Isotridecan-1-ol

Endpoint summary

Description of key information

90 -day, rat: NOAEL = 150mg/kg, based on effects on body weight, clinical chemistry and urinanalysis, excluding peroxisome proliferation (BASF 1996, OECD 408, GLP) - data generated for CAS 10042 -59 -8  

14 -day screening, male rats (Rhodes et al., 1983)

no effects on testes, liver, and body weight at 1mM/kg b.w.

NOAEL = 184 mg/kg bw (Isotridecanol, CAS 27458 -92 -0)

NOAEL = 168 mg/kg bw (Isodecanol, CAS 25339 -17 -7)

NOAEL = 144 mg/kg bw (Isononanol, CAS 27458 -94 -2)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

see justification attached to chapter 13

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

urinalysis

Critical effects observed:

yes

Lowest effective dose / conc.:

600 mg/kg bw/day (actual dose received)

System:

hepatobiliary

Organ:

kidney

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Comparative screening study to investigate selectively the effect on testis and liver morphology and function.

GLP compliance:

not specified

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: ICI Alderley Park, UK
- Housing: single
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 1 week

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

Application volume: 10 ml/kg bw

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

14 d

Frequency of treatment:

daily

Dose / conc.:

184 mg/kg bw/day (actual dose received)

Remarks:

1 mM/kg bw

No. of animals per sex per dose:

10 per control group, 5 per dose group

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

Body weights were determined. The animals were killed by halothane overdose and blood samples for clinical pathology (plasma cholesterol and plasma triglyceride) were taken. The liver was weighed and samples for light and electron microscopy, morphometric analysis were investigated. Remaining liver was processed for investigation of catalase and CN-insensitive palmitoyl CoA oxidation.

Dose descriptor:

NOEL

Effect level:

184 mg/kg diet

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No effects observed

Critical effects observed:

no

Tridecanol did not impair body weight and had no effect on relative liver and testis weight. Neither clinical pathology parameter nor peroxisome associated enzymes were affected. Liver histology differed not from the concurrent control group.

Reference 3

Endpoint:

short-term repeated dose toxicity: oral

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Comparative screening study to investigate selectively the effect on testis and liver morphology and function.

GLP compliance:

not specified

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: ICI Alderley Park, UK
- Housing: single
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 1 week

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

Application volume: 10 ml/kg bw

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

14 d

Frequency of treatment:

daily

Dose / conc.:

168 mg/kg bw/day (actual dose received)

Remarks:

1 mM/kg bw

No. of animals per sex per dose:

10 per control group, 5 per dose group

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

Body weights were determined. The animals were killed by halothane overdose and blood samples for clinical pathology (plasma cholesterol and plasma triglyceride) were taken. The liver was weighed and samples for light and electron microscopy, morphometric analysis were investigated. Remaining liver was processed for investigation of catalase and CN-insensitive palmitoyl CoA oxidation.

Dose descriptor:

NOAEL

Effect level:

168 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: no effects observed

Critical effects observed:

no

Isodecanol did not impair body weight and had no effect on relative liver and testis weight. Neither clinical pathology parameter nor peroxisome associated enzymes were affected. Liver histology differed not from the concurrent control group.

Reference 4

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Comparative screening study to investigate selectively the effect on testis and liver morphology and function.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: ICI Alderley Park, UK
- Housing: single
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 1 week

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

Animals received a dose level equivalent of 1 mmol/kg/day dissolved in polyethylene glycol 300 (10 ml/kg/day)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

14 days

Frequency of treatment:

Once daily

Dose / conc.:

144 mg/kg bw/day (actual dose received)

Remarks:

1mM /kg b.w.

No. of animals per sex per dose:

10 per control group, 5 per dose group

Control animals:

yes, concurrent vehicle

Details on study design:

No data provided.

Positive control:

No data provided.

Observations and examinations performed and frequency:

Body weights were determined. The animals were killed by halothane overdose and blood samples for clinical pathology (plasma cholesterol and plasma triglyceride) were taken. The liver was weighed and samples for light and electron microscopy, morphometric analysis were investigated. Remaining liver was processed for investigation of catalase and CN-insensitive palmitoyl CoA oxidation.

Sacrifice and pathology:

Morphology of the liver.

