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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (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: Comparable to guideline study (draft guideline) with acceptable restrictions. The study is read across from octadecan-1-ol (CAS 112-92-5).
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Principles of method if other than guideline:
Conducted according to Draft OECD guideline 422 Combined repeated dose and reproductive/developmental toxicity screening test
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1-ocatadecanol
- Substance type: no data
- Physical state: no data
- Analytical purity: 99%
- 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.: L5751
- 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:
Wistar
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Moellegard Breeding Centre
- Age at study initiation: 8 (males) and 7 (females) weeks
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: 2 rats/cage for acclimatization period then individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±10
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): fluorescent light was on from 8 pm to 8 am

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Diet preparation involved first mixing the octadecanol with the barley component, the proportion of which varied for each dose level. The other components of the diet were then added.
- Rate of preparation of diet (frequency): not specified
- Mixing appropriate amounts with (Type of food): IT chow 101 diet
- Storage temperature of food: not specified
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to 22 days
- Proof of pregnancy: vaginal plug referred to as day 0 or, if the plug was recorded during the morning, day 1 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged: individually in steel wire cages type 3 until day 20 in pregnancy where the pregnant females were placed in macrolon cages type 3.
- Any other deviations from standard protocol: none
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Exposure period: males 45 days, females up to 54 days
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: males 45 days, females up to 54 days
Frequency of treatment:
continuous in diet
Details on study schedule:
- Age at mating of the mated animals in the study: 10 (males) and 9 (females) weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1500, 7500 or 30,000 ppm (ca 0, 100, 500, 2000 mg/kg/bw/day)
Basis:
nominal in diet
No. of animals per sex per dose:
12
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: Doses chosen from the results of a preliminary test.
- Rationale for animal assignment (if not random): Randomized into 4 groups with the same mean body weight
Positive control:
none

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: not specified

BODY WEIGHT: Yes
- Time schedule for examinations: During the experiment the males were weighed once/week. The females were weighed during the premating period and during pregnancy once/week. Pup litter weight was determined on days 1 and 4 after birth.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OTHER: haematology and clinical biochemistry conducted in the males
Oestrous cyclicity (parental animals):
Exposure was for 14 days premating covering at least 2 oestrous cycles. Ovaries were weighed and examined histopathologically at section (5 days after birth).
Sperm parameters (parental animals):
Parameters examined in male parental generation: other: Exposure 14 days premating, no specific sperm analyses carried out, the testes & epididymes were weighed and examined histopathologically.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, postnatal mortality, presence of gross anomalies, weight gain, other: examined for internal malformations.

GROSS EXAMINATION OF DEAD PUPS:
no
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals sacrificed after 45 days of dosing
- Maternal animals: All surviving animals sacrificed on postnatal day 5

GROSS NECROPSY
Gross necropsy consisted of full macroscopic examination.

HISTOPATHOLOGY / ORGAN WEIGHTS
The liver, kidneys, thymus, testes and epididymides were weighed; the liver, kidneys, adrenals, brain, heart, spleen, ovaries, thymus, testes, epididymides and any organs showing abnormality on macroscopic examination were fixed and the tissues from all controls and top dose treated rats (except the thymus) plus abnormalities were examined.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 5 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
Gross necropsy consisted of external malformations including the head (especially eyes and cleft palate). Animals were then opened to the abdomen and thoracic cavity for a study of malformations of the internal organs.

HISTOPATHOLOGY / ORGAN WEIGHTS
No histopathology or organ weights measured.
Statistics:
Analysis of variance followed if significant differences were established by Dunnetts t-test to assess possible intergroup differences. For pregnancy rate a Chi-squared test was carried out to confirm lack of significance.
Reproductive indices:
Pregnancy rate, length of gestation, implantations, corpora lutea and resorptions were recorded.
Offspring viability indices:
none

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not examined
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:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): None reported

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): No treatment related effects

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): Not reported

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): Not reported

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): Not reported

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): There was no statistically significant difference in pregnancy rates (confirmed using a Chi-squared test) although they were reduced in treated groups C 92%, 100 & 500 mg/kg 75%, 2000 mg/kg/day 67% these were within the normal historical control range according to the authors (actual historical control data not presented).

ORGAN WEIGHTS (PARENTAL ANIMALS): There were no statistically significant dose related changes in organ weights including the testes, epididymides and ovaries.

GROSS PATHOLOGY (PARENTAL ANIMALS): There were no changes attributable to exposure to the test compound.

HISTOPATHOLOGY (PARENTAL ANIMALS): There were no treatment related histopathological changes including no effects in the testes and ovaries.

OTHER FINDINGS (PARENTAL ANIMALS): Duration of gestation was comparable in treated and control dams (mean 22 days for all groups) and no clinical biochemical findings, examined in the males only, were considered of biological significance. Haematological examination in the males only showed changes in plasma free cholesterol, triglycerides and glucose although the significance is unclear. The changes were observed at all doses levels but were not dose related and may be related to differences in dietary composition. There was no significant differences in the numbers of implantations between treated and control groups (Mean 13 in controls and low-dose, 15 in mid- and high-dose groups); resorptions mean for controls and low-dose 0, for mid- and high-dose 1; no significant differences between treated and control groups with respect to number of corpora lutea (mean controls 13, low and mid dose 14, high dose 15).

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: mortality; body weight; food consumption and compound intake; gross pathology; organ weights; histopathology; number of implantation sites; duration of pregnancy; pregnancy index

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING): Not examined

CLINICAL SIGNS (OFFSPRING): Not examined

BODY WEIGHT (OFFSPRING): Litter weights day 1 mean 69, 61, 75 and 75 g; Day 4 mean 96, 84, 101 and 101 g for controls, low, mid and high dose respectively

SEXUAL MATURATION (OFFSPRING): No treatment related effects.

ORGAN WEIGHTS (OFFSPRING): Not examined

GROSS PATHOLOGY (OFFSPRING): No treatment related effects

HISTOPATHOLOGY (OFFSPRING): Not examined

OTHER FINDINGS (OFFSPRING): No effect of treatment on litter size (mean litter size 11.73, 10.0, 13.6 and 13.38 for controls, low, mid and high dose respectively) and post natal survival until day 5 was similar in the treated and control groups.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
2 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: litter size; litter weight; sex ratio; survival index

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a reliable study conducted according to draft OECD guideline 422, parental NOAEL was 2000 mg/kg bw/day and the NOAEL for reproductive and developmental effects can be considered as >2000 mg/kg bw/day (highest dose level). The result is read across from octadecan-1-ol (CAS 112-92-5).