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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to a test protocol that is comparable to the appropriate OECD test guideline. 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:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
Principles of method if other than guideline:
Well-conducted study according to a protocol very similar to OECD guideline 408, but with a treatment duration of 26 weeks
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
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 oral 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
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
26 weeks
Frequency of treatment:
daily, 7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
10, 100, 1000 mg/kg bw/day
Basis:
other: nomnial 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
- Rationale for selecting satellite groups: additional 10/sex per treatment group for toxicokinetic study, 6/sex controls
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): random
Positive control:
none

Examinations

Observations and examinations performed and frequency:
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

OPHTHALMOSCOPIC EXAMINATION: Yes, prestudy and at weeks 12 and 25

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 14 and 26
- Anaesthetic used for blood collection: Yes - halothane/nitrous oxide
- Animals fasted: Yes
- How many animals: 10/sex per dose level
- Parameters examined: packed cell volume, haemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, mean cell haemoglobin concentration, mean cell haemoglobin, mean cell volume; blood film samples examined for abnormal morphologhy and unusual cell types including normoblasts; prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 14 and 26
- Animals fasted: Yes
- How many animals: 10/sex per dose level
- Parameters examined: alkaline phosphatase activity, alanine amino transferase, aspartate amino transferase, gamma-glutamyl transpeptidase, glucose, total bilirubin, total cholesterol, urea, total triglyceride, total protein, electrolyte levels (Na, Cl, Ca), inorganic phosphorus, electrophorectic protein, creatine concentration

URINALYSIS: Yes
- Time schedule for collection of urine: weeks 12 and 25
- Metabolism cages used for collection of urine: No data
- Animals fasted: No, but water deprived
- Parameters examined: pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, specific gravity, appearance, volume

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
- Bone marrow samples from femur: myeloid:erythroid ratio, cellularity and composition of marrow
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

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

HISTOPATHOLOGY: Yes - adrenals, brain, eyes, optic nerve, femur, heart, kidneys, liver, lungs, seminal vesicles, spinal cord, stomach, thyroid, uterus
Other examinations:
Satellite group for toxicokinetic study:
- Blood taken from satellite groups (3M+3F) non-fasted  on days 1, during weeks 13 and 26 at 0.5, 1, 2, 4, 8 and 24 hours after  dosing.
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).
Student's t-test (haematology, clinical chemistry, urinalysis).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
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

WATER CONSUMPTION
- not examined

OPHTHALMOSCOPIC EXAMINATION
- no effects

HAEMATOLOGY
- no effects
- no effects seen in bone marrow smears

CLINICAL CHEMISTRY
- no effects

URINALYSIS
- no effects

NEUROBEHAVIOUR
- not examined

ORGAN WEIGHTS
- no effects

GROSS PATHOLOGY
- no effects

HISTOPATHOLOGY: NON-NEOPLASTIC
- no effects

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- no effects

HISTORICAL CONTROL DATA (if applicable)
- no data

OTHER FINDINGS
- toxicokinetic study: concentrations of behenyl alcohol in the blood were measured on  day 1 and in weeks 13 and 26; maximum mean plasma concentration (Cmax) of behenyl alcohol occurred 1 hour after dosing in all males and most females; 24 hours after dosing plasma concentrations were below the limit of quantification  (<10ng/ml) at the 10 and 100 mg/kg dose levels while levels following  administration of 1000 mg/kg/day remained quantifiable on each sampling  day; Cmax in the top dose group ranged from 203.68 to 528.82 ng/ml throughout the duration of the study; statistically significant differences in area under the curve  (AUC24) were observed between males and females treated with 10 and 1000  mg/kg/day on day 1 and during week 13; the rate and extent of systemic  exposure to rats as shown by AUC24 and Cmax on day 1 and in weeks 13 and 26 increased with increasing dose level; increases were less than the proportionate dose increment and there was statistically significant evidence of non-proportionality on each sampling day.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a reliable study conducted according to a protocol very similar to OECD guideline 408, a repeated oral dose (26-week) NOAEL of 1000 mg/kg bw/day was determined in the rat. The study was performed in compliance with GLP. The result is a read across from 1-docosanol (CAS 661-19-8).