Registration Dossier

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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

There are no reliable data available reproduction toxicity of N,N-Dimethyldodecan-amide (CAS 3007-53-2). In order to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, the substance listed below are selected as reference substances for hazard assessment.

 

 

Target Substance

Source Substance 1

Source Substance 2

Source Substance 3

 

N,N-Dimethyldodecan-amide

N,N-Dimethyldecan-amide

N,N-Dimethyloctanamide

Mixture of N,N-Dimethyloctanamide and N,N-Dimethyldecanamide

CAS

3007-53-2

14433-76-2

1118-92-9

67359-57-3

Reproduction/Developmental toxicity

RA to 67359-57-3

RA to 67359-57-3

RA to 67359-57-3

OECD 414, rats, not teratogenic up to highest dosage 450mg/kg, NOAELmaternal = 50mg/kg bw/d, NOAEL fetotoxicity = 150mg/kg bw/d, fetotoxicity correlates to serve clinical signs in maternal dams (Bayer 1991)

 

The above mentioned substances are considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for N,N-Dimethyldodecan-amide (CAS 3007-53-2). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Mixture of dimethylamides (CAS 67359-57-3):

Fertility:

No independent studies for toxicity to fertility are available. 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 .

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. Based on this and according to Mangelsdorf et al. 2003 (Regulatory Toxicology and Pharmacology 37 (2003) 356-369) further testing did not may add an additional value and is, with focus on “last resort” not performed.


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

Justification for selection of Effect on fertility via oral route:
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.

Effects on developmental toxicity

Description of key information
- oral, rat, gavage, 6-15 post coitum, RA to 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; discreminating dose teratogenicity 450mg/kg bw  (no teratogenic potential). (RCC 1991, H. Becker) 
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
450 mg/kg bw/day
Species:
rat
Additional information

Justification for grouping of substances and read-across

There are no reliable data available reproduction toxicity of N,N-Dimethyldodecan-amide (CAS 3007-53-2). In order to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, the substance listed below are selected as reference substances for hazard assessment.

 

 

Target Substance

Source Substance 1

Source Substance 2

Source Substance 3

 

N,N-Dimethyldodecan-amide

N,N-Dimethyldecan-amide

N,N-Dimethyloctanamide

Mixture of N,N-Dimethyloctanamide and N,N-Dimethyldecanamide

CAS

3007-53-2

14433-76-2

1118-92-9

67359-57-3

Reproduction/Developmental toxicity

RA to 67359-57-3

RA to 67359-57-3

RA to 67359-57-3

OECD 414, rats, not teratogenic up to highest dosage 450mg/kg, NOAELmaternal = 50mg/kg bw/d, NOAEL fetotoxicity = 150mg/kg bw/d, fetotoxicity correlates to serve clinical signs in maternal dams (Bayer 1991)

 

The above mentioned substances are considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for N,N-Dimethyldodecan-amide (CAS 3007-53-2). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Mixture of dimethylamides (CAS 67359-57-3):

Developmental toxicity:

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.

As the study shows only toxic effect to maternal and fetal organism and further the maternal organism reacts earlier and the fetus is only affected in higher dosages but did not show any teratogenic effect despite the general toxic effects. Conclusive no teratogenic effect can be derived from the study. Fetal toxicity is seen in connection to the maternal toxicity only and judged as secondary effect to the strong maternal effect observed at the respective dose. Therefore, no separate fetal or teratogenic can be oberserved. Further 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, even as there are better studies (90d beagle study) available.

For developmental toxicity there are only studies with the mixture of dimethylamides (CAS 67359-57-3) available. The most relevant and reliable study concerning these endpoint is described above. Nevertheless there are also additional studies with rabbits (oral) conducted, which results were rated less relevant and reliable as not in contrast to the finding above. Therefore, these studies are not integrated.

As source and target substances contain the same structure (reactive) elements and further a concrete trend in acute toxicity and irritation with lower toxicity if chain length is increased can be observed. Therefore, the result from reproduction toxicity study with the source substance can be transferred as worst case assumption to the target substance.

Hence, taking reliability, adequacy and availability into account, the following information on repeated dose toxicity is used for assessment:

- oral, rat, gavage, 6-15 post coitum, RA to 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; discriminating dose teratogenicity 450mg/kg bw (no teratogenic potential). (RCC 1991, H. Becker)


Justification for selection of Effect on developmental toxicity: via oral route:
Most adequat reliable result, see discussion.

Justification for classification or non-classification

Due to citeria of legislation GHS (Regulation (EU) 1272/2008) for reproductive toxicans ("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 toxican as there is no evidence from the current available data. Also according to DSD (67/548/EEC) the available test results led not to a classification as a substance with toxicity to reproduction.

Labelling for toxicity to reproduction:

GHS: no classification

DSD: no classification

Additional information