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EC number: 222-376-7 | CAS number: 3452-97-9
- 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
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study (SIDS documents; Iuclid reference [28]; Reliability assigned: 1)
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
- Reference Type:
- other: summary of toxicity studies
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
- Reference Type:
- secondary source
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Remarks:
- Estrous cycle length and pattern, and anogenital distances were not performed because the test was conducted by the TG adopted in 1990.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 3,5,5-trimethylhexan-1-ol
- EC Number:
- 222-376-7
- EC Name:
- 3,5,5-trimethylhexan-1-ol
- Cas Number:
- 3452-97-9
- Molecular formula:
- C9H20O
- IUPAC Name:
- 3,5,5-trimethylhexan-1-ol
- Details on test material:
- - Source: KYOWA HAKKO KOGYO CO., LTD.
- Analytical purity: 92.7 %
- Lot/batch No.: 70713
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: no data
- Age at study initiation: 10 weeks
- Weight at study initiation: 335-399g for males,204-260g for females
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Isononanol was dissolved in olive oil to give concentrations of 0.24, 1.2, and 6 % weight/volume.
New solutions were prepared every 7 days.
DIET PREPARATION
- Rate of preparation of diet (frequency): n.a.
- Mixing appropriate amounts with (Type of food): n.a.
- Storage temperature of food: n.a.
VEHICLE
- vehicle: olive oil
- Justification for use and choice of vehicle: test substance insoluble in water
- Concentration in vehicle: 0.24, 1.2, and 6 % weight/volume
- Amount of vehicle (if gavage): 5 mL/kg bw
- Lot/batch no. Yakuhan Pharmaceutical Ltd.
- Purity: Japan Pharmacopoiea - Details on mating procedure:
- no data
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The Japan Food Analytical Center (Foundation) confirmed that the prepared solution of the drug in various concentrations had the prescribed concentration and that it was uniform. No further technical details are reported.
- Duration of treatment / exposure:
- Males 46 days, females 14 days before mating to day 3 of lactation
- Frequency of treatment:
- once daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0 (vehicle), 12, 60, 300 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on the results of a range finding study; details cf. the study summary contained in section 7.5.1
- Positive control:
- Not required
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations were included
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): n.a.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): n.a.
OTHER:
- parental repeated toxicity: cf. Chapter 7.5.1, MHLW (1997) - Oestrous cyclicity (parental animals):
- Yes
- Sperm parameters (parental animals):
- No
- Litter observations:
-
PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
- number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies
GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated were prepared for microscopic examination and weighed, respectively:
all animals: liver, kidney, spleen, heart, lung, brain, pituitary gland, thymus, adrenal, thyroid, stomach, small intestine, appendix, large
intestine, prostate gland and ovary, testes and epididymes (see also same study summary in section 7.5.1 for further details) - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]
Detail information not contained in secondary source ("Foetal:all macroscopic examination of all pups")
HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
etail information not contained in secondary source ("Foetal:all macroscopic examination of all pups") - Statistics:
- Chi-square test (data on sexual cycling, copulation rate, conception rate, birthrate, nursing rate), Fisher's direct probability test, Bartlett's test, Kruskal-Wallis test, Dunnett's test or Mann-Whitney's U-test
- Reproductive indices:
- Copulation index: No. of pairs with succesful copulation/no. of pairs mated)x100
Implantation index: No. of implantation sites/no. of corpora lutea)x100
Live birth index: No. of live pups born/no. of pups born)x100 - Offspring viability indices:
- Live birth index: No. of live pups born/no. of pups born)x100
Viability index: No. of live pups on day 4/no.of live pups born)x100
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- effects observed, treatment-related
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
Details on results (P0)
cross reference to the same study in Chapter 7.5.1
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS):
cross reference to the same study in Chapter 7.5.1
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS):
n.a., gavage study
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
Estrous cycle length and pattern, and anogenital distances were not performed because the test was conducted by the TG adopted in 1990.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Not examined
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
As for the reproductive ability of parental animals, no effects were detected in any dose group in males.
In females prolongation of diestrous phase and decrease in implantation rate were observed in the 300 mg/kg group.
Total litter loss in two dams of the 300 mg/kg group was observed. The number of pups born alive were decreased in the 60 and 300 mg/kg groups.
ORGAN WEIGHTS (PARENTAL ANIMALS)
cross reference to the same study in Chapter 7.5.1
GROSS PATHOLOGY (PARENTAL ANIMALS)
cross reference to the same study in Chapter 7.5.1
HISTOPATHOLOGY (PARENTAL ANIMALS)
cross reference to the same study in Chapter 7.5.1
OTHER FINDINGS (PARENTAL ANIMALS)
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: No effect at the highest tested dose
- Dose descriptor:
- NOAEL
- Effect level:
- 60 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: Prolongation of diestrous Decrease in implantation rate Total litter loss in 2/12 dams at 300 mg/kg bw/day
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, treatment-related
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings:
- not specified
Details on results (F1)
Viability on day 4 of lactation was decreased in the 300 mg/kg group male and female pups of the 300 mg/kg group showed lower body weights on day 0 of lactation.
