Amides, C16-18, N-[3-(dimethylamino)propyl]

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

For justification for read-across see endpoint summary "Sensitisation".

Reason / purpose for cross-reference:

read-across source

Positive control results:

The Sensitisation rate after application of the positive control substance Mercaptobenzothiazole (15 % in Vaseline) was 70 %, confirming the
reliability of the test system.

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

2 %

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 2 %. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

2 %

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 2 % . No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

2 %

No. with + reactions:

0

Total no. in group:

5

Clinical observations:

no

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 2 % . No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

2 %

No. with + reactions:

0

Total no. in group:

5

Clinical observations:

no

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 2 %. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.

Skin reaction after induction exposure:

 

Intradermal Induction (24hours reading):

Injection site 1:      Erythema grade 1 in all control- and 7/10 test animals

Injection site 2:  Erythema grade 1in 6/10 test animals; eschar in 2/10 test animals; necrosis in 5/10 test animals

Injection site 3:  No signs of irritation were recorded for the control animals.

                                 Erythema grade 1 in 1/5 control animals and in 7/10 test animals

                                 Eschar in 2/10 test animals

                                 Necrosis in 2/10 test animals

Intradermal Induction (48 hours reading):

Injection site1:    Erythema grade 1in 7/10 test animals

Injection site2:    Erythema grade 1in 5/10 test animals

                                  Eschar in 3/10 test animals

                                  Necrosis in 5/10 test animals

                                  Oedema grade1in 1/10 test animals

Injection site 3:   Erythema grade 1 in 6/1 0 test animals

                                  Eschar in 3/10 test animals

                                  Necrosis in 2/10 test animals.

                                  Oedema grade 1 in 1/10 test animals

                                  No signs of irritation were recorded for the control animals.

 

 

Dermal Induction (48 hours exposure, occlusive):

Immediately after removing the patch:     Erythema grade 1 in 4/10 test animals

                                                                       Erythema grade 2 in 6/10 test animals

                                                                       Oedema grade 1 in 8/10 test animals

                                                                       All animals showed necrosis.

24 hours after removing the patch:           Erythema grade 1 in 8/10 test animals

                                                                       Erythema grade 2 in 2/10 test animals

                                                                       Oedema grade 1 in 8/10 test animals

                                                                       All animals showed necrosis.

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: other: CLP, EU GHS (Regulation (EC) No 1272/2008)

Conclusions:

In this study, Sthe analogue source test substance stearic acid 3-(dimethylaminopropyl)amide (a.i. > 99 %), is not a dermal sensitiser.

Executive summary:

In a dermal sensitisation study according to OECD TG 406, 1992) with he analogue source test substance Stearic acid 3-(dimethylaminopropyl)amide (a.i. > 99 %) in paraffinum perliquidum, young adult Dunkin-Hartley guinea pigs were tested using the Maximization test method. Positive control substance was mercaptobenzothiazole with a sensitisation rate of 70 %.

 

Mild to moderate skin reactions and necrosis were observed after intradermal induction (2.5 %) and dermal induction (1 %) in the test substance animals. After challenge exposure (2 %) no skin reactions were observed in test or control animals at any observation time. Therefore the sensitisation rate was 0 %.

 

For the challenge concentration, which is the highest non-irritant dose, 2 % of the test item was used. The higher challenge concentration compared to the dermal induction concentration can be explained by the different exposure times, i.e. 48 hours for the dermal induction and 24 hours for the challenge.

 

In this study, Stearic acid 3-(dimethylaminopropyl)amide (a.i. > 99 %), is not a dermal sensitiser.

It can be expected that the study results are also applicable to the target substance Amides, C16-18 (even numbered), N-[(dimethylamino)propyl].

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

No sensitisation data are available for C16-18 DMAPA amidoamine. However, a Guinea Pig Maximisation Test is available with the structurally closely related source substance Stearic acid 3-(dimethylaminopropyl)amide. A justification for read-across is given below.

