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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to OECD guideline under GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Chemical name: mixture of N,N-Dimethydecan-1-amide and N,N-Dimethyloctan-1-amide
- Physical state: liquid
- Storage condition of test material: at room temperature in the dark
- Batch number: 903069
- Stable until November 17, 1990

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd. / Wolferstrasse 4 / CH 4414 Fullinsdorf / Switzerland
- Age at study initiation(pairing): 11 week minimum
- Weight at study initiation (day 0 post coitum): 179-226 g
- Housing: housed under standard laboratory conditions, housed individually in Macrolon cages(type-3) with wire mesh
tops and standardised granulated softwood bedding (Lignocel, Schill AG, CH 4132
Muttenz / Switzerland)
- Diet (e.g. ad libitum): ad libitum; Pelleted standard Kliba 343 rat/mouse maintenance diet ("Kliba", Klingentalmuehle AG, CH 4303 Kaiseraugst/Switzerland)
- Water (e.g. ad libitum):Tap water was available ad libitum
- Acclimation period: From July 27 to August 6, 1990 under test conditions, after veterinary examination

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 40-70%
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light):12 hours artificial fluorescent light/12 hours dark with background music (Schweizerischer Telefonrundspruch) played at a centrally defined low volume for at least 8 hours during the light period

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Bi-distilled water with 0.5% Cremophor (BASF)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The mixtures of the test article and vehicle were prepared daily before administration. The test substance was weighed into a glass beaker on a tared precision balance (Mettler PE 360) and the vehicle added (w/w). The mixtures were prepared using a homogenizer. During the daily administration period, homogeneity was maintained using a magnetic stirrer.

The test article was administered orally, by gavage, once daily in the morning from day 6 through to day 15 post coitum. All groups received a dose volume of 10 ml/kg body weight, with a daily adjustment of the individual volume to the actual body weight. Control animals were similarly dosed with the vehicle alone
VEHICLE
- Justification for use and choice of vehicle (if other than water): common vehicle
- Concentration in vehicle: 5mg/ml, 15mg/ml, 45mg/ml
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Photometric analytical verification (UV/Vis)
Concentrations (5, 15, 150 mg/ml) and stability in bidestilled water with 0.5% Cremophor was verified.
Result: Recovery between 99.4 and 103.8%
Homogeneity varies from -4 to + 5%
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Further matings after two unsuccessful attempts: no information
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
from day 6 through to day 15 post coitum
Frequency of treatment:
once daily in the morning
Duration of test:
21 days (from successful mating to termination, excluding acclimatisation etc)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
50mg/kg bw
Basis:
nominal conc.
in bidestilled water with 0.5% Cremophor
Remarks:
Doses / Concentrations:
150mg/kg bw
Basis:
nominal in water
in bidestilled water with 0.5% Cremophor
Remarks:
Doses / Concentrations:
450mg/kg bw
Basis:
nominal conc.
in bidestilled water with 0.5% Cremophor
No. of animals per sex per dose:
25 mated female rats
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dosages were based on the results of the dose range-finding study
(RCC Project 274972).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked in table were included. Signs of moratlities reaction to treatment and of ill health were observed.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: daily recorded from day 0 to 21


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: Post mortem examination, including gross macroscopic examination of all internal organs, with emphasis on the uterus, uterine contents, position of fetuses in the uterus and number of corpora lutea, was performed and the data recorded
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 (embryonic resoption): Yes
- Number of late resorptions (fetal resorption): Yes
- Number of Pre-Implantation loss: yes
- Number of Post-Implantation loss: yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
Univariate one-way analysis of variance was used to assess the significance of intergroup differences.
If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-one t-test), based on a pooled variance estimate, was
applied for the comparison between the treated groups and the control group.
The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information.
Indices:
according to guideline
Historical control data:
Historical Reproduction Data and Spontaneous Abnormal Findings of Wistar/HAN Rats (WIST, Outbred, SPF Quality) from 1987, 1988 and 1989

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
The dams at 450 mg/kg body weight/day group showed severe clinical signs of reaction to treatment, reduced food consumption and reduced body weight gain.
Additionally, at this dose level slightly increased post-implantation loss, reduced mean fetal body weights, an increased incidence of fetuses with common abnormal skeletal findings and retardations in skeletal development were noted

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 50 - < 150 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
In the dams at 450 mg/kgdose level slightly increased post-implantation loss, reduced mean fetal body weights, an increased incidence of fetuses with common abnormal skeletal findings and retardations in skeletal development were noted.
External and visceral examination of the fetuses, did not reveal any treatment related effects up to and including the dose level of 450 mg/kg body weight/day

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 150 - < 450 mg/kg bw/day (nominal)
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
>= 450 mg/kg bw/day (nominal)
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

At skeletal examination of the fetuses, the slightly increased incidence of fetuses with abnormal findings and the retardation in skeletal development noted for the fetuses at 450 mg/kg correlated with the reduced mean fetal body weight noted in this group. The abnormal skeletal findings in the 450 mg/kg group were not considered to be a specific teratogenic effect of the test article.

Applicant's summary and conclusion

Conclusions:
Under the conditions described in this study the test substance did not reveal any teratogenic potential up to and including the highest dose level of
450 mg/kg body weight/day. No-observed adverse effect level for the maternal organism was considered to be 50 mg/kg body weight/day and for the fetal organism 150 mg/kg body weight/day
Executive summary:

Confidential substance name was administered orally by gavage, once daily, to mated female Wistar rats at dosages of 50, 150 or 450 mg/kg body weight/day from day 6 through to day 15 post coitum in order to assess the effects on embryonic and fetal development.

In the dams at 450 mg/kg body weight/day, severe clinical signs of reaction to treatment, reduced food consumption and reduced body weight gain were observed. Additionally, at this dose level slightly increased post-implantation loss, reduced mean fetal body weights, an increased incidence of fetuses with common abnormal skeletal findings and retardations in skeletal development were noted.

At 150 mg/kg body weight/day, there was a slight reduction in food consumption during the dosing period. At this dose level no effects on the maternal reproduction parameters or on the fetal parameters were noted.

External and visceral examination of the fetuses, did not reveal any treatment related effects up to and including the dose level of 450 mg/kg body weight/day.

Based on these results, the no-observed adverse effect level for the maternal organism was considered to be 50 mg/kg body weight/day and for the fetal organism 150 mg/kg body weight/day. Under the conditions described in this study, confidential substance name did not reveal any teratogenic potential up to and including the highest dose level of 450 mg/kg body weight/day.