Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2006
Report Date:
2006

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Rat Wistar aged 8 (males) - 9 (females) weeks at start of exposure period. 12M+12F/group

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
- Type of exposure: Dietary
- Duration of test/exposure: males 41-44 d, females approx. 54 d
- Treatment: Control group and treatment
- Vehicle: Diet
- Concentration in vehicle: 0, 1500, 7500 & 30,000 ppm
Details on mating procedure:
14 d premating exposure, then 1M+1F caged together. Inspection for vaginal plugs thrice daily. If mating did not occur after 14 d cohabitation the female was placed with another male for 8 d.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Actual dose received: 0, 100, 500 and 2000 mg/kg bw/day
Duration of treatment / exposure:
Males 41 - 44 d
Females up to 54 d
Frequency of treatment:
continuous in diet
Doses / concentrationsopen allclose all
Remarks:
0, 1500, 7500 & 30,000 ppm test substance in diet
Remarks:
Actual dose received: 0, 100, 500, 2000 mg/kg bw/day
No. of animals per sex per dose:
12 animals per sex per dose
Control animals:
yes

Examinations

Parental animals: Observations and examinations:
Body weight, weight gain, food consumption, and food efficiency were recorded.
Oestrous cyclicity (parental animals):
Exposure was for 14 d premating covering at least 2 oestrous cycles. Ovaries were weighed and examined histopathologically at section (21 d after birth).
Sperm parameters (parental animals):
Exposure 14 d premating, no specific sperm analyses carried out, the testes & epididymis were weighed and examined histopathologically.
Postmortem examinations (parental animals):
- Organ weights P: liver, kidneys, thymus, testis, and epididymis.
- Histopathology P: liver, kidneys, adrenals, brain, heart, spleen, ovaries, thymus, testes, epididymides and any organs showing abnormality on macroscopic examination were fixed. The above tissues from all controls and top dose treated rats (except the thymus) plus abnormalities were examined.
- Macroscopic P: Full macroscopic examination.
Statistics:
Analysis of variance followed if significant differences were established by Dunnett’s T-test to assess possible intergroup differences. For pregnancy rate a Qui2-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:
Offspring (and dams) were sacrificed on post-natal Day 5 and the pups were weighed and examined for external malformations than sexed and examined for internal malformations.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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
Haematological findings:
no effects observed
Description (incidence and severity):
None considered of biological significance
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
None considered of biological significance
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no treatment related histopathological changes including no effects in the testes and ovaries.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Description (incidence and severity):
Not reported
Reproductive function: sperm measures:
not specified
Description (incidence and severity):
Not reported
Reproductive performance:
no effects observed
Description (incidence and severity):
There was no statistically significant difference in pregnancy rates although they were reduced in treated groups C 92%, 100 & 500 mg/kg bw/day 83%, 2000 mg/kg bw/day 75% these were within the normal historical control range according to the authors (actual historical control data not presented).
- Fertility index: Not reported
- Precoital interval: Not reported
- Duration of gestation: Comparable in treated and control dams (23 d in all groups).
- Gestation index: Not reported
- Changes in lactation: Not reported
- Number of implantations: No significant differences in the numbers of implantations between treated and control groups (mean 13 in control group, 14 in each treated group). There were no resorptions.
- Number of corpora lutea: No significant differences between treated and control groups (mean 14 in test and controls).
- Ovarian primordial follicle counts: Not reported

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 2 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed on reproductive parameters

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
None considered of biological significance
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
None considered of biological significance
Histopathological findings:
no effects observed
Description (incidence and severity):
There were no treatment related histopathological changes including no effects in the testes and ovaries.
Other effects:
no effects observed
Description (incidence and severity):
- Litter size and weights: No effect of treatment. Litter size mean Controls 13.25, low dose 13.27, mid dose 13.2, high dose 13.33. Mean litter weights at day 1 were 75, 75, 71 and 77 gm and at day 4 106, 107, 101 and 104 gm for control, low, mid and high dose respectively. No statistical significance.
- Sex and sex ratios: No treatment related effects.
- Post natal survival until Day 5: Similar in treated and control groups.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 2 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed at highest tested dose

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Under the study conditions, the test substance NOAEL for reproductive and developmental effects was determined to be 2000 mg/kg/day.
Executive summary:

A study was conducted to determine the toxicity to reproduction of the test substance, 1-dodecanol (purity not specified) according to the method similar to the OECD Guideline 422, in compliance with GLP. The test substance at 0, 1500, 7500 and 30000 ppm was administered as dietary feed to male Wistar rats up to 41 to 44 d, whereas to female Wistar rats up to 54 d (12 animals per sex per dose). Actual received doses were calculated to 0, 100, 500 and 2000 mg/kg bw/day. After 14 d premating exposure, one male and one female were caged together. Inspection for vaginal plugs were thrice daily. If mating did not occur after 14 d cohabitation the female was placed with another male for 8 d. Body weight, weight gain, food consumption and food efficiency were examined. Ovaries, testes and epididymis were weighed and examined histopathologically. Pregnancy rate, length of gestation, implantations, corpora lutea and resorptions were recorded. Offspring (and dams) were sacrificed on post-natal Day 5 and the pups were weighed and examined for external malformations than sexed and examined for internal malformations. Organ weights were examined for liver, kidneys, thymus, testis, and epididymis. Liver, kidneys, adrenals, brain, heart, spleen, ovaries, thymus, testes, epididymides and any organs showing abnormality on macroscopic examination were fixed. The above tissues from all controls and top dose treated rats (except the thymus) plus abnormalities were examined. Haematological and biochemical parameters were measured. There were no treatment related effects observed on food/water consumption, body weight, organ weights, duration of gestation, biochemistry and haematological parameters. There was no statistically significant difference in pregnancy rates although they were reduced, 92% in control, 83% in 100 & 500 mg/kg bw, 75% in 2000 mg/kg bw/day, these were within the normal historical control range according to the study authors (actual historical control data not presented). There were no changes attributable to exposure to the test substance noted in gross pathology and histopathology. No significant differences in the numbers of implantations between treated and control groups (mean 13 in control group, 14 in each treated group) were noted. There were no resorptions, also no significant differences between treated and control groups (mean 14 in test and controls) were noted for number of corpora lutea. No statistical significant difference noted in litter size and weights, sex and sex ratios and post-natal survival until Day 5. No adverse effects were observed on reproductive parameters and the NOAEL for reproductive and developmental effects can be considered as 2000 mg/kg/day. Under the study conditions, the test substance NOAEL for reproductive and developmental effects was determined to be 2000 mg/kg/day (OECD SIDS, 2006).