 

In a dermal sensitisation study according to OECD TG 406, 1992) with Stearic acid 3-(dimethylaminopropyl)amide (a.i. > 99%) in paraffinum perliquidum, young adult Dunkin-Hartley guinea pigs were tested using the Maximization test method. Positive control substance was mercaptobenzothiazole with a sensitisation rate of 70%.

Mild to moderate skin reactions and necrosis were observed after intradermal induction (2.5%) and dermal induction (1%) in the test substance animals. After challenge exposure (2%) no skin reactions were observed in test or control animals at any observation time. Therefore the sensitisation rate was 0%.

For the challenge concentration, which is the highest non-irritant dose, 2% of the test item was used. The higher challenge concentration compared to the dermal induction concentration can be explained by the different exposure times, i.e. 48 hours for the dermal induction and 24 hours for the challenge.In this study, Stearic acid 3-(dimethylaminopropyl)amide (a.i. > 99%), is not a dermal sensitiser.

There is no information available for respiratory sensitisation. Therefore, there is a data gap in this respect. However, the data gap cannot be fulfilled with experimental data, since there is no internationally accepted animal model for respiratory sensitisation. In case human data for respiratory sensitisation emerges, this will be taken into account.

 

Justification for read-across

1. Read-across hypothesis and justification

This read-across is based on the hypothesis that source and target substances have similar toxicological properties because

·        they are manufactured from similar resp. identical precursors under similar conditions

·        the metabolism pathway leads to comparable products (amine backbone and long chain fatty acids) and non-common products predicted to have no toxicological effects (long chain fatty acids).

 

Therefore, read-across from the existing irritation studies on the source substance is considered as an appropriate adaptation to the standard information requirements of Annex VII, 8.1, 8.2, Annex VIII, 8.1.1, and 8.2.1 of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

The justification of the proposed read-across approach is elaborated in the next chapters.

 

 

2. Justification for read-across

 

2.1 Substance Identity

 

Table 1: Substance identities

	Source substance	Target substance
	Stearic acid 3-(dimethylaminopropyl)amide	C16-18 DMAPA amidoamine
	mono constituent substance	UVCBsubstance
CAS number	7651-02-7
Chain length distribution	< C16: < 1.6% C16: < 7% C18: > 89.8% > C18: < 1.6%	C14: <= 5 % C16: 25-35 % C18: >= 61 %
DMAPA	<0.002%	<=0.01%

 

2.1 Substance Identity

Substance descriptions

The target substanceC16-18 DMAPA amidoamine is a UVCB substance manufactured from saturated C16-18 fatty acids and N, N-dimethylpropylenediamine (DMAPA). It is composed of C16 and C18 amides of DMAPA, with C18 being the larger part (>/= 61%)

 

The source substanceStearic acid 3-(dimethylaminopropyl)amide is manufactured from octadecanoic acid andN, N-dimethylpropylenediamine. It is composed of mainly C18 amides (> 89.8%) of DMAPA and small amounts of the C16 amide (<7%).

 

 

2.2 Common breakdown products

The source substance Stearic acid 3-(dimethylaminopropyl)amide is the main component of the UVCB target substanceC16-18 DMAPA amidoamine. The only difference is the chain length distribution: the target substance also contains a significant amount of the C16 amide.

This is not considered to be of relevance for metabolism.Both substances are amides which after resorption may be hydrolysed by amidases resulting in free fatty acids and DMAPA. The carboxylic acids then are further degraded by the mitochondrial beta-oxidation process (for details see common text books on biochemistry). The fatty acids enter normal metabolic pathways and are therefore indistinguishable from fatty acids from other sources including diet. The amine compounds are not expected to be further metabolised, but excreted via the urine mainly unchanged. 

 

2.3 Differences

The slight differences in fatty acid chain length (higher percentage of C16 in the target substance vs. corresponding higher percentage C18 in the source substance) are not considered to be of major relevance for local effects.

