Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-Guideline Study, tested with the source substance CAS 112-85-6. In accordance to ECHA guidance document "Practical guide 6: How to report read-across and categories (May 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

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
Details on test material:
- Name of test material (as cited in study report): Docosanoic acid
- Physical state: white powder
- Analytical purity: 85.9%
- Lot/batch No.: 60805X
- Impurities (identity and concentrations): C14-C20 fatty acids: 10.9%, C24 fatty acids: 2.3 percent
- Storage condition of test material: at room temperature in the dark

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

Maternal developmental toxicity

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
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)

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.

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