9-Decenamide, N,N-dimethyl-

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No independent studies for toxicity to fertility are available for N,N-dimethyldec-9-enamide or for the

analogue substance, a mixture of N,N-dimethyldecanamide and N,N-dimethyloctanamide (with traces of N,N-dimethyl-dodecanamide and N,N-dimethyl-hexanamide) (CAS No. 67359-57-3).

However a 90 days repeated dose studies with a mixture of a mixture of N,N-dimethyldecanamide and N,N-dimethyloctanamide in beagle dogs via gavage (40, 200 and 1000 mg/kg bw/d; Bayer 2000, J. Ruf) reported no relevant findings regarding the male or female fertility/developmental toxicity . This study is read-across to N,N-dimethyldec-9-enamide.

It is assumed that a reproductive screening study or two generation study does not need to be conducted as results from a developmental toxicity study and a subchronic toxicity study did not reveal any reason of concern for offspring and for parent animals with respect to developmental toxicity or fertility.

Short description of key information:
No effects on fertility are expected.

Effects on developmental toxicity

Description of key information

- oral, rat, gavage, 6-15 post coitum, mixture of N,N-dimethyl-decanamide and N,N-dimethyl-octanamide, OECD 414: NOAEL (maternal) 50 mg/kg bw/d; NOAEL (fetal) 150 mg/kg bw/d; no teratogenic potential. (RCC 1991, H. Becker) 

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: According to OECD guideline under GLP. Reliability reduced due to read-across

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system 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

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)

Remarks:

Doses / Concentrations:
50mg/kg bw
Basis:
nominal conc.
in bi-distilled water with 0.5% Cremophor

Remarks:

Doses / Concentrations:
150mg/kg bw
Basis:
nominal in water
in bi-distilled water with 0.5% Cremophor

Remarks:

Doses / Concentrations:
450mg/kg bw
Basis:
nominal conc.
in bi-distilled 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).

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

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

Dose descriptor:

NOAEL

Effect level:

>= 50 - < 150 mg/kg bw/day (nominal)

Basis for effect level:

other: maternal toxicity

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

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

Abnormalities:

not specified

Developmental effects observed:

not specified

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.

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

450 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

One reliable study is available on a read-across substance

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Studies used in this section were conducted with a mixture of a mixture of N,N-dimethyldecanamide and N,N-dimethyloctanamide (with traces of N,N-dimethyl-dodecanamide and N,N-dimethyl-hexanamide) (CAS No. 67359-57-3). The results from this study are read-across to N,N-dimethyldec-9-enamide.

In a study according to OECD 414 (RCC 1991, H. Becker) the mixture 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 author concluded that, the no-observed adverse effect level (NOAEL) 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 and that 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.

Assessment of teratogenicity:

The study shows toxic effect to maternal and fetal organism, whereas the maternal organism reacts earlier and the fetus is only affected in higher dosages but the study did not show any teratogenic effect up to and including the highest dosage tested. The NOAELs derived were only based on weight reduction/slight reduced food comsumption by the author and considered by the applicant as not suitable for risk assessment, because there are better studies available.

Justification for classification or non-classification

Due to criteria of legislation GHS (Regulation (EU) 1272/2008) for reproductive toxicants ("Suspected human reproductive toxicant Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information......") the substance is not be classified as reproductive toxicant as there is no evidence from the current available data from a read-across substance. Also according to DSD (67/548/EEC) the available test results do not lead to a classification as reproductive toxicant.

Labelling for toxicity to reproduction:

GHS: no classification

DSD: no classification