CLINICAL SIGNS (OFFSPRING)
No data
BODY WEIGHT (OFFSPRING)
Male and female pups of the 300 mg/kg group showed lower body weights on day 0 of lactation.
SEXUAL MATURATION (OFFSPRING)
No data
ORGAN WEIGHTS (OFFSPRING)
No data
GROSS PATHOLOGY (OFFSPRING)
No findings
HISTOPATHOLOGY (OFFSPRING)
No data
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 12 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Number of live pups born / on day 4: reduced at 60 mg/kg bw/day Reduced implantation index at 60 mg/kg bw/day is considered to reflect embryotoxicity
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
As for the reproductive ability of parental animals, no effects were detected in males, but continuous diestrous was observed in females of the 300 mg/kg group on estrous cycle examination. All litters of animals in the 300 mg/kg group died, and implantation rate and number of pups born alive were decreased in the 60 and 300 mg/kg groups, along with numbers of implantations and pups born in the 300 mg/kg group. With regard to the effects on neonates, viability on day 4 of lactation was decreased in the 300 mg/kg group, and male and female pups of the 300 mg/kg group showed lower body weights on day 0 of lactation.
On the basis of these findings, NOAELs of 3,5,5-trimethylhexan-1-ol for reproductive/developmental toxicity were considered to be 300 mg/kg/day for males, 60 mg/kg/day for females, and 12 mg/kg/day for the F1 generation, respectively.
Detail Information:
Reproduction Toxicity parental animals
In sexual cycle findings for females, continuation of anestrus for 8 to 10 days was confirmed in four cases in the 300 mg/kg group. Although copulation and pregnancy were successful in three of these cases, there was one case of unsuccessful copulation. Compared to the control group, there was no significant difference in the number of days to copulation, the copulation rate and the conception rate.
The number of implantations was decreased at 60 and 300 mg/kg bw; therefore, the implantation index was significantly reduced (p<0.05) at these dose levels. Maternal toxicity was also seen at 60 and 300 mg/kg bw (cf. summary of the same study in section 7.5.1).
Dose level (mg/kg bw/day) |
||||
0 |
12 |
60 |
300 |
|
No. of animals |
12 |
12 |
12 |
12 |
No. of pregnant |
11 |
11 |
12 |
11 |
No. of dead or sacrificed |
0 |
0 |
0 |
4 |
No. of examined |
11 |
11 |
12 |
7 |
Duration of mating (days, Mean±S.D.) |
3.4±1.6 |
3.2±0.9 |
2.6±0.9 |
4.2±3.4 |
Copulation index (%) (a) |
100.0 |
100.0 |
100.0 |
91.7 |
Fertility index (%) (b) |
91.7 |
91.7 |
100.0 |
100.0 |
No. of corpora lutea |
16.3±1.7 |
16.4±1.5 |
16.4±2.5 |
16.1±3.6 |
No. of implantation sites |
15.8±1.7 |
15.0±1.5 |
14.3±1.8 |
13.4*±2.1 |
Implantation index (%) (c) |
97.4±3.8 |
91.5±9.8 |
88.2* ±12.0 |
85.0*±14.5 |
Gestation length (days) |
22.3±0.5 |
22.1±0.3 |
22.3±0.7 |
22.1±0.4 |
Gestation index (%) (d) |
100.0 |
100.0 |
100.0 |
63.6 |
Values are expressed as Mean±S.D.
Significantly different from 0 mg/kg group; * p=0.05 **p=0.01
(a) (No. of pairs with succesful copulation/no. of pairs mated) x 100
(b) (No. of pregnant animals/No. of pairs with successful copulation) x 100
(c) (No. of implantation sites/no. of corpora lutea) x 100
(d) (No. of females with live pups delivered/No. of pregnant females) x 100
Fetal data
Compared to controls, low values for the number of nidations, nidation rate, number of births and the number of live births were seen at 60 mg/kg bw/day and in the 300 mg/kg/day group; a level of significance up to p<0.01 was gained for some of the parameters. Male and female pup weight at birth was reduced at 60 mg/kg bw/day and at 300 mg/kg bw/day (p<0.5 (males), p<0.01 (females)). Survival of pups until day 4 after birth was significantly reduced (p<0.01) in the group at 300 mg/kg bw/day.
No aberrations were confirmed in any of the cases in necropsies of deaths and newborn pups sacrificed on day 4 of nursing.
Dose level (mg/kg bw/day) |
||||
0 |
12 |
60 |
300 |
|
Number of dams examined |
11 |
11 |
12 |
7 |
No. of pups born |
14.9±1.8 |
14.3±2.1 |
12.6±2.3 |
11.7±3.3* |
Delivery index (%) (a) |
94.1±5.4 |
95.3±4.2 |
88.1±13.2 |
87.5±19.1 |
No. of live pups born |
14.8±1.7 |
14.2±2.0 |
12.5±2.4* |
10.1±2.7** |
Live birth index(%) (b) |
99.4±1.9 |
99.5±1.7 |
99.2±2.6 |
88.9±18.4 |
Sex ratio (M/F) |
1.29±0.48 |
1.12±0.69 |
0.81±0.37** |
1.53±0.93 |
No. of dead pups born |
0.1±0.3 |
0.1±0.3 |
0.1±0.3 |
1.6±2.9 |
Live pups on day 4 |
14.5±1.9 |
14.0±1.9 |
12.0±2.4* |
6.6±5.1** |
Viability index(%) (c) |
98.0±3.4 |
98.8±2.6 |
96.3±8.4 |
64.9±44.6** |
Body weight of pups (gr) |
||||
Male, day 0 |
6.49±0.61 |
6.15±0.41 |
6.26±0.72 |
5.36±1.21* |
Male, day 4 |
10.55±1.02 |
9.58±0.68 |
10.51±1.60 |
10.22±1.75 (d) |
Male body weight gain (%) (e) |
62.63±5.60 |
55.74±6.02** |
67.55±13.40 |
71.59±8.50 (d) |
Female, day 0 |
6.25±0.74 |
5.94±0.47 |
5.91±0.63 |
5.03±1.21** |
Female, day 4 |
10.14±1.42 |
9.22±0.88 |
9.96±1.50 |
9.74±1.89 (d) |
Female body weight gain (%) (e) |
61.97±5.41 |
55.36±9.63 |
68.08±12.64 |
73.22±9.89 (d) |
Values are expressed as Mean±S.D.
Significantly different from 0 mg/kg group; * p=0.05 **p=0.01
(a) (No. of pups born/no. of implantations) x 100
(b) (No. of live pups born/no. of pups born) x 100
(c) (No. of live pups on day 4/no.of live pups born) x 100
(d) number of dams: 5
(e) (Body weight gain/body weight on day 0) x 100
Applicant's summary and conclusion
- Conclusions:
- Toxicity to reproduction, but no teratogenicity, was seen at 60 and 300 mg/kg bw /day. No toxicity to reproduction was seen in the absence of maternal toxicity. The NOAELs (reproduction) were males: 300 mg/kg bw/day.; females: 60 mg/kg bw/day; embryotoxicity: 12 mg/kg bw/day.
- Executive summary:
3, ,5 ,5 -trimethylhexan-1-ol was tested in a combined repeated toxicity/reproduction toxicity screening test according to OECD TG 422 under GLP conditions in rats at 0, 12, 60, and 300 mg/kg bw/day (gavage). The repeated dose NOAEL was12 mg/kg bw/day in male and female parental animals (findings of this study are summarized in Chapter 7.5.1).
As to reproduction, the following deviations from normal were seen:
Continuation of anestrus for 8 to 14 days in 4 of the high dose females; pregnancy occurred in 3 of these.
The number of implantations was decreased at 60 and 300 mg/kg bw; therefore, the implantation index was significantly reduced (p<0.05) at these dose levels. Maternal toxicity was also seen at 60 and 300 mg/kg bw (cf. summary of the same study in section 7.5.1). Thus, compared to controls, low values for the number of nidations, nidation rate, number of births and the number of live births were seen at 60 mg/kg bw/day and in the 300 mg/kg/day group; a level of significance up to p<0.01 was gained for some of the parameters.
Male and female pup weight at birth was slightly reduced at 60 mg/kg bw/day, and statistically significantly reduced at 300 mg/kg bw/day (p<0.5 (males), p<0.01 (females)). Male and female body weights increased and were comparable with that of the controls on day 4 past parturition.
The viability index, i.e. survival of pups from birth until day 4 after birth, was significantly reduced in the group at 300 mg/kg bw/day (p<0.01). The authors related this to maternal toxicity during fetal development and during lactation.
No external aberrations were confirmed in any of the cases in necropsies of deaths and newborn pups sacrificed on day 4 of nursing.
The authors derived the following NOAELs related to reproduction:
Males: 300 mg/kg bw/day; basis: no effect on virility
Females: 60 mg; basis: anestrus in 4 of 12 animals at high dose
Pups: 12 mg/kg bw/day; basis: nidation reduced, i.e. significantly reduced implantation index and lower number of fetuses at 60 mg/kg bw.
Overall, toxicity to reproduction was seen at maternal toxic dose levels (Yoshimura, 1997).
The study is considered to be suitable for assessment. It should, however, be noted that compared to the more specific guideline studies for this endpoint (e.g. OECD 416) the list of parameters to be examined is reduced. Further, the animal number is relatively low in screening studies and the statistical power is therefore reduced compared to an endpoint-specific OECD guideline study. The reduced implantation index seen at the 60 mg/kg dose level may therefore have failed to gain a level of statistical significance, making it difficult to assign correctly NOAEL-values.
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