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Description of key information

Skin: In vitro skin irriation, C12 (CAS 3007-53-2),  OECD 431 and 439, irritant (cat 2) but not corrosive (BASF, 2014), further underlined by in vivo, C10 (Cas 14433-76-2), rabbit, semiocclusive, 4h, OECD 404: Moderate to severe skin reactions, erythema 2.7 and oedema 2.8, full reversible within 21 days. (Cognis 1997, M.Hoyer)
Eye: In vitro eye irritation test battery with C12 (CAS 3007-53-2): BCOP OECD 437 (BASF, 2014), IVIS 20.2; EpiOcular, viability 30% (BASF, 2014); combined result irritating to eye cat 2; further undelined by; in vivo, C10 (Cas 14433-76-2) ,rabbit, OECD 405: Moderate to severe eye reactions, cornea opacity 1.0; iris lesion 0.0; redness of conjunctiva 2.6; oedema of conjunctiva 2.8, full reversible within 21 days. (Cognis 1997, M.Hoyer)
Respiratory system: in vivo, rat, OECD 403, LC50, RA to mixture of dimethylamides (mainly C8/C10): >3551 mg/m3, but irritation of the respiratory tract (e.g. slower breathing, serous nasal discharge, dyspnea, stridor, hypothermia) (Bayer 1991; J. Pauluhn)

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Justification for grouping of substances and read-across

There are no reliable data available for the irritation 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 2

 

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

Skin irritation

In vitro skin irriation, OECD 431 and 439, irritant (cat 2) but not corrosive (BASF, 2014)

Further underlined by RA to 14433-76-2

OECD 404, rabbit, irritant to skin cat 2 (BASF, 1997)

RA to 67359-57-3

49 CFR, rabbit, no interpretation possible (Stepan 1990)

OECD 404, rabbit, corrosive(Bayer 1990)

OECD 404, rabbit, irritant cat 2(Clariant 1993)

Eye irritation

 

In vitro eye irritation tes battery: BCOP OECD 437 (BASF, 2014), IVIS 20.2; EpiOcular, viability 30% (BASF, 2014); combined result irritating to eye cat 2

Further underlined by RA to 14433-76-2

OECD 405, rabbit, irritant to eye cat 2 (BASF, 1997)

 

RA to 67359-57-3

OECD 405, rabbit, severe eye damage cat 1 (Stepan 1990)

OECD 405, rabbit, severe eye damage cat (Clariant 1993)

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).

 

Skin:

N,N-dimethyldecanamide (CAS 14433-76-2)

The acute skin irritant effect of N,N-Dimethyldecan-1-amide was investigated according to OECD Guideline No. 404 and EEC Guideline B.4 (Cognis 1997, M.Hoyer). Three female albino rabbits were exposed to the test article at two skin sites on the back. After 4hours of exposure the test article was removed and the skin was examined 1, 24, 48 and 72 hours as well as 7, 14 and 21 days after termination of exposure. Moderate to severe skin reactions were observed. Under the experimental conditions described in this report, the mean score for erythema was 2.7 (2.00, 3.00, 3.00) and for oedema 2.8 (2.00, 3.33, 3,00). After 21 days rests of scales on both sides were observed in all animals.

Mixture of dimethylamides (CAS 67359-57-3)

To assess the irritant potential of a mixture of N,N-dimethyldecanamide and N,N-dimethyloctanamidea skin irritation test (Clariant 1993, Kreiling) according to EG-Guideline B.4. “Akute Toxizität Hautreizung der Richtlinie 84/449/EWG” fullfilling also the OECD guideline 404 was conducted. Therefore 3 New Zealand White rabbits were exposed to the test substance for 4h. After washing gradings were scored after 0.5h, 24h, 48h, 72h, 7d, 14d and 21d. 0.5-1h after removing the patch all animal showed moderate to severe erythema and slight to severe edema. Average reading values (24h, 48h and 72h reading, mean from all animals) are: erythema 3.3 and edema 3.0. Full reversibility was observed after 21 days, whereas a moderate erythema could be observed at day 7 reading and slight erythema and edema were observed 14 day after exposure. No signs of corrosion were reported. Based on this result the substance has to be labelled as irritating to skin according to EU GHS EC 1272/2008.

