N-[3-(dimethylamino)propyl]docosanamide

Endpoint summary

Description of key information

not sensitising

- GPMT (OECD guideline 406); DIMAPDO lactate

- GMPT (OECD guideline 406); Stearic acid 3-(dimethylaminopropyl)amide

Guinea pig maximisation test: Not sensitising (comparable to OECD guideline 406 / EU method B.6), Induction: intradermal with 0.2% test substance concentration, epidermal with 30% test substance concentration on day 8; Challenge: topical with up to 30% test substance concentration; no signs of erythema or oedema in any dose group

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:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
• they are manufactured from similar or identical precursors under similar conditions
• they share structural similarities with common functional groups: tertiary amines, amides, and fatty acid chains with comparable length and degree of saturation (corresponding to scenario 2 of the read-across assessment framework)

The read-across hypothesis is based on structural similarity of target and source substances. The target and source chemicals have a very similar structure in that they are comprised of a hydrophobic (alkyl) and hydrophilic (amine headgroup) end. Due to this motif they form micelles (colloidal dispersions) and have surfactant properties.
Based on available experimental data, including key physicochemical properties and data from genotoxicity studies, the read-across strategy is supported by a similar toxicological profile of all substances.

Therefore, read-across from the existing toxicity studies conducted with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

A justification for read-across is attached to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See justification for read-across attached to IUCLID section 13.

3. ANALOGUE APPROACH JUSTIFICATION
See justification for read-across attached to IUCLID section 13.

4. DATA MATRIX
See justification for read-across attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

DIMAPDO is a surface active chemical with the alkyl moieties being composed of C22 residues.
In recently published articles in peer reviewed journals it is clearly demonstrated that for the realistic assessment of the skin sensitization potential of surfactants the LLNA (OECD 429) is much less suitable than the Magnusson & Kligman method (OECD 406) and could lead to confounding results.
In particular, the OECD 429 guideline specifies that “In addition, test substance classes or substances containