Registration Dossier

Administrative data

Description of key information

3,5,5-trimethylhexan-1-ol is of moderate acute oral and dermal toxicity (both the LD50 (oral, rat) and the LD50 (dermal, rabbit) were >2000 mg/kg). No target organ could be identified.
The vapor pressure of isononanol is too low to cause toxic atmospheres.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study (see also: SIDS documents in section 13; Iuclid reference [27]; Reliability assigned: 1)
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Japan Charles River Co.
- Age at study initiation: 5-6 weeks old for both sexs
- Weight at study initiation: mean 156.7 g (149-165 g) for males; mean 133.9 g (126-144 g) for females
- Fasting period before study: 17 to 18 hours
- Housing: in groups of 5 animals in metal cages
- Accimatisation: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 3°C
- Humidity (%): 55 ± 10 %,
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 40 % test substance (w/v %)
- Amount of vehicle (if gavage): dose volume 5 mL/kg bw
- Lot/batch no. (if required):
- Purity: pharmaceutical grade (Japan Pharmacopoiea)


MAXIMUM DOSE VOLUME APPLIED:
5 mL/kg bw
Doses:
Definitive study: 2000 mg/kg bw
Selected based on results of preliminary study: 0, 500, 1000, and 2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations daily until day 14; animals were weighed on days 1, 3, 5, 10 and 14 after the drug was administered
- Necropsy of survivors performed: yes
- Other examinations performed: histopathology (organs examined: liver, kidneys, spleen, heart, lungs, brain (cerebrum, cerebellum), stomach (anterior stomach, glandular stomach), duodenum, jejunum, ileum, cecum, colon, rectum and ovaries, testes, epididymis)
Statistics:
not needed
Preliminary study:
There were no deaths in the preliminary study (i.e. LD50 was >2000 mg/kg bw); clinical sign (reduced movements) was seen after dosing, but was reversible within one day; significantly reduced body weight was seen in males throughout days 1-14, in females on days 1-3; there were no histopathological changes noted.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no death occurred
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no death occurred
Mortality:
No death occurred of either males or females
Clinical signs:
A decrease in spontaneous motor activity was observed; this was reversible on the day of administration.
Body weight:
Body weight gains were significantly suppressed following administration in males (days 1-14) and females (days 1-3).
Gross pathology:
No changes were detected on autopsy or histopathological examination.
Other findings:
- Histopathology: no changes noted
- Potential target organs: none identified

No deaths occurred of either males or females and the LD50 was estimated to be more than 2000 mg/kg bw. A reversible decrease in spontaneous motor activity was observed on the day of administration, and body weight gains were suppressed or tended to be suppressed from days 1 to 14 of administration in males and females. No changes were detected on autopsy or histopathological examination.

LD50: Male, > 2000 mg/kg bw; female, > 2000 mg/kg bw

Interpretation of results:
relatively harmless
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 (oral, rat, 14 days) was >2000 mg/kg body weight. No target organ could be identified.
Executive summary:

The acute oral LD50 (oral, rat, 14 days) of 3, 5, 5 -trimethylhexan-1-ol was >2000 mg/kg body weight in a study conducted according to OECD TG 401 and under GLP conditions using groups of 5 rats per sex and dose in a preliminary study (0, 500, 1000, 2000 mg/kg bw) and in the definitive study (2000 mg/kg bw).

No deaths occurred of either males or females. A reversible decrease in spontaneous motor activity was observed on the day of administration, and body weight gains were suppressed or tended to be suppressed from days 1 to 14 of administration in males and females. No changes were detected on autopsy or histopathological examination, i.e. a target organ could not be identified (Yoshimura et al., 2007).

The study is considered to be acceptable for assessment.

