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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Docosanoic acid
EC Number:
204-010-8
EC Name:
Docosanoic acid
Cas Number:
112-85-6
IUPAC Name:
docosanoic acid
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Hino, Tokyo
- Age at study initiation: 8 weeks
- Weight at study initiation: 312.1-363.7 g males; 205.3-230.8 g females
- Housing: metal wire floor cages
- Diet (ad libitum): CE-2, CLEA Japan
- Water (ad libitum): tap water
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24±1 ºC
- Humidity (%): 50-65 %
- Air changes (per hr): 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Solutions prepared more frequently than once a week. Aliquots kept refrigerated in airtight conditions.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Insoluble in water
- Amount of vehicle (if gavage): 5 mL/kg bw
- Lot/batch no. (if required): V6H2050
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: up to two weeks
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Further mating after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually
Duration of treatment / exposure:
Exposure duration:
Males, 42 days
Females, from 14 days prior to mating to day 3 of lactation
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
vehicle
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
13 animals per sex and dose.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on preliminary result in a 14 day-repeated dose toxicity study, where no signs of toxicity were found

Examinations

Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once a day

BODY WEIGHT: Yes
- Time schedule for examinations: once a week

FOOD CONSUMPTION:
- Time schedule for examinations: once a week

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 42 days, prior to sacrifice
- Anaesthetic used for blood collection: Yes (identity): pentobarbital sodium
- Animals fasted: 18 - 24 hours before sacrifice
- How many animals: all surviving animals
- Parameters checked: Red blood cell count (RBC), white blood cell count (WBC), platlet count, hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV),mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), differentiation of leukocytes (band neutrophil, segmented neutrophil, eosinophil, basophil, monocyte, lymphocyte).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 42 days, prior to sacrifice
- Animals fasted: 18 - 24 hours before sacrifice
- How many animals: all surviving animals
- Parameters checked: total protein, albumin, A/G, blood urea nitrogen (BUN), creatinine, glucose, total cholesterol, total bilirubin, triglyceride, sodium (Na), potassium (K), chloride (Cl), calcium (Ca), inorganic phosphorus (IP), alkaline phosphatase (ALP), GPT, GOT, γ-GTP.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
Clinical observations (once a day), body weight on day 0 and 4 of lactation.

DEVELOPMENTAL PARAMETERS:
Day 0 of lactation: number of pups born, delivery index, number of live pups, birth index, live birth index, sex ratio.
Day 4 of lactation: number of live pups, viability index, sex ratio.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals, on the day after the administration period.
- Maternal animals: All surviving animals, on the day 4 of lactation. Females with no delivery were killed 4 days after the delivery expected date. Females with no copulation were sacrificed at the termination of mating period.

GROSS NECROPSY
- Organs examined: Males: tyroid gland, thymus, lung, liver, spleen. Females: thymus, spleen, adreanl gland, kidney.
- Organs weights: Males: heart, liver, kidneys, thymus, testes, epididymides. Females: heart, liver, kideny and thymus.

HISTOPATHOLOGY / ORGAN WEIGHTS
- Organs examined: Males: brain, heart, liver, spleen, thymus, kidney, urinary bladder, testis, epididymis. Females: brain, heart, liver, thymus, kidney, urinary bladder, adrenal gland, ovary.

REPRODUCTION PERFORMANCE:
Number of mated pairs, number of copulated pairs, copulation index, number of pregnant females, fertility index, pairing days until copulation and frequency of vaginal estrus.

DEVELOPMENTAL PARAMETERS:
Number of pregnant females, number of pregnant females with live pups, gestation index, gestation length in days, number of corporea lutea, number of implantation sites, implantation index.
Postmortem examinations (offspring):
GROSS NECROPSY
- Full macroscopic examinations on all of pups (external and visceral observation).
Statistics:
Dunnett’s or Scheffe’s test for continuous data, Chi square test for copulated index and fertility index, and Mann-Whitney U test or Fisher’s test for histopathological examination data.
Reproductive indices:
Copulation index, fertility index, implantation index, gestation index.
Offspring viability indices:
Delivery index, birth index, live birth index, viability index, sex ratio.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No abnormalities in general condition were observed in any of the treated groups.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No deaths were observed in any of the treated groups.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no changes related to the dosing of compound in body weight gain.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no changes related to the dosing of compound in food consumption.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No adverse effects were found in hematological examinations.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No adverse effects were found in biochemical examinations.
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
At autopsy following treatment for 42 days in males and on postpartum day 4 in females, no adverse effects were found in the histopathological examinations.
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
The compound showed no adverse effects on copulation or fertility.
No changes related to the dosing of compound were observed in gestation length, gestation index, delivery and lactation.
The compound did not demonstrate any adverse effects on the sex ratio of pups.

Effect levels (P0)

Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment-related effects observed at the highest dose

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
The compound did not demonstrate any adverse effects on viability of pups.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The compound did not demonstrate any adverse effects on body weights of pups.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No morphological abnormalities in pups were observed in any of the treated groups.
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
The compound did not demonstrate any adverse effects on the sex ratio of pups.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment-related effects observed at the highest dose.

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
The NOEL of docosanoic acid for maternal and reproductive toxicity was 1000 mg/kg/day both in males and females.
Executive summary:

A combined repeated dose and reproduction/developmental screening was performed on docosanoic acid according to OECD Guideline 422. 13 rats per sex and per dose were exposed to 0 (vehicle), 100, 300 and 1000 mg/kg bw/day, males for 42 days and females from 14 days prior to mating to day 3 of lactation. The compound showed no adverse effects on copulation or fertility. No changes related to the dosing of compound were observed in gestation length, gestation index, delivery and lactation. The compound did not demonstrate any adverse effects on the sex ratio, body weights or viability of pups. Also, no morphological abnormalities in pups were observed in any of the treated groups. Based on these results the NOEL for maternal and reproductive toxicity was determined to be 1000 mg/kg bw/day for both males and females.