2-decyltetradecanoic acid

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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 for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Materials and methods

Test guideline

Qualifier:

according to guideline

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

Test material information

Constituent 1

Reference substance name:

Docosanoic acid

EC Number:

204-010-8

EC Name:

Docosanoic acid

Cas Number:

112-85-6

Molecular formula:

C22H44O2

IUPAC Name:

docosanoic acid

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 or test system 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)

1

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

2

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)