Further in a corrosivity study (Stepan 1990, S.R. Harris) the corrosive potential of a mixture of N,N-dimethyldecanamide and N,N-dimethyloctanamide (with traces of N,N-dimethyl-dodecanamide and N,N-dimethyl-hexanamide) was evaluated in general compliance with the conditions specified by the Department of Transportation Hazardous Materials Regulation (49 CFR). Therefore 6 New Zealand White rabbits were dermal exposed to 0.5ml test substance semi occlusive covered. Grading were recorded immediately, 24h and 48h after exposure. Critical changes were noted in the coloration and/or texture of the skin included coriaceousness, light brown discoloration, and dark brown discoloration. No evidence of corrosion (necrosis) was found. Based on this information the test material is not c1assified as a corrosive by dermal application, as defined by the Department of Transportation Hazardous Material Regulation (49 CFR). No long term observation was performed. According to the registrant less information does not allow a classification according to GHS.

And in another primary skin irritancy study (Stepan 1990, Kreuzmann) a mixture of N,N-dimethyldecanamide and N,N-dimethyloctanamide (with traces of N,N-dimethyl-dodecanamide and N,N-dimethyl-hexanamide) was evaluated in compliance with the conditions specified in the regulation for the enforcement of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines with the exception of the number of animals employed for testing. Therefore one New Zealand White rabbit was exposed to 0.5ml test substance for 4h semi occlusive covered. The application sites was scored for each rabbit approximately 1/2 - 1 hour, 24 hours, 48 hours, and 72 hours after application. Due to the suspected irritation potential of this test material, a single animal was initiated on this primary skin irritation study. Due to the effects exhibited in this single animal, this study was ultimately terminated without testing in additional animals. Severe irritation persisted 72 hours following application. The Primary Irritation Index (PII) was found to be 7.0 based on erythema and edema in the single animal tested. Critical changes noted in the coloration and/or texture of the skin included necrosis, slight fissures, coriaecousness, and light and dark brown discoloration. Evidence of corrosion (necrosis) was found. Although the full complement of animals was not used on this test, based on the findings in this single animal , the test material is classified in Toxieity Category I (40 CFR 156, Proposed by dermal administration).

According to the registrant only one study (Clariant 1993, Kreiling) for the dimethylalkylamide mixture does fully comply with current guidelines including the prolonged observation time to assess irreversible effects. Two studies were conducted with main focus on CFR regulation limited by observation time and/or number of animals. Whereas one CFR compatible study (Stepan 1990, Kreuzmann) shows signs of corrosion a later performed study (Stepan 1990, S.R. Harris) assessing the corrosive potential could not confirmed the corrosive result. In result, due to the registrant, the substance has to be classified as severely irritating to skin as long term observations are not performed in both CFR studies leading to a lower reliability of both studies which were therefore degraded. Furthermore a skin irritation study conducted with N,N-Dimethyldecan-1-amide (Cognis 1997, M.Hoyer) which shows also only skin irritation and no corrosion.