Dose descriptor:

NOAEL

Effect level:

144 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: no effects observed

Critical effects observed:

no

Executive summary:

In a two-week oral study, five male rats were dosed by oral gavage with 144 mg/kg bw/day of isononanol. In the control group, ten animals received the vehicle, PEG (polyethylene glycol) 300, daily for 14 days.  Animals were sacrificed after 14 days and blood was analyzed for plasma cholesterol and triglycerides.  The liver was removed for histopathological analysis, analysis of catalase, and CN-insensitive palmitoyl CoA oxidation.  Testicular weight was also determined. Isononanol did not significantly influence bodyweight gain, liver to bodyweight ratio, testis to bodyweight ratio, or palmitoyl CoA oxidase activity. It is concluded that the NOAEL is 144 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

No subchronic study for the registered substance is available. Instead, data from the structurally related branched alcohol propylheptanol (CAS 10042-59-8) were adopted. For a detailed justification of this approach, please see the attached document to IUCLID chapter 13.

Animals were observed for clinical signs at least daily. Gross and microscopic examinations were performed on all animals from all dosage groups. Also, clinical chemistry, haematology, urinalysis or ophthalmoscopic examinations were conducted and organ weights were taken. Substance-related effects were seen at 600 mg/kg in both sexes and at 150 mg/kg in one female, only.

No substance-related deaths occurred. All high dose males and females showed salivation one hour after administration and urine-smeared fur in the anogenital region was recorded for males and females for 3 to 4 hours after administration. Reduced food consumption was recorded in animals of both sexes as well as impaired body weight gain including reduced body weights at the end of administration in males. Ophthalmoscopy revealed no treatment-related changes. Haematology showed a decrease in platelets. The toxicological relevance of this singular finding is unclear. Globulins and cholesterol were decreased in both sexes and triglycerides only in males, while albumin was increased. These changes might be indicative of increased liver metabolism. There was also an increase in cyanide- insensitive palmitoyl-CoA-oxidation in both sexes, which is typical for peroxisome proliferation. Correspondingly, pathology showed an increased absolute and relative liver weight in both sexes, which was associated with diffuse hepatic hypertrophy. There was also a loss of fatty infiltration of liver cells in males only. Diffuse follicular hypertrophy in the thyroid gland in males and vacuolation of basophilic (thyrotrophic) cells in the glandular part of the pituitary gland in males are also secondary to peroxisome proliferation and parallel induced xenobiotic metabolism, which results in an increased elimination of T3/T4 from rat serum by increased glucuronidation. In females, the urinary volume was increased, leading to a reduced specific gravity. The number of squamous epithelial cells in urine were increased in both sexes. Females additionally had more transitional epithelial cells in the urine.

At 150 mg/kg bw/day, one female showed diffuse hepatic hypertrophy, resulting in an increase in relative liver weight in one female only.

Thus, the NOAEL was 150 mg/kg bw/day in males and 30 mg/kg bw/day in females mainly based on liver effects indicative for peroxisomal proliferation. Peroxisomal proliferation is a rodent-specific effect and not relevant for human hazard. Therefore the NOAEL relevant for human hazard is 150 mg/kg bw based on body weight effects and urinalysis.

A comparative screening study was conducted to investigate selectively the effect on testis and liver morphology and function for several branched long chain primary alcohols used as read across substances (isodecyl alcohol and Isononyl alcohol) and the registered substance itself (Rhodes, C. et al., 1983). The test substance (1mM/kg bw in polyethylene glycol 300) was administered orally via gavage to 5 male Wistar rats on 14 consecutive days. Body weights were determined. The animals were killed by halothane overdose and blood samples for clinical pathology (plasma cholesterol and plasma triglyceride) were taken. The liver was weighed and samples for light and electron microscopy, morphometric analysis were investigated. The remaining liver was processed for investigation of catalase and CN-insensitive palmitoyl CoA oxidation. None of the three tested alcohols impaired body weight or had any effect on relative liver and testis weight. Neither clinical pathology parameter nor peroxisome associated enzymes were affected. Liver histology did not differ from the concurrent control group. Dose levels were 144 mg/kg for isononanol, 168 mg/kg for isodecanol, and 184 mg/kg for isotridecanol.

Justification for classification or non-classification

In a subchronic study, effects on liver and kidney were observed at 600mg/kg. This is above the threshold for classification according to 1272/2008/EC (CLP).