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

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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: Comparable to guideline study without detailed documentation (publication). 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: II. Reproduction studies in rats and rabbits

Author:

Iglesias G, JJ Hlywka, JE Berg, MH Khalil, LE Pope and D Tamarkin

Year:

2002

Bibliographic source:

Regulatory Tox. and Pharm. 36, 80-85 2002b

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: ICH Harmonized Tripartite Guideline S5 (R2) for Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility

Deviations:

no

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

(non standard examination of soft tissue and head of foetuses)

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: saturated 22-carbon, long-chain aliphatic alcohol
- 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.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Froxfield SPF Rabbits Ltd., UK
- Age at study initiation: 18-26 weeks on arrival
- Weight at study initiation: 3.29-4.98 kg at start of study
- Fasting period before study: no data
- Housing: individually in suspended stainless-steel cages (TR6)
- Diet (e.g. ad libitum): standard rabbit diet (Special Diets Services Ltd., UK), ad libitum
- Water (e.g. ad libitum): public supply, ad libitum
- Acclimation period: >=1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18
- 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% Tween 80

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- test material weighed into glass container and heated to ~80 deg C until molten
- vehicle heated to 75 deg C
- test material and vehicle combined using coninuous magnetic stirring, 20% behenyl alcohol
- suspension cooled slowly to <60 deg C
- further cooled to 30 deg C
- slowly homogenized <=2 min
- cooled to room temperature
- 20% suspension prepared weekly
- 20% suspension provided top dose
- mid and low dose prepared on day of use by dilution with vehicle; 20% suspension magnetically stirred prior to removal of aliquots for dilution; dilutions hand swirled prior to magnetic stirring

VEHICLE
- Justification for use and choice of vehicle (if other than water): not stated
- Concentration in vehicle: 20, 2 and 0.2%
- Amount of vehicle (if gavage): 10 ml/kg bw for vehicle control and top dose groups; 0.625 and 2.5 ml/kg bw for low and mid dose groups respectively
- Lot/batch no. (if required): no data
- Purity: 1%

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- Impregnation procedure: cohoused with males of establised fertility
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation: no data
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: no data
- Further matings after two unsuccessful attempts: no data
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: not specified, but referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no data

Duration of treatment / exposure:

days 6-19 of gestation

Frequency of treatment:

daily

Duration of test:

females killed on day 29 of gestation

Doses / concentrations

Remarks:

Doses / Concentrations:
125, 500, 2000 mg/kg bw
Basis:
nominal conc.

No. of animals per sex per dose:

22

Control animals:

yes, concurrent vehicle

Details on study design:

Sex: female
Duration of test: 28 days
- Dose selection rationale: based on previous range-finding study
- Rationale for animal assignment (if not random): randomly allocated to the four treatment groups in order of mating "to evenly distribute the mated females among the groups"
- Other:
- approximately 2 weeks prior to arrival of females at testing facility, oestrus synchronised by supplier by intravenous injection of 25 IU luteinizing hormone
- following insemination, females injected intravenously with 25 IU luteinizing hormone to ensure successful ovulation
- examined on day 6 of gestation, prior to dosing, to determine suitability for use in study

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: evidence of reaction to treatment or moribund condition

DETAILED CLINICAL OBSERVATIONS: no data

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: Yes
- Time schedule for examinations: days 1-5, days 6-12, days 13-19, days 20-23, days 24-28

WATER CONSUMPTION: Yes
- Time schedule for examinations: daily

POST-MORTEM EXAMINATIONS: yes, macroscopic examination
- Sacrifice on gestation day 29
- Organs examined in addition to uterine contents and ovaries: no data

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
- Number of viable young: males, females and total
- Distribution of foetusus in each uterine horn
- Uterus of any female presumed non-pregnant stained and examined for implantation sites

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter - cervical, thoracic and abdominal cavities dissected and contents examined microscopically
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: one third per litter
- Other: all per litter
- foetal body weight
- position of foetus in uterus
- placental weight

Statistics:

One-way analysis of variance, t-tests - body weight, body weight change, food and water consumption; Dunnett's or Behren's-Fisher's tests - organ weights; nested analysis of variance, weighted t-tests - foetal and placental weights

Indices:

no data

Historical control data:

no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
no effects other than pale faeces in animals of the top dose group

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
no effects

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 1: Reproductive and developmental parameters

Observation	Dose (mg/kg bw/day)
	0	125	500	2000
Animals Assigned (Mated)	22	22	22	22
Animals Pregnant Pregnancy Rate (%)^a	20 91%	19 86%	19 86%	20 91%
Nonpregnant	2	3	3	2
Total litter loss (%)^a	1 10.0%	1 5.3%	1 5.3%	0 0.0%
Corpora Lutea/Dam (mean±SD)	12.8±3.1	12.9±2.2	12.6±3.0	12.2±3.9
Implantations/Dam (mean±SD)	11.4±3.9	11.1±2.6	11.0±3.3	10.6±4.3
Live Fetuses/Dam (mean±SD) Male (mean±SD) Female (mean±SD)	10.1±3.7 4.6±2.6 5.5±2.4	9.8±2.1 4.8±1.5 4.9±1.7	9.3^b±2.6 3.8±1.5 5.5±2.1	9.0±3.8 4.7±2.2 4.3±2.5
Resorptions/Dam (mean±SD) Early (mean±SD) Late (mean±SD)	1.4±1.2 0.4±0.6 1.0±1.0	1.3±1.2 0.3±0.5 1.1±1.0	1.7±1.3 0.4±0.6 1.2±1.1	1.6±1.2 0.7±0.8 0.9±0.9
Preimplantation Loss (%)	10.4	14.2	13.9	13.5
Postimplantation Loss (%)	12.1	12.0	15.2	14.7

^aCalculated for this table

^bIncludes one foetus not sexed at necropsy

Applicant's summary and conclusion

Conclusions:

In a reliable study, conducted according to a protocol similar to OECD guideline 414, the NOAEL for maternal toxicity, teratogenicity and foetotoxicity in rabbits, was 2000 mg/kg/day (highest dose tested). The study was performed in compliance with GLP. The result is a read across from 1-docosanol (CAS 661-19-8).