N,N-Dimethyldodecan-amide (CAS 3007-53-2), in vitro studies

The potential of N,N Dimethyldodecane-1-amide to cause dermal corrosion/irritation was assessed by a single topical application of 50 μL (corrosion test) or 30 μL (irritation test) of the undiluted test substance to a reconstructed three dimensional human epidermis model (EpiDerm™) according to OECD 431 and 439 (BASF, 2014). For the corrosion test two EpiDerm™ tissue samples were incubated with the test substance for 3 minutes and 1 hour, respectively. The irritation test was performed with three EpiDerm™ tissue samples, which were incubated with the test substance for 1 hour followed by a 42-hours post-incubation period. Tissue destruction was determined by measuring the metabolic activity of the tissue after exposure/post-incubation using a colorimetric test. The reduction of mitochondrial dehydrogenase activity, measured by reduced formazan production after incubation with a tetrazolium salt (MTT) was chosen as endpoint. The formazan production of the testsubstance treated epidermal tissues is compared to that of negative control tissues. The quotient of the values indicates the relative tissue viability. The EpiDerm™ skin corrosion/irritation test showed the following results:

The test substance is able to reduce MTT directly. However, this ability of direct MTT reduction did not impair the study result as demonstrated by the concurrently performed exposure of control tissues inactivated by freezing (performed with corrosion test, only). Corrosion test: The mean viability of the test-substance treated tissues determined after an exposure period of 3 minutes was 103%, and it was 104% after an exposure period of 1 hour. Irritation test: The mean viability of the test-substance treated tissues determined after an exposure period of 1 hour with about 42 hours post-incubation was 3%. Based on the observed results it was concluded, that N,N Dimethyldodecane-1-amide shows a skin irritation potential in the EpiDerm™ skin corrosion/irritation test under the test conditions chosen.

In summary the toxicity in general decrases with increase chain length of the carbon acid part, and an overestimation concerning also for irritation can be anticipated, when transferring results from source to target substance. Therefore the result from N,N-Dimethyldecan-1-amide can be used as worst case assumption for the longer chain length, furthermore this result is underlined using an in vitro skin irritation test showing a comparable result to the read across. Taken together plausibility of the read across is confirmed by this endpoint.

Eye:

N,N-dimethyldecanamide (CAS 14433-76-2)

The acute eye irritant effect of N,N-Dimethyldecan-1-amide was investigated according to the method recommended in the OECD Guideline No. 405 and EEC Guideline B.5 (Cognis 1997, M. Hoyer).Three female albino rabbits were exposed to 0.1 ml of the test article in the left eye. The eyes were examined and the changes were graded according to a numerical scale 1, 24, 48 and 72 hours as well as 7, 14 and in two animals 21 days after dosing.Moderate to severe signs of eye irritation were observed among the rabbits. The following mean values, based on the results from the 24, 48 and 72 hour readings, were calculated: Cornea opacity 1.0; Iris lesion 0.0; Redness of conjunctiva 2.6; Oedema of conjunctiva 2.8.After 14 days all animals showed hairless areas around the eye. Treatment related adverse eye reactions were fully reverse within 14 (1 animal) and 21 days.

 

Mixture of dimethylamides (CAS 67359-57-3)

To assess the irritant potential of a mixture of N,N-dimethyldecanamide and N,N-dimethyloctanamide a eye irritation test according to EG-Guideline B.5. Akute Toxizität Augenreizung der Richtlinie 84/449/EWG fulfilling also the OECD guideline 405 was conducted (Clariant 1993, Kreiling). Therefore one New Zealand White rabbit was exposed to 0.1ml test substance and gradings were scored after 1h, 24h, 48h, 72h and 7 days. 1 h to 7 days after installation of the test substance a strong to crimson red conjunctivia as well as a clear swelling (up to half closed lid) was observed. Additional a clear iritis and diffuse to significant opacity was recorded. Clear discharge was seen during the whole experiment. The calculated scores (average of 24h, 48h and 72h) are: cornea opacity 1, iritis 1, conjunctivia redness 3 and chemosis 3. Effects observed were not reversible within the experiment (7d observation). After 7 days an increased vascularisation was noted.