 

Endpoint conclusion
Dose descriptor:
LD50
2 000 mg/kg bw

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Pre-guideline study. Basic data given: comparable to guideline studies. Restriction: methods described in previous publications (1944, 1988; cf. references)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
Pre-guideline study
Deviations:
no
GLP compliance:
no
Remarks:
Pre-GLP study
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Sex:
not specified
Details on test animals and environmental conditions:
no data
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: no data
- Type of wrap if used: impervious rubber film, or vinyl plastic

REMOVAL OF TEST SUBSTANCE
- Washing: yes
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied: several unspeified doses. Up to 20 mL/kg possible with this method.
- Concentration: undiluted
- Constant volume or concentration used: no
Duration of exposure:
24 hours
Doses:
not specified
No. of animals per sex per dose:
6
Details on study design:
- Duration of observation period following administration: 14 days
Statistics:
Method of Thompson (1947)
Sex:
male/female
Dose descriptor:
approximate LD50
Effect level:
2 307 mg/kg bw
Based on:
act. ingr.
Conclusions:
The dermal LD50 (rabbit) was 2307 mg 3,5,5-trimethylhexan-1-ol/kg bw
Executive summary:

The dermal toxicity of 3,5,5-trimethylhexan-1-ol was tested using a pre-guideline protocol that is comparable to OECD TG 402. In brief, several volumes of undiluted test material was placed onto the shaved skin of rabbits, 6 animals per dose group. The test material was held in place for 24 hours by an impervious cover, i.e. under occlusive conditions. Mortality was observed for 14 days, the LD50 was calculated using the method of Thompson (1947).

TheLD50(rabbit) was 2.8 mL/kg bw, equivalent to 2307 mg 3,5,5-trimethylhexan-1-ol / kg bw (Smyth and Carpenter, 1949).

 

The study is considered to be acceptable for assessment.

 

Endpoint conclusion
Dose descriptor:
LD50
2 307 mg/kg bw

Additional information

Oral

The acute oral LD50 (oral, rat, 14 days) of 3, 5, 5 -trimethylhexan-1-ol was >2000 mg/kg body weight in a study conducted according to OECD TG 401 and under GLP conditions using groups of 5 rats per sex and dose in a preliminary study (0, 500, 1000, 2000 mg/kg bw) and in the definitive study (2000 mg/kg bw).

No deaths occurred of either males or females. A reversible decrease in spontaneous motor activity was observed on the day of administration, and body weight gains were suppressed or tended to be suppressed from days 1 to 14 of administration in males and females. No changes were detected on autopsy or histopathological examination, i.e. a target organ could not be identified (Yoshimura et al., 2007).

This finding is in line with an earlier finding (LD50, rat: 3250 mg/kg bw) reported by Smyth and Carpenter (1949). In addition, the acute oral LD50 was 2300 mg Isononanol/kg bw in rats in a study that was conducted similar to OECD TG 401 (Opdyke, 1977). The documentation of this study is limited but the study results are in line with those from other studies and suitable for assesssment.

Inhalation

There was no inhalation toxicity seen in rats exposed to higher aliphatic alcohols. It was concluded that the vapor pressure of long chain aliphatic alcohols with carbon chain lengths of C5 and more, including 1 -octanol, 1-nonanol, and 1 -decanol, is too low to reach vapor concentrations that cause toxicity following single or repeated inhalation exposure (6 or 7 h/day, days 1-19 of gestation in a combined repeated toxicity/reproduction toxicity study) (Nelson et al., 1990).

Dermal

The dermal toxicity of 3,5,5-trimethylhexan-1-ol was tested using a pre-guideline protocol that is comparable to OECD TG 402. In brief, several volumes of undiluted test material was placed onto the shaved skin of rabbits, 6 animals per dose group. The test material was held in place for 24 hours by an impervious cover, i.e. under occlusive conditions. Mortality was observed for 14 days, the LD50 was calculated using the method of Thompson (1947). TheLD50(rabbit) was 2.8 mL/kg bw, equivalent to 2307 mg 3,5,5-trimethylhexan-1-ol / kg bw (Smyth and Carpenter, 1949).

 

 

Justification for classification or non-classification

Regulation 67/548/EEC: classification criteria not met

Regulation 1272/2007/EC: classificationcriteria not met