Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

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: Read across from dodecanol (CAS 112-53-8). Comparable to guideline study (draft guideline) with acceptable restrictions.
Cross-reference
Reason / purpose:
reference to same study

Data source

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

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Draft OECD 422 Combined Repeat dose and Reproductive/Developmental Toxicity Screening Test.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1-Dodecanol
- 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.: 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:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Moellegard breeding centre
- Age at study initiation: F 8 weeks, M 7 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 2/cage, steel wire cages type 3 (up to day 20 of gestation); macrolon cages type 3 (from day 20 of gestation)
- Diet (e.g. ad libitum): IT chow 101, presumably ad libitum
- Water (e.g. ad libitum): acidified tapwater, ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2
- Humidity (%): 55 +- 10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

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): no data
- Mixing appropriate amounts with (Type of food): IT chow 101
- Storage temperature of food:no data
- Preparation procedure: Diet preparation involved first mixing an aqueous dodecanol solution with the barley component, which varied for each dose level. The other components of the diet were then added.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug recorded during the morning referred to as day 1 of pregnancy; vaginal plug recorded at lunch time or during the afternoon referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male for up to 8 days
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): in steel wire cages type 3 until day 20 of pregnancy, placed in macrolon cages type 3 thereafter
- Any other deviations from standard protocol: none
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Exposure period: Males 41-44 days , females up to 54 days
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: Males 41-44 days, females up to 54 days
Frequency of treatment:
continuous in diet
Details on study schedule:
- One-generation study (only parental animals mated)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1500, 7500 & 30,000 ppm (approx 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: preliminary test via a dermal route
- Rationale for animal assignment (if not random): 2 days prior to the start of dosing, animals randomised into four groups with same mean body weight
Positive control:
none

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: mortality

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: males once per week; females premating once per week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption in g body weight gain/kg food per week calculated from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
Oestrous cyclicity (parental animals):
no data (exposure was for 14 days premating covering at least 2 oestrous cycles; ovaries were weighed and examined histopathologically at necropsy)
Sperm parameters (parental animals):
Parameters examined in male parental generation: testis weight, epididymis weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no (one-generation screening study)

PARAMETERS EXAMINED
- The following parameters were examined in F1 offspring: number of pups on days 1, 4 and 5; sex of pups on day 5; postnatal mortality from day 1 to day 4; weight gain from day 1 to day 4; mean body weight of male and female pups on day 5; presence of gross abnormalities on day 5

GROSS EXAMINATION OF DEAD PUPS: yes, on day 5, for external abnormalities including the head (especially the eyes and cleft palate), abdomen and thoracic cavity examined internally for malformations; possible cause of death was not determined for pups born or found dead
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after 41-44 days of dosing
- Maternal animals: All surviving animals on day 5 after birth

ORGAN WEIGHT: males - liver, kidneys, thymus, testes, epididymides; females - liver, kidneys, thymus

ORGANS FIXED IN FORMALIN: males - liver, kidneys, adrenals, brain, heart, spleen, thymus, organs with pathological changes, testes and epididymides fixed in Bouin's solution; females - liver, kidneys, adrenals, brain, heart, spleen, ovaries, thymus, other organs with observed pathological changes

HISTOPATHOLOGY: Yes, control and top dose group, all fixed organs except thymus
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age: not applicable (1-generation study)
Statistics:
Using the SAS-stat program; analysis of variance; all statistically significant findings further evaluated by Dunnett's t-test; chi-squared test for pregancy rate
Reproductive indices:
pregnancy rate; length of gestation; numbers of corpora lutea, implantations, resorptions and pups at birth
Offspring viability indices:
number of pups at birth and on days 4 and 5, number of pups per litter, pup deaths between days 1 and 4

Results and discussion

Results: P0 (first parental animals)

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
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY
- Mortality and time to death: None
- Clinical signs: None reported

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: No differences between treated and controls of either sex.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Males: 102.4, 530.8 and 2046.4 mg/kg bw/day (mean of values reported for 2 weeks prior to mating and 3 weeks after mating)
Females: 130.5, 657.5 and 2870.5 mg/kg bw/day (mean of values reported 2 weeks prior to mating)

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
no data

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
no data

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- no statistically significant effects on pregnancy rate, length of gestation or numbers of corpora lutea, implantations, resorptions or pups at birth
- pregnancy rate was reduced in treated groups: 0 mg/kg bw/day 92%, 100 & 500 mg/kg bw/day 83%, 2000 mg/kg/day 75%; these were within the normal historical control range according to the investigators (actual historical control data not presented); lack of statistical significance confirmed using chi-squared test
- mean length of gestation: 23 days in all groups
- mean number of corpora lutea: 14 in all groups
- mean number of implantations: 13 in controls, 14 in all treated groups
- no resorptions in any group

ORGAN WEIGHTS (PARENTAL ANIMALS) (see table 2)
- There were no dose related changes in organ weights, including the testes, epididymides and ovaries; in males only there was a reduction in relative and absolute liver weights at the low dose level and a reduction in relative liver weight at mid doses, the top dose was comparable to controls.

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.

OTHER (PARENTAL ANIMALS)
- Haematology and clinical chemistry data for parental males (reported elsewhere)

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Dietary concentrations of 1500, 7500 and 30000 ppm provided nominal dose levels of 100, 500 and 2000 mg/kg bw/day

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
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)
- no statistically significant effect
- litter size mean on day 1: controls 13.25, low dose 13.27, mid dose 13.2, high dose 13.33. 

CLINICAL SIGNS (OFFSPRING)
- no effects

BODY WEIGHT (OFFSPRING)
- no statistically significant effects
- mean litter weights at day 1 were 75, 75, 71 and 77 g and at day 4 106, 107, 101 and 104 g for control, low, mid and high dose respectively

SEXUAL MATURATION (OFFSPRING)
- not applicable (1-generation screening study)

ORGAN WEIGHTS (OFFSPRING)
- not applicable (1-generation screening study)

GROSS PATHOLOGY (OFFSPRING)
- no effects

HISTOPATHOLOGY (OFFSPRING)
- no data

OTHER FINDINGS (OFFSPRING)
- no statistically significant effects on pup body weight on day 5

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: Dietary concentrations of 1500, 7500 and 30000 ppm for parental animals provided nominal dose levels of 100, 500 and 2000 mg/kg bw/day

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Read across from dodecanol (CAS 112-53-8) was obtained in a reliable study conducted to the draft OECD guideline 422. A parental NOAEL of 2000 mg/kg bw/day (highest dose tested) was determined for male and female rats. No adverse effects were observed on reproductive parameters and the NOAEL for reproductive and developmental effects was also 2000 mg/kg bw/day. The study was performed in compliance with GLP.