In another study (Stepan 1990, Kreuzmann) the primary ocular irritancy of a mixture of N,N-dimethyldecanamide and N,N-dimethyloctanamide (with traces of N,N-dimethyl-dodecanamide and N,N-dimethyl-hexanamide) was evaluated in compliance with the conditions specified in the regulation for the enforcement of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines with the exception of the number of animals employed for testing. One New Zealand White rabbit was exposed to 0.1ml test substance and gradings were scored after 1h, 24h, 48h, 72h and 4 days. Due to the suspected irritation potential of this test material, a single animal was initiated on this primary eye irritation study. Due to the effects exhibited in this single animal, this study was ultimately terminated without testing in additional animals.

The test material produced corneal opacity, iritis, and conjunctival irritation persisting for the 4 day duration of this test when applied without rinsing to the eye of one New Zealand White rabbit. In addition, corneal vascularisation became apparent at day 4.

Irritation scores in the one animal are: cornea score 1.7, iris score 1, conjunctivia 2.7 and chemosis 4. No evidence of corrosion was noted in the animal.

 

N,N-Dimethyldodecan-amide (CAS 3007-53-2), in vitro studies

The potential of N,N Dimethyldodecane-1-amide to cause serious damage to the eyes was assessed by a single topical application of 750 μL of the undiluted test substance to the epithelial surface of isolated bovine corneas according to OECD 437 (BASF, 2014). Three corneas were treated with the test substance for 10 minutes followed by a 2-hours post-incubation period. In addition to the test substance a negative control (NC; de-ionized water) and a positive control (PC; 100% dimethylformamide) were applied to three corneas, each. Corneal opacity was measured quantitatively as the amount of light transmitted through the cornea. Permeability was measured quantitatively as the amount of sodium fluorescein dye that passes across the full thickness of the cornea. Both measurements were used to calculate an In Vitro Irritancy Score of the test substance. In addition H&E-stained cross sections were evaluated for the irritation potential of the test substance. The following results were obtained in the BCOP test: IVIS score 20.2; Histological evaluation revealed changes indicating moderate to severe eye damage.

Futher the potential of N,N Dimethyldodecane-1-amide to cause ocular irritation was assessed by a single topical application of 50 μL of the undiluted test substance to a reconstructed three dimensional human cornea model (EpiOcular™) (BASF, 2014). Two EpiOcular™ tissue samples were incubated with the test substance for 30 minutes followed by a 2-hours post-incubation period. Tissue destruction was determined by measuring the metabolic activity of the tissue after exposure/post-incubation using a colorimetric test. The reduction of mitochondrial dehydrogenase activity, measured by reduced formazan production after incubation with a tetrazolium salt (MTT) was chosen as endpoint. The formazan production of the testsubstance treated epidermal tissues is compared to that of negative control tissues. The quotient of the values indicates the relative tissue viability. The EpiOcular™ eye irritation test showed the following results: The test substance is able to reduce MTT directly. However, this ability of direct MTT reduction did not impair the study result as demonstrated by the concurrently performed exposure of control tissues inactivated by freezing. The mean viability of the test-substance treated tissues was 30%. Based on the observed results it was concluded, that N,N Dimethyldodecane-1-amide shows an eye irritation potential in the EpiOcular™ eye irritation test under the test conditions chosen.

The result of the single EpiOcular does not exclude a severe irritation potential of the test substance. For final assignment, results from another study would be needed. Therefore, a BCOP test was performed to receive additional information about the irritancy of the substance. Both results were used as a combined testing strategy leading to resulting eye irritating effects.

 

Assessment of eye irritation / Assignment of key study.

Two studies of same quality are available assessing the eye irritation potential of a mixture of N,N-dimethyldecanamide and N,N-dimethyloctanamide. As both studies lead to the same results but were only conducted with one animal each and therefore both were used as WoE. These both studies indicate some irreversible effects, but another study with N,N-dimethyldecanamide does not underline these effects. Further as know from the acute toxicity behavior decreases the toxicity of the substance with increases in chain length, therefore the trend showing lower irritation increasing the chain length from c8/10 to c10 is plausible. Furthermore, some in vitro studies does also not underline irreversible effects for C12. Therefore based on the irritation grading of C10 and the result of the in vitro studies the substance has to be classified as “Irritating to eyes (Cat. 2)”. Further the result from N,N-Dimethyldecan-1-amide can be used as worst case assumption and all studies available indicate plausibility of the read across used.

