Ethene, homopolymer, oxidized, hydrolyzed, distn. residues, from C16-18 alcs. manuf.

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

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

Adequacy of study:

key study

Study period:

not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well-conducted study which meets basic scientific principles. The study is a read across from 1-docosanol (CAS 661-19-8).

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

review article or handbook

Title:

The toxicity of behenyl alcohol: I. Genotoxicity and subchronic toxicity in rats and dogs

Author:

Iglesias G, J J Hlywka, J E Berg, M H Khalil, L E Pope and D Tamarkin

Year:

2002

Bibliographic source:

Regulatory Tox. and Pharm. 36, 69-79 2002a

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Repeated dose toxicity test in which rats were orally dosed daily for 26 weeks and reproductive organs assessed

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Docosan-1-ol

EC Number:

211-546-6

EC Name:

Docosan-1-ol

Cas Number:

661-19-8

Molecular formula:

C22H46O

IUPAC Name:

docosan-1-ol

Details on test material:

- Name of test material (as cited in study report): behenyl alcohol
- Substance type: colourless, waxy solid
- Physical state: solid
- Analytical purity: 98%
- 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.: obtained from Condea, Germany
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data
- Other:
- Melting point: 70 deg C
- Soluble in: ethanol and chloroform
- Insoluble in: water

Test animals

Species:

rat

Strain:

other: CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: ~21-28 days at purchase
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5/cage in stainless steel cages, containing absorbent paper
- Diet (e.g. ad libitum): expanded rodent diet (Special Diets Services, UK), ad libitum
- Water (e.g. ad libitum): public supply (Suffolk Water Company, UK), ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 55
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 1% aqueous Tween 80

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- test material heated to approx. 80 deg C
- vehicle heated to approx. 75 deg C
- vehicle added to test material while being magnetically stirred at high speed
- resulting 20% (w/w) suspension homogenized and slowly cooled to below 60 deg C
- when cooled to 30 deg C, suspension slowly homogenized again for >=2 min
- cooled to room temp.
- stored at 13 deg C
- prepared once weekly
- 20% suspension used for top dose; for low and mid doses, suspension magnetically stirred and aliquots taken for dilution on day of use; constant dose volume of 5 ml/kg bw per dose
- dilutions mixed by hand swirling followed by magnetic stirring

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 1%
- Amount of vehicle (if gavage): 5 ml/kg bw per dose
- Lot/batch no. (if required): no data
- Purity: no data

Details on mating procedure:

No mating - screening test

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

26 weeks

Frequency of treatment:

daily, 7 days/week

Details on study schedule:

No mating - screening test

Doses / concentrations

Remarks:

Doses / Concentrations:
10, 100, 1000 mg/kg bw/day
Basis:
nominal conc.

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): random
- Other:
- Repeated dose toxicity (oral) study - acceptable as reproductive screen since reproductive organs were included in those evaluated

Positive control:

none

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS (including mortality): Yes
- Time schedule: >=twice daily
- Cage side observations included: evidence of reaction to treatment or moribund condition, evidence of ill health such as blood or loose faeces

DETAILED CLINICAL OBSERVATIONS: Yes, individual observations
- Time schedule: once daily during week 1, twice weekly during weeks 2 to 4, once weekly during weeks 5 to 13, once every 2 weeks from week 14 onwards

BODY WEIGHT: Yes
- Time schedule for examinations: pre-study, weekly during the study or more frequently if appropriate (for animals in moribund condition), at necropsy

FOOD CONSUMPTION:
- Food consumption for each cage determined: Yes

FOOD EFFICIENCY:
- Weekly group mean food conversion efficiencies calculated from the consumption and body weight gain data: Yes, for the first 14 weeks of treatment

WATER CONSUMPTION: No

OTHER: Ophthalmoscopic examination, haematology, clinical chemistry, urinalysis - reported elsewhere

Oestrous cyclicity (parental animals):

not examined; ovaries and uterus (with cervix) weighed and examined

Sperm parameters (parental animals):

not examined; testes and epididymides weighed and examined

Litter observations:

no litters - not mated - screening test

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: after 26 weeks of treatment
- Maternal animals: after 26 weeks of treatment

GROSS NECROPSY
- Yes

ORGAN WEIGHTS: adrenals, brain, kidneys, liver, lungs (with main stem bronchi), ovaries, pituitary, prostate, spleen, testes, thymus, thyroid (with parathyroids), uterus, cervix

HISTOPATHOLOGY: Yes - adrenals, brain, eyes, optic nerve, femur, heart, kidneys, liver, lungs, seminal vesicles, spinal cord, stomach, thyroid, uterus

Postmortem examinations (offspring):

no offspring - not mated - screening test

Statistics:

Bartlett's test for homogeneity of variance (organ weights, body weight changes); if significant, Behrens-Fisher test, otherwise Dunnett's test.
Two-tailed Fisher's exact test (macroscopic/microscopic pathological findings).

Reproductive indices:

not mated - screening test

Offspring viability indices:

no offspring - not mated - screening test

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

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
- one male in the mid-dose group died at week 25 (examination suggested aspiration of test material through mis-dosing; not considered to be treatment-related)
- no other clinical signs of systemic toxicity or mortality

BODY WEIGHT AND WEIGHT GAIN
- no effects

FOOD CONSUMPTION
- presumably no effects

FOOD EFFICIENCY
- no effects

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

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

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- not examined - screening test

ORGAN WEIGHTS (PARENTAL ANIMALS), including testis, epididymis, ovaries, uterus (with cervix)
- no effects

GROSS PATHOLOGY (PARENTAL ANIMALS), including testis, epididymis, ovaries, uterus (with cervix)
- no effects

HISTOPATHOLOGY (PARENTAL ANIMALS), including testis, epididymis, ovaries, uterus (with cervix)
- no effects

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: Generation: not mated - screening study (migrated information)

Results: F1 generation

General toxicity (F1)

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

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

Details on results (F1)

no offspring - not mated - screening test

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In a reliable screening study, a repeated oral dose NOAEL of 1000 mg/kg bw/day was determined for effects on reproductive organs in the rat. The result is a read across from 1-docosanol (CAS 661-19-8).