Hexahydro-4,7-methano-1H-indenyl acrylate

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:

other: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

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)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Hexahydro-4,7-methano-1H-indenyl acrylate

EC Number:

235-697-2

EC Name:

Hexahydro-4,7-methano-1H-indenyl acrylate

Cas Number:

12542-30-2

Molecular formula:

C13 H16 O2

IUPAC Name:

2-Propenoic acid hexahydro-4,7-methano-1H-indenyl ester

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): Dihydrodicyclopentadienylacrylate
- Physical state: liquid/colorless, clear
- Analytical purity: 97.7 corr area% as a sum of four singel peaks. The main peak fo these four peaks has 91.3 corr area%
- Lot/batch No.: 110019P040

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany
- Age at study initiation: 11 - 13 weeks old
- Weight at study initiation: 314.3 - 345.7 g (male); 194.5 g - 220.7 g (female)
- Housing: housed individually, Makrolon type M II cages; During overnight matings, male and female mating partners were housed together in
Makrolon type M III cages. Pregnant animals and their litters were housed together until PND 4.
- Diet (e.g. ad libitum): ad libitum (Kliba maintenance diet mouse/rat "GLP" meal)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70 %
- 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:
The test substance solutions in corn oil were prepared at the beginning of the administration period and thereafter in intervals, which took into account the analytical results of the stability verification.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical verifications of the stability of the test substance in corn oil for a period of 7 days at room temperature were carried out prior to the start of the study.
Samples of the test substance solutions were sent to the analytical laboratory once at the beginning of the study for verification of the concentrations.

Details on mating procedure:

- M/F ratio per cage:1:1
- Length of cohabitation:overnight for a maximum of 2 weeks
- Proof of pregnancy: sperm in vaginal smear referred to as [day 0] of pregnancy

Duration of treatment / exposure:

The duration of treatment covered a 2-week pre-mating and a mating period in both sexes, 1 week post-mating in males, and the entire gestation period as well as approximately 2 weeks of the lactation period.

Frequency of treatment:

daily

Duration of test:

49 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw
Basis:

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CLINICAL OBSERVATION:
Morbidity, pertinent behavioral changes and signs of overt toxicity. Abnormalities and changes were documented daily for each animal.
The parturition and lactation behavior of the dams was generally evaluated in the mornings in combination with the daily clinical inspection of the dams.

BODY WEIGHT:
Body weight of the male and female parental animals was determined once a week at the same time of the day (in the morning) until sacrifice.
The following exceptions are notable for the female animals:
• During the mating period the parental females were weighed on the day of positive evidence of sperm (GD 0) and on GD 7, 14 and 20.
• Females with litter were weighed on the day of parturition (PND 0) and on PND 4.

FOOD CONSUMPTION:
Food consumption was determined once a week for male and female parental animals:
• Food consumption was not determined after the 2nd premating week (male parental animals) and during the mating period (male and female F0 animals).
• Food consumption of the F0 females with evidence of sperm was determined on gestation days (GD) 0, 7, 14 and 20.
• Food consumption of F0 females, which gave birth to a litter was determined on PND 1 and 4.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of implantations: Yes

Fetal examinations:

All pups delivered from the F0 parents (F1 litter) were examined as soon as possible on the day of birth to determine the total number of pups, the sex and the number of liveborn and stillborn pups in each litter. At the same time, the pups were also being examined for macroscopically evident changes. Pups, which died before this initial examination, were defined as stillborn pups.

PUP VIABILITY/MORTALITY
In general, a check was made for any dead or moribund pups twice daily.

CLINICAL OBSERVATION
The live pups were examined daily for clinical symptoms.

BODY WEIGHT
The pups were weighed on the day ater birth (PND1) an on PND 4.

All pups with scheduled sacrifice on PND 4. All pups were examined externally and eviscerated; their organs were assessed macroscopically.

Statistics:

DUNNETT-test (twosided)
FISHER'S EXACT test
WILCOXON-test (onesided)
WILCOXON-test (twosided)
KRUSKAL-WALLIS test (two-sided)

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Details on maternal toxic effects:
CLINICAL EXAMINATIONS/ REPRODUCTIVE PERFORMANCE/ CLINICAL PATHOLOGY/ PATHOLOGY
1000, 300, and 100 mg/kg bw/d F0 PARENTAL ANIMALS

• No test substance-related adverse findings

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

NOAEL

Remarks:

general, systemic toxicity

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
No toxicologically-relevant developmental differences in the F1 generation were detected during this study. At all doses, the pups developed normally.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified