Alcohols, C12-14

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

other: published data

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

Data source

Reference

Reference Type:

publication

Title:

Exhibit II.

Author:

Scientific Associates, Inc.

Year:

1966

Bibliographic source:

Final report on thirteen-week subacute feeding of Alfol 6 and Alfol 16 to rats.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats treated via the diet for 90 days with limited evaluation

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hexadecan-1-ol

EC Number:

253-149-0

EC Name:

Hexadecan-1-ol

Cas Number:

36653-82-4

Molecular formula:

C16H34O

IUPAC Name:

hexadecan-1-ol

Test material form:

solid: compact

Details on test material:

- Name of test material (as cited in study report): Alfol 16 (tradename)- Substance type: white, waxlike solid, with an odour similar to coconut oil- Physical state: solid- Analytical purity: no data- Impurities (identity and concentrations): no data- Composition of test material, percentage of components: no data- Isomers composition: no data- Purity test date: no data- Lot/batch No.: 624-6537 and 624-6539 from the Continental Oil Company, USA- Expiration date of the lot/batch: no data- Stability under test conditions: no data- Storage condition of test material: no data

Test animals

Species:

rat

Strain:

other: albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: no data but "young"
- Weight at study initiation: males 104.1 g, females 90.5 g
- Fasting period before study: no data
- Housing: individually in suspended wire-mesh cages
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data but "controlled within narrow limits"
- Humidity (%): no data but "controlled within narrow limits"
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): basal laboratory diet (Purina Laboratory Chow)
- Storage temperature of food: no data

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

continuous in diet

Doses / concentrations

Remarks:

Doses / Concentrations:
1%, 2.5%, 5-10%
Basis:
nominal in diet

No. of animals per sex per dose:

10 (treated), 20 (controls)

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: no satellite groups

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 5 days/week
- Cage side observations included: general physical appearance, gross signs of systemic toxicity and/or pharmacological effect, behaviour, mortality

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as mg/kg bw/day: Yes

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: days 30 and 90
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5/sex per group
- Parameters examined: microhaematocrit, haemoglobin, total and differential leukocyte count

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: days 30 and 90
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- How many animals: 5/sex per group (samples pooled)
- Parameters examined: albumin, acetone, bilirubin, colour, occult blood, sugar, pH, appearance, microscopic examination of sediment

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: brain, thyroid, heart, liver, spleen, kidneys, adrenals, gonads (testes or ovaries)

HISTOPATHOLOGY: Yes
- brain, thyroid, parathyroid, heart, lung, liver, spleen, stomach, small intestine, large intestine, pancreas, kidney, urinary bladder, adrenal, gonad, lymph node, bone, bone marrow
- all listed tissues from 5/sex from high dose and controls examined

Other examinations:

none

Statistics:

Chi-squared test for comparing relative organ weights. Original organ weight analyses using the Chi square test were supplemented by Tukey tests carried out by the Weinberg group (see 'Any other information on materials and methods')

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
- all animals survived the 13 week treatment period.
- all surviving animals appeared normal

BODY WEIGHT AND WEIGHT GAIN
- significantly reduced (84.7 - 89.8% of controls) in top dose males for most study weeks, in mid dose females at weeks 4-13 and high dose females (81.7-89.7%) throughout the study
- changes were attributed at least in part to reduced food consumption and the high content of test material in the diet.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- significantly reduced (76.4 - 89.2% of controls) in top dose males at weeks 1 and 12, in mid dose males at week 13, in mid dose females at week 1 and high dose females weeks 1 and 12 (79.1 - 89.9% of controls).

FOOD EFFICIENCY
- no data

WATER CONSUMPTION
- not examined

OPHTHALMOSCOPIC EXAMINATION
- not examined

HAEMATOLOGY
- no effects

CLINICAL CHEMISTRY
- not examined

URINALYSIS
- no effects

NEUROBEHAVIOUR
- not examined

ORGAN WEIGHTS
- the original report indicated that there were significant differences in some relative organ weights from treated groups compared to controls. These were reanalysed by the Weinberg Group using the Tukey test (see 'Remarks on results' section)

GROSS PATHOLOGY
- unremarkable

HISTOPATHOLOGY: NON-NEOPLASTIC
- there were no treatment related histopathological changes in the control and top dose animals examined (including testes & ovaries).

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- not applicable

HISTORICAL CONTROL DATA (if applicable)
- no data

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

> 4 257 mg/kg bw/day (nominal)

Based on:

other: based on highest dose tested.

Sex:

male

Basis for effect level:

other: see 'Remark'

2

Dose descriptor:

NOAEL

Effect level:

> 4 567 mg/kg bw/day (nominal)

Based on:

other: based on highest dose tested.

Sex:

female

Basis for effect level:

other: see 'Remark'

3

Dose descriptor:

NOAEL

Effect level:

723 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: based on the reductions in body weight gain and food consumption

4

Dose descriptor:

NOAEL

Effect level:

875 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: based on the reductions in body weight gain and food consumption

5

Dose descriptor:

NOAEL

Effect level:

750 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The NOAEL for this 13 week dietary feeding study in rats is ca 750 mg/kg/day (males 723, females 875) based on reduced weight gain and food consumption.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

In a 13-week study in rats1-hexadecanol was administered in the diet at concentrations of 0 (control), 1, 2.5 or 5%; the level in the highest dose group being increased stepwise to 10% during the last 3 weeks of the study. Reductions in body weight gain (82-90% of control values) and food consumption (76 – 90% of control values) in the highest dose group and, occasionally, at the 2.5% level were the main findings of this study. Relative liver weights were increased in males at the top dose level (124% of control values) but in the absence of any microscopic findings the significance of this change is uncertain. A NOAEL was established at a dietary concentration of 1% (equivalent toca.750 mg/kg/day) based on the reductions in body weight gain and food consumption

Applicant's summary and conclusion

Conclusions:

The NOAEL for this 13 week dietary feeding study in rats is ca 750 mg/kg/day (males 723, females 875) based on reduced weight gain and food consumption. The toxicological significance of observed changes in organ weights, all in the absence of histopathological change, is questionable. Increased liver weights at higher dose levels may be indicative of a mild adaptive effect on the liver.
Hexadecan-1-ol (C16) is supporting substance for Alcohols,C12-C14 and the one of the component in Alcohols,C12-C14
In view of the structural and chemical similarities, it is considereed that the results of this study can be used for read-across to Alcohols, C12-14.

Executive summary:

The NOAEL for this 13 week dietary feeding study in rats is ca 750 mg/kg/day (males 723, females 875) based on reduced weight gain and food consumption. The toxicological significance of observed changes in organ weights, all in the absence of histopathological change, is questionable. Increased liver weights at higher dose levels may be indicative of a mild adaptive effect on the liver.

Hexadecan-1-ol (C16) is supporting substance for Alcohols,C12-C14 and the one of the component in Alcohols,C12-C14 .

In view of the structural and chemical similarities, it is considereed that the results of this study can be used for read-across to Alcohols, C12-14.