 

If valid information for the target substance is available this information is rated as highest in adequacy to judge about the skin or eye irritating effects of N,N-dimethydodecanamide. As further the toxicity of the homologues increases with shorter carbon chain length towards C8 information from the next close homologue (N,N-dimethyldecanamide) is used if no information for the target is available or to underline less reliable target information. If no valid information from this close homologue (N,N-dimethyldecanamide) is available the Mixture of dimethylamides (CAS 67359-57-3) is used as information source followed by the pure N,N-dimethyloctanamid.

Hence, taking reliability, adequacy and availability into account, the following information on skin and eye irritation is used for assessment:

Skin: In vitro skin irriation, C12 (CAS 3007-53-2), OECD 431 and 439, irritant (cat 2) but not corrosive (BASF, 2014), further underlined by in vivo, C10 (Cas 14433-76-2), rabbit, semiocclusive, 4h, OECD 404: Moderate to severe skin reactions, erythema 2.7 and oedema 2.8, full reversible within 21 days. (Cognis 1997, M.Hoyer)

Eye: In vitro eye irritation test battery with C12 (CAS 3007-53-2): BCOP OECD 437 (BASF, 2014), IVIS 20.2; EpiOcular, viability 30% (BASF, 2014); combined result irritating to eye cat 2; further undelined by; in vivo, C10 (Cas 14433-76-2) ,rabbit, OECD 405: Moderate to severe eye reactions, cornea opacity 1.0; iris lesion 0.0; redness of conjunctiva 2.6; oedema of conjunctiva 2.8, full reversible within 21 days. (Cognis 1997, M.Hoyer)

Respiratory system: in vivo, rat, OECD 403, LC50, RA to mixture of dimethylamides (mainly C8/C10): >3551 mg/m3, but irritation of the respiratory tract (e.g. slower breathing, serous nasal discharge, dyspnea, stridor, hypothermia) (Bayer 1991; J. Pauluhn)


Justification for selection of skin irritation / corrosion endpoint:
Most adequat reliable result, see discussion.

Justification for selection of eye irritation endpoint:
Most adequat reliable result, see discussion.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Classification skin irritation

Clear skin irritating effects were observed in an invitro skin irritation study (BASF, 2014) underlined by skin irritating effects observed for a close homologue in a in vivo study a skin irritation study (Cognis 1997, M.Hoyer). The scores obtained from these studies led to a classification as an irritating to skin (cat. 2) due to criteria of GHS (Regulation (EU) 1272/2008) and to classification irritating to skin R-38 according to EU-criteria DSD (67/548/EEC)

Labelling for skin irritation:

GHS: Irritating to skin (cat. 2)

DSD: Irritating to skin R-38

 

Classification eye irritation

Eye:

Clear eye irritating effect were observed in an invitro eye irritation testing battery (BASF, 2014) underlined by skin irritating effects observed for a close homologue in a in vivo eye irritation study (Cognis 1997, M.Hoyer): The scores obtained in these studies led to a classification as an irritating to eye (cat. 2) due to criteria of GHS (Regulation (EU) 1272/2008) and Xi R-36 according to EU-criteria DSD (67/548/EEC)

Labelling for eye irritation:

GHS: irritating to eye (cat. 2)

DSD: Xi R-36

Classification for respiratory irritation:

Based on irritating effects observed in a acute inhalation study (Bayer 1991, J. Pauluhn) with a homologue (mainly C8/C10) the substance has to be labelled as STOT single cat 3 "May cause respiratory irritation" due to criteria of GHS (Regulation (EU) 1272/2008) and Irritating to respiratory system R 37 according to EU-criteria DSD (67/548/EEC)