 

3. Physicochemical properties:

Table 2: Physicochemical properties

 

Endpoints	Source substanceStearic acid 3-(dimethylaminopropyl)amide	Target substanceC16-18 DMAPA amidoamine
Molecular weight	368.64 g/mol	340.59 - 368.64
Physical state at 20°C / 1013 hPa	Solid (paste)	Solid (waxy)
Melting point	OECD TG 102, RL1, non-GLP 67.4°C	OECD TG 102, RL1, non-GLP 41.8°C
Boiling point	OECD TG 103, RL1, non-GLP 412.3°C	OECD TG 103, RL1, non-GLP 320.5°C
Surface tension	ISO 4311, plate method, RL1, non-GLP 37.86 mN/m at 0.22 g/L	OECD TG 115, ring method, RL1, non-GLP 26.7 mN/m at 2.7 mg/L
Water solubility	OECD TG 105, RL1, non-GLP 10 mg/L at 20°C	OECD guideline 105/EU method A.6, slow stirring method/HPLC, RL1, non-GLP 3.65 mg/L at 23°C
Log Kow	---	Calculation (ACD/Labs Release 12.00, Product version 12.01 ) >6.6
	EU method A.8, calculation based on solubility in n-Octanol and water; RL2, non-GLP 2.01 at 20°C, pH7	Read-across from Stearic acid 3-(dimethylaminopropyl)amide
Vapour pressure	OECD TG 104, RL1, ISO17025 compliance 3.4E-08 Pa at 20°C	Read-across from Stearic acid 3-(dimethylaminopropyl)amide

 

4. Comparison of data from human health endpoints

4.1 Toxicity data of the target and source substances

Table 3: General toxicological profiles forStearic acid 3-(dimethylaminopropyl)amide andC16-18 DMAPA amidoamine

Endpoints	Source substance Stearic acid 3-(dimethylaminopropyl)amide	Target substanceC16-18 DMAPA amidoamine
Acute toxicity oral	OECD TG 423, RL1,GLP   LD50(rat) > 2000 mg/kg bw	OECD TG 423, RL1,GLP   LD50(rat) > 2000 mg/kg bw
Eye irritation	OECD TG 405, RL1, GLP   Category 1 (irreversible effects on the eye)	No data; read-across
	OECD TG 437, RL1, GLP   not severely irritating /not corrosive	No data; read-across
Skin irritation	OECD TG 439, RL1, GLP   not irritating	OECD TG 439, RL1, GLP   not irritating
	OECD TG 404, RL1, GLP   not irritating	No data; read-across
Sensitisation	OECD TG 406 (GPMT), RL1, GLP   not sensitising	No data; read-across
Genotoxicity	OECD TG 471 (Ames test), RL1, GLP   Negative	OECD TG 471, RL1, GLP   Negative
	OECD TG 467 (MLY), RL1, GLP   Negative	No data; read-across
	OECD TG 473 (Chromosome aberrations), RL1, GLP   Negative	No data; read-across
Repeated dose toxicity oral	Similar to OECD TG 407 (14 d DRF), rat, RL1, GLP   clinical signs/mortality (all animals at 500 mg/kg bw/d were sacrificed for humane reasons); haematology (slightly lower red blood cell and higher reticulocyte counts in males at 50 and 200 mg/kg bw/d); clinical biochemistry (higher ALAT activity in 2 males at 50 mg/kg bw/d, 2 males and 1 female at 200 mg/kg bw/d, higher alkaline phosphatase activity in 1 female at 200 mg/kg bw/d, higher potassium level in males at 50 and 200 mg/kg bw/d)	No data; read-across
Repeated dose toxicity dermal	Similar to OECD TG 411, rabbit, RL2, GLP   NOAEL(systemic) = 200 mg/kg bw/d (highest dose administred)	No data; read-across
Reproduction / Developmental Toxicity Screening Test	OECD TG 421, rat, RL1, GLP   NOAEL(parental)= 70 mg/kg bw/d; NOAEL(fertility females)= 70 mg/kg bw/d; NOAEL (fertility males) = 200 mg/kg bw/d; NOAEL(development)= 200 mg/kg bw/d	No data; read-across
Prenatal developmental toxicity	Similar to OECD TG 414, rabbit, RL2, GLP   NOAEL(development)=200 mg/kg bw/d (highest dose administered)	No data; read-across

 

Experimental data for the target substance C16-18 DMAPA amidoamine are available for acute oral toxicity, skin irritation (in vitro) and genotoxicity (bacterial reverse mutation assay).

No experimental data are available for the target substance C16-18 DMAPA amidoamine concerning the endpoints eye irritation, sensitisation, repeated dose toxicity, and reproductive/developmental toxicity. However, as demonstrated above, the source substance Stearic acid 3-(dimethylaminopropyl)amide is the main constituent of the target substance. The additional minor constituents with differing fatty acid chain lengths are not considered to influence the outcome of the toxicological studies.

This is supported by the similar results observed in acute oral toxicity studies: Both, the target substance C16-18 DMAPA amidoamine and the source substance Stearic acid 3-(dimethylaminopropyl)amide are of low acute toxicity when administered orally. The LD50 for both substances was > 2000 mg/kg bw. In both studies, 2/6 animals died during the observation period.

Both, the target substance C16-18 DMAPA amidoamine and the source substance Stearic acid 3-(dimethylaminopropyl)amide were not irritating to skin in an in vitro skin irritation test.

Both, the target substance C16-18 DMAPA amidoamine and the source substance Stearic acid 3-(dimethylaminopropyl)amide were not mutagenic in the bacterial reverse mutation assay when tested up to cytotoxic concentrations.

 

4.2 Quality of the experimental data of the analogues:

The source substance has been tested in GLP compliant OECD Guideline 406 (GPMT) study (RL1). The available data are sufficiently reliable and can be used in an analogue approach.

 

4.4 Classification and labelling

Concerning human health hazards, the source substance Stearic acid 3-(dimethylaminopropyl)amide is classified for irreversible effects on the eye (Eye Damage, Category 1, H318: Causes serious eye damage. / Xi; R41 Risk of serious damage to eyes). Based on the read-across, the target substance C16-18 DMAPA amidoamine will be classified accordingly.

 

5. Conclusion

The structural similarities between the source and the target substances and the similarities in their breakdown products presented above support the read-across hypothesis. Adequate and reliable scientific information indicates that the source and target substances and their subsequent degradation products have similar toxicity profiles.

Certain endpoints such as skin sensitisation and genotoxicity are characterised by covalent binding as a rate determining step or MIE (molecular initiating event). The consistency across endpoints - both, source substances and target substance were not genotoxic in the bacterial reverse mutation assay - also helps to increase confidence in the read-across approach especially when MIEs are common for example, skin sensitisation and genotoxicity are underpinned by electrophilicity.

 

The source substance Stearic acid 3-(dimethylaminopropyl)amide was not sensitising in the Guinea Pig Maximisation test. The target substance C16-18 DMAPA amidoamine contains a small amount of additional Palmitic acid 3-(dimethylaminopropyl)amide (C16), which is not considered to have a major influence on sensitisation potential properties. Thus, the target substance is not classified for skin sensitisation as well.

Migrated from Short description of key information:
Guinea pig maximisation test: not sensitising (OECD guideline 406; GLP); Induction: intradermal; Challenge: topical; read-across from Stearic acid 3-(dimethylaminopropyl)amide

Justification for selection of skin sensitisation endpoint:
OECD & EC guideline study, no deviations, GLP

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on reliable, adequate and relevant data obtained with the source substance Stearic acid 3-(dimethylaminopropyl)amide, C16-18 DMAPA amidoamine does not need to be classified for skin sensitisation according to regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC.