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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
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:
2004
Report date:
2004

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Remarks:
conducted under the Cuban Good Laboratory Practices (GLP) guidelines
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Octacosanoic acid
EC Number:
208-041-8
EC Name:
Octacosanoic acid
Cas Number:
506-48-9
Molecular formula:
C28H56O2
IUPAC Name:
octacosanoic acid
Details on test material:
D-003 is a mixture of long-chain fatty acids isolated and purified from sugar cane wax whose major component is 1-octacosanoic acid, followed by 1-triacontanoic, 1-dotriacontanoic, and 1-tetratriacontanoic acids. Other acids are present at lower concentrations

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: CENPALAB (La Habana, Cuba)
- Age at study initiation: no data
- Weight at study initiation: 2.5-3.5 kg
- Housing: individually
- Diet: CENPALAB-certified Rabbit Lab chow ad libitum
- Water: tap water ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 50%
- Air changes (per hr): not indicate
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: suspension of water with 1% Acacia Gum
Remarks:
maximum dosing volume 5 mL/kg bw
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing suspensions were prepared fresh weekly and refrigerated after corroborating their stability in such
conditions.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: no data
- Proof of mating: indicated as copulation observed
Duration of treatment / exposure:
days 6 through 18 of gestation
Frequency of treatment:
daily
Duration of test:
until day 29 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
27 mated females per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: 1000 mg/kg bw is considered an acceptable upper limit dose by ICH/OECD guidelines.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes daily

BODY WEIGHT: Yes on regular basis and at least on day 0, 6, 18 and 29

FOOD CONSUMPTION Yes, on regular basis

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: not specified
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
All fetuses: body weight, sex

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter(examined by freehand coronal sectioning)
Statistics:
Maternal initial body weight, maternal weight gain, fetal body weights were analyzed using a parametric analysis of variance followed by Tukey's multiple comparison test. Data on numbers of corpora lutea, implantations, resorptions, dead and alive fetuses, sex ratio and litter size were analyzed by the Kruskal–Wallis (nonparametric) test followed by Mann–Whitney U-test to determine which treatment groups differed from the control. The incidence of fetuses and litters with malformations was compared to that of the control group by using Chi square and Fischer's exact probability test, respectively.
Trend analysis via ANOVA, Jonckheere's test and the Cochran–Armitage test.
Indices:
no data
Historical control data:
NA

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
1 female at 500 mg/kg bw and 1 female at 1000 mg/kg bw
Body weight and weight changes:
no effects observed
Description (incidence and severity):
see table
Food consumption and compound intake (if feeding study):
no effects observed
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
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
statement in the publication
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
in both treament groups and in controls 2 abortions/group were reported (see table)
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Preimplantation loss ( [(Corpora lutea minus implant sites)/corpora lutea] x100): 24, 13 and 11 at 0, 500 and 1000 mg/kg bw
Postimplantation loss ([(Implant sites minus viable fetuses)/implant sites] x 100): 14, 23 and 22 at 0, 500 and 1000 mg/kg bw
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
total resorptions : 2, 1 and 1 at 0, 500 and 1000 mg/kg bw
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
Early 0.3 ± 0.6, 0.8 ± 1.5 and 0.5 ± 0.5 at 0, 500 and 1000 mg/kg bw
Late 0.05 ± 0.2, 0.05 ± 0.2 and 0.2 ± 0.5 at 0, 500 and 1000 mg/kg bw
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
Dead fetuses 0.2 ± 1.1, 0 and 0.2 ± 0.7 at 0, 500 and 1000 mg/kg bw
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
pregnancy rate: 23/27, 21/27 and 21/27 at 0, 500 and 1000 mg/kg bw

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: absence of effects

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
fetal body weight (mean/litter) 35.0 ± 5.5, 36.8 ± 5.9 and 33.8 ± 8.7 g at 0, 500 and 1000 mg/kg bw
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Live fetuses 4.3 ± 1.8, 4.2 ± 1.5 and 4.8 ± 2.2 at 0, 500 and 1000 mg/kg bw
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratio (M/F) 44/46, 44/35 and 43/48 at 0, 500 and 1000 mg/kg bw
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
see table
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
delayed ossification in controls and in both treatment groups (see table)
Visceral malformations:
no effects observed
Description (incidence and severity):
see table

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of adverse effects

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
The substance does not induce any developmental or teratogenic effects in rabbits.The NOAEL is 1000 mg/kg bw
Executive summary:

Pregnant New Zealand rabbits were given D-003 as oral doses of 500 and 1000 mg/kg/day on days 6 through 18 of gestation without any evidence of embryotoxicity or teratogenicity. The no-observed-effect dose in these two experimental studies was 1000 mg/kg/day. After assessment of the potential of high doses of D-003 to act on developing embryo, no evidence supports the conclusion that D-003 is a developmental toxicant/teratogen.