Alcohols, C16-18

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

other: Repeat dose study with histopathology of reproductive organs.

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

Alcohols, C16-18 is a member and is from Long Chain Alcohols (C6-22 primary aliphatic alcohols) category.
The Long Chain Alcohols (C6-22 primary aliphatic alcohols) category is considered suitable as a source of data for Alcohols, C16-18.
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.

Long Chain Alcohols (C6-22 primary aliphatic alcohols) category covers a family of 30 primary aliphatic alcohols within a carbon chain length range of C6-C22. Commercial products generally include several aliphatic alcohol components, with a range of carbon chain lengths present. The family consists of alcohols with varying compositions and structures. Composition depends on the route to manufacture and the related feedstocks. Most of the alcohols have linear carbon chains but certain manufacturing processes create branched structures. Data are also available for eleven other similar substances, which support the category. Non-sponsored alcohols may not be HPV or may not be produced by members of the consortium, but have structures similar to sponsored linear alcohols.

Key points are that the members share:
• The same structural features
• Similar metabolic pathways
• Common mode of ecotoxicological action
• Common levels and mode of human health related effects.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2022

Reference 2

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:

equivalent or similar to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Principles of method if other than guideline:

Rats treated via the diet for 90 days with limited evaluation, but including reproductive organs.
Groups of 20 rats (10 of each sex) were fed Alfol 16 in the diet for 13 weeks. The control group consisted of 20 males and 20 females at dose levels of 1, 2.5 and 5% with the top dose level increasing at week 11 to 7.5% and for weeks 12& 13 to 10% in the diet. At termination, all animals were necropsied and tissues from 5 males and 5 females (including gonads) of the high dose group and a similar number of controls were examined histopathologically. Testes and ovary weights were recorded together with other organ weights.

GLP compliance:

not specified

Remarks:

Pre-dates widespread introduction of GLP

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 Charles river

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
- Use of restrainers for preventing ingestion (if dermal): not applicable
- 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 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

Details on mating procedure:

no mating - screening study

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Exposure period: 13 weeks

Duration of test: 13 weeks

Frequency of treatment:

continuous in diet

Details on study schedule:

no mating - screening study

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

10 other: %

Remarks:

nominal in diet

Doses / concentrations 2

Dose / conc.:

5 other: %

Remarks:

nominal in diet

Doses / concentrations 3

Dose / conc.:

2.5 other: %

Remarks:

nominal in diet

Doses / concentrations 4

Dose / conc.:

1 other: %

Remarks:

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

Positive control:

none

Examinations

Parental animals: Observations and examinations:

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

WATER CONSUMPTION: No

OTHER: Haematology and urinalysis (reported elsewhere)

Oestrous cyclicity (parental animals):

no data

Sperm parameters (parental animals):

Parameters examined in males: testis weight

Litter observations:

no litters - no mating - screening study

Postmortem examinations (parental animals):

SACRIFICE
- Males: All surviving animals, after 13 weeks of treatment
- Females: All surviving animals after 13 weeks of treatment

GROSS NECROPSY
- Gross necropsy included external and internal examinations of the cervical, thoracic, and abdominal viscera

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, gonads (testes or ovaries), lymph node, bone, bone marrow
- all listed tissues from 5/sex from high dose and controls examined

Postmortem examinations (offspring):

no offspring - no mating - screening study

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')

Reproductive indices:

no mating - screening study

Offspring viability indices:

no offspring - no mating - screening study

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

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:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- none of the animals displayed overt signs of intoxication due to oral exposure to hexadecanol during the 13 weeks of the experiment.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- food consumption and body weights differed significantly for both males and females at various times in the intermediate and high dose levels.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
- animals in the low, mid and high dose groups were administered dietary concentration of 1%, 2.5% and 5-10% respectively
- average compound intake for males, calculated from weekly food consumption data, was 723, 1822 and 4257 mg/kg bw/day respectively
- average compound intake for females, calculated from weekly food consumption data, was 875, 2064 and 4567 mg/kg bw/day respectively

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
- not examined

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
- not examined

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- not examined

ORGAN WEIGHTS (PARENTAL ANIMALS)
- the relative testes weights were increased over control levels in all treatment groups reaching signficance in the low and high dose group according to the study report. The organ weight data were reanalysed by the Weinberg Associates using a Tukey test when significance was attained only at the high dose level (see 'Remarks on results' section)
- there were no significant changes in ovary weight

GROSS PATHOLOGY (PARENTAL ANIMALS)
- no effects

HISTOPATHOLOGY (PARENTAL ANIMALS)
- histopathological examination revealed no treatment-related changes in the ovaries or testes.

OTHER FINDINGS (PARENTAL ANIMALS)

Effect levels (P0)

1

Key result

Dose descriptor:

NOAEL

Effect level:

1 822 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: see 'Remark'

2

Key result

Dose descriptor:

NOAEL

Effect level:

4 567 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: see 'Remark'

Results: F1 generation

General toxicity (F1)

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Other effects:

not examined

Details on results (F1)

no offspring - no mating - screening study

Effect levels (F1)

Generation:

F1

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: no offspring - no mating - screening study

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Gonad weight mean relative:

	Control	Low	Mid	High
Males	0.793	0.768*	0.787	0.902*+
SD	0.062	0.003	0.084	0.052

*Significant using Chi square test as reported in original report. +Significant in Tukey test. 

Applicant's summary and conclusion

Conclusions:

In a reliable screening study, a repeated oral dose NOAEL of 1822 mg/kg/day for males and 4567 mg/kg/day (the highest dose tested) in females was determined for effects on reproductive organs in the rat.