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Toxicological information

Toxicity to reproduction

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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: Study reasonably well documented, meets generally accepted scientific principles, acceptable for assessment. The result is a read across 1-hexanol.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1966

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, but including reproductive organs
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Alfol 6 (tradename)
- Substance type: colourless liquid with "viscosity of fine household oil"
- Physical state: liquid
- 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.: 601-6544 and 601-6545 from 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
- Other:
- Specific gravity: 0.823

Test animals

Species:
rat
Strain:
other: albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: no data but "young"
- Weight at study initiation: males 103.6 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:
13 weeks
Frequency of treatment:
continuous in diet
Details on study schedule:
no mating - screening study
Doses / concentrations
Remarks:
Doses / Concentrations:
0.25%, 0.50%, 1.0-6.0% w/w
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
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 (but 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
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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

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 low dose group died during week 9; cause of death was said to be unrelated to treatment
- occasional bloody encrustations of the eyes and nose
- otherwise no effects

BODY WEIGHT
- no effects

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- food consumption 87.8% of controls in females in high dose group during week 13
- otherwise no effects

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

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

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- not mated - screening study

ORGAN WEIGHTS (PARENTAL ANIMALS)
- some statistically significant effects (but see 'Remarks on results')

GROSS PATHOLOGY (PARENTAL ANIMALS)
- no effects

HISTOPATHOLOGY (PARENTAL ANIMALS)
- no effects

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 127 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
1 243 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: see 'Remark'

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:
no effects observed

Details on results (F1)

no offspring - no mating - screening study

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX (means calculated from individual weekly dietary intake data)
0.25% M 182 mg/kg/day; F 216 mg/kg/day
0.5% M 374 mg/kg/day; F 427 mg/kg/day
1% M 1127 mg/kg/day; F 1243 mg/kg/day

Terminal organ weights (including gonads) were sporadically different from controls at different times. The original study report indicated significant differences between control and treated testes weights at all dose levels and indicated that a chi-squared test had been used to analyse the data. Weinberg Associates reanalysed the data using a Tukey test and found that male gonad weights were not significantly different from the controls at any test concentration. There were no histopathological changes in any organs examined including the gonads. The NOAEL for reproductive endpoints is therefore the highest dose level administered (1243 mg/kg bw for females and 1127 mg/kg/day for males).

Applicant's summary and conclusion

Conclusions:
In a reliable screening study, a repeated oral dose NOAEL of 1243 mg/kg/day in females and 1127 mg/kg/day for males was determined for effects on reproductive organs in the rat. The result was read across from 1-hexanol.