-743-8
- EC Name:
- 2,2-bis[[(2-ethyl-1-oxohexyl)oxy]methyl]propane-1,3-diyl bis(2-ethylhexanoate)
- Cas Number:
- 7299-99-2
- Molecular formula:
- C37H68O8
- IUPAC Name:
- 3-[(2-ethylhexanoyl)oxy]-2,2-bis{[(2-ethylhexanoyl)oxy]methyl}propyl 2-ethylhexanoate
- Test material form:
- other: Liquid, colorless and transparent
- Details on test material:
- - Name of test material (as cited in study report): Hexanoic acid, 2-ethyl, 2,2-bis[[(2-ethyl-l-oxohexyl)oxy]methyl]-1,3-propanediyl ester- Molecular formula (if other than submission substance): C37H68O8- Molecular weight (if other than submission substance): 640.94- Physical state: Liquid, colorless and transparent- Analytical purity: 98.4% (GC%)- Stability under test conditions: stable- Storage condition of test material: Room temperature, shade
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: CHARLES RIVER LABORATORIES JAPAN, INC. Atsugi breeding center
- Age at study initiation: (P) 10 wks- Weight at study initiation: (P) Males: 330.8-420.4 g; Females: 207.2-245.0 g
- Housing: 2 animals per cage at mating
- Diet: ad libitum
- Water: ad libitum- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0-25.0
- Humidity (%): 40.0-75.0
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hrs. dark/12 hrs light
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on mating procedure:
- - M/F ratio per cage: 1/1- Length of cohabitation: up to 2 weeks- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as Day 0 of pregnancy
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentration of test substance was analyzed by GC method (mean content 107-110%)
- Duration of treatment / exposure:
- 42 days for males and 42-54 days for females
- Frequency of treatment:
- Once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 12 animals (5 animals for satelite groups)
- Control animals:
- yes, concurrent vehicle
- Positive control:
- Not applicable
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily during breeding period and recovery period, twice daily during dosing
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: once a week
BODY WEIGHT: Yes
- Time schedule for examinations: for males weekly and at necropsy, for females weekly during dosing and on Days 0, 7, 14 and 20 of gestation and on Days 0 and 4 of lactation and at necropsy - Oestrous cyclicity (parental animals):
- Mean time of estrous cycle and incidence of animals with estrous cycle other than a 4 day cycle per dose was determined beginning at the start of dosing until confirmation of mating.
- Sperm parameters (parental animals):
- Not applicable
- Litter observations:
- Number of (live) pups and sex ratio on Days 0 and 4.
- Postmortem examinations (parental animals):
- SACRIFICE- Male animals: Animals were sacrificed 43 days after satrting dosing or 16 days after starting recovery period. - Maternal animals: Animals were sacrificed 15 days after starting lactation. Animals that did not deliver were saclificed 26 days after pregnancy. For satelite group, sacrifice was done 15 days after starting recovery period.
- Postmortem examinations (offspring):
- Not applicable
- Statistics:
- Fisher’s exact test (significance level: 5%) was performed on the function test results, on the incidence of animals showing changes in estrous cycle, on the copulation rate, on the impregnation rate and on the incidence of morphological abnormalities in the offspring.Among the histopathological findings in the test substance treatment groups, the graded data was tested for significance in relation to the control group using Mann-Whitney U-testing (significance level: 5%), while the total values for positive grades were tested for significance with the control group using Fisher’s exact one-sided testing (significance level: 5%).For the other data, the values obtained for each individual or the mean values for each litter were used as single samples, and these samples were compared with the values within the satellite group or within the other groups. Where two groups were used in the analysis, F-testing was performed first, followed by Student t-testing if no significant differences were observed. If a significant difference was observed in the F-testing, Aspin-Welch testing was performed. When three or more groups were used in the analysis, the Bartlett method was used first in order to test for uniformity of variance in each group (significance level: 5%).If the variance was uniform, one-way analysis of variance (significance level: 5%) was performed. If a significant difference was observed between groups, the Dunnett method was used to perform a multiple comparison (significance level: 5%). On the other hand, if the variance in any of the groups was 0 and if the variance was not uniform, Kruskal-Wallis rank testing (significance level: 5%) was performed. If a significant difference was observed between groups, the Dunnett testing method was used to perform a multiple comparison (significance level: 5%).
- Reproductive indices:
- Copulation index, Fertility index, Gestation index, Imlantation index, Delivery index.
- Offspring viability indices:
- Birth index, Live birth index, Viability index.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- Estrous cycle: no treatment related effect on incidence and length of estrous cycle
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Reproductive performance: No significant differences were observed between the control group and any of the treatment groups in impregnation rate, number of days to copulation or number of estrous during this period. No significant differences were observed for corpus luteum count, implantation count or implantation rate between control and treated groups.
Systemic toxicity details for parental animals are described at 7.5.1 Repeated dose toxicity: oral section.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: There were no effects related to test substance treatment.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
Details on results (F1)
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: There were no effects related to test substance treatment.
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Under the study conditions, the NOAEL for fertility and fetal toxicity of the substance in rats was determined to be greater than 1000 mg/kg bw/day.
- Executive summary:
A study was conducted to determine the repeated dose toxicity of the substance in rats according to OECD Guideline 422, in compliance with GLP. A combined repeated dose-reproductive developmental screening study was conducted in rats in which the test substance was administered to groups of 12 animals per sex through oral gavage at dose levels of 100, 300 and 1000 mg/kg bw/day for 42 days (males) or 42 -54 days (for females). Males and females were co-habited in 1:1 ratio in the cages during the dosing period for a period of 2 weeks till there is proof of pregnancy. Mortality, clinical signs, food consumption and body weight measurements were performed on a regular basis during the dosing period. After the scheduled necropsy of the pregnant females, reproductive and fetal developmental parameters were examined. Apart from few non-treatment related effects, no adverse effects were observed in any of the treated groups. Under the study conditions, the NOAEL for fertility and fetal toxicity of the substance in rats was determined to be greater than 1000 mg/kg bw/day (MHLW, 2005).
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