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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:
other: GLP - Guideline study
Justification for type of information:
The carbon chain length of this acid and that of the Category member 2-decyltetradecanoic acid, is very similar. Both substances are long chain acids which have no other functional group. Based on the similar structure and therefore similar expected toxicokinetic it is likely that the test result of this substance is also valid for the Category member (Please see attached Category Approach.)
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: bulk
Details on test material:
- Name of test material (as cited in study report): docosanoic acid
- Physical state: white solid
- Analytical purity: 85.9 %
- Lot/batch No.: 60805X
- Storage condition of test material: The test substance was kept under room temperature before use.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Hino, Japan
- Age at study initiation: 8 weeks
- Weight at study initiation: male: 312.1 - 363.7 g; female: 205.3 - 230.8 g
- 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
- Humidity (%): 50 - 65
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
prepared more frequently than once a week; aliquots were kept by each concentration refrigerated in airtight conditions

VEHICLE
- Justification for use and choice of vehicle (if other than water): due to insolubility in water
- Amount of vehicle (if gavage): 5 mL/kg bw
- Lot/batch no. (if required): V6H2050
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- 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:
- males: 42 days
- females: from 14 days prior to mating to day 3 of lactation
Frequency of treatment:
once daily
Duration of test:
from 14 days prior to mating to day 3 of lactation
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300, 1000 mg/kg bw /d
Basis:
nominal conc.
No. of animals per sex per dose:
13 in each group
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

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once a day
- Cage side observations checked in table were not included.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: males: days 1, 8, 15, 22, 29, 36, 42; pregnancy females: premating days 1, 8, 15; pregnancy days: 0, 7, 14, 20; lactation days: 0, 4; non pregnancy females: day 1, 8, 15, 22, 25

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: No

POST-MORTEM EXAMINATIONS: Yes
- Organs examined: brain, liver, spleen, thymus, kidney, adrenal, bladder, heart, ovary, uterus
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: No
- Head examinations: No
Statistics:
Yates test, Mann-Whitney U test, Fisher exact test, Bartlett test, Dunnett test, Scheffe test, Kruskal-Wallis test
Indices:
Reproductive indices
- Copulation index = (number of copulated pairs / number of pairs mated) x 100
- Fertility index = (number of pregnant animals / number of copulated pairs) x 100
- Gestation index = (number of pregnant females with pups alive / number of pregnant females) x 100
- Implantation index = (number of implantation sites / number of corpora lutea) x 100

Offspring viability indices
- Delivery index = (number of pups born / number of implantation sites) x 100
- Birth index = (number of pups alive on day 0 / number of implantation sites) x 100
- Live birth index = (number of pups alive on day 0 / number of pups born) x 100
- Sex ratio = (number of males pups alive on day 0 / number of female pups alive on day 0) x 100
- Viability index = (number of pups alive on day 4 / number of pups alive on day 0) x 100

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
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
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- Females: no deaths were observed in any treatment group

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- Females: no significant changes in body weight were noted and there were no changes related to the dosing of compound in body weight gain and food consumption. A significant decrease (p<0.01) compared to control was observed during lactation in 100 mg/kg group. However, since no other changes in food consumptio was noted in 300 mg/kg and 1000 mg/kg, it was considered not to be related to the dosing of compound.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There were no significant differences in number of corpora lutea, implantation rate, number of implantations and all other reproductive parameters in all treated groups compared to the control group

ORGAN WEIGHTS (PARENTAL ANIMALS)
- Females: kidney weight was significantly reduced in the 300 mg/kg bw group. No other weight changes were noted. Thus, this finding lacks a dose-dependency and was regarded as incidental.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Females:
- Brain: one animal of the high-dose group showed abnormal mineral deposition in the thalamus
- Liver: focal necrosis and fibrosis was found in one animal of the control group, while one animal of the high-dose group showed only focal necrosis
- Spleen: brown pigmentation and extramedullary haematopeiosis was found in animals of the control and the high-dose group, but no varying degrees of frequency was observed
- Thymus: atrophy and bleeding was observed in animals of both groups, control and high-dose group, respectively
- Kidney: basophilic tubules of the cortex and a dilatation of the renal pelvis was seen in the control and high-dose group
- Adrenal gland: cortical necrosis was observed in one animal of the control group
- Heart: no abnormal findings noted
- Bladder: no abnormal findings noted

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects. Remark: no adverse substance -related findings were noted

Details on embryotoxic / teratogenic effects:
VIABILITY (OFFSPRING)
No change in numbers of birth, birth rate, infant live birth rate, infant survival and birth rates at day 4 was found in all dose groups when compared to the values of the control group.

BODY WEIGHT (OFFSPRING)
No difference in body weight of pups of the dose groups and the control group was found.

GROSS PATHOLOGY (OFFSPRING)
No morphological abnormalities were found in all groups.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1. Summary of development up of pups from dams treated orally with docosanoic acid in the combined repeat dose and reproductive/developmental toxicity screening test: Mean ± S.D. (N)

Dose group (mg/kg)

0

100

300

1000

Number of pregnant females

13

12

12

13

Number of pregnant females with live pups

13

12

12

13

Gestation index

100

100

100

100

Gestation length in days

22.2 ± 0.4 (13)

22.4 ± 0.5 (12)

22.3 ± 0.5 (12)

22.2 ± 0.4 (13)

Number of corpora lutea

16.6 ± 1.6 (13)

16.7 ± 1.8 (12)

16.8 ± 2.3 (12)

16.2 ± 1.5 (13)

Number of implantation sites

16.1 ± 1.5 (13)

15.8 ± 2.1 (12)

16.0 ±1.5 (12)

15.2 ± 3.1 (13)

Implantation index

96.9 ± 5.1 (13)

94.8 ± 7.1 (12)

96.1 ± 6.0 (12)

93.1 ± 15.2 (13)

Day 0 of lactation

 

 

 

 

Number of pups born

15.2 ± 1.6 (13)

14.8 ± 2.2 (12)

15.2 ± 1.5 (12)

14.3 ± 2.7 (13)

Delivery index

94.5±8.0 (13)

93.5±3.9 (12)

94.9±4.3 (12)

94.9±6.2 (13)

Number of live pups

14.9±1.6 (13)

14.3±2.2 (12)

15.1±1.6 (12)

14.1±2.7 (13)

Birth index

93.1±8.8 (13)

90.7±8.7 (12)

94.3±5.1 (12)

93.5±7.2 (13)

Live birth index

98.5±2.8 (13)

97.0±8.5 (12)

99.4±2.2 (12)

98.5±4.0 (13)

Sex ration on day 0

50.0±11.3 (13)

46.7±9.8 (12)

54.8±12.3 (12)

48.9±13.4(13)

Day 4 of lactation

 

 

 

 

Number of live pups

14.7±1.4 (13)

13.0±4.7 (12)

15.1±1.6 (12)

14.1±2.7 (13)

Viability index

98.6±2.7 (13)

89.4±28.8 (12)

100.0±0.0 (12)

100.0±0.0 (13)

Sex ration on day 4

49.8±11.5 (13)

46.3±10.3 (11)

54.8±12.3 (12)

48.9±13.4(13)

Applicant's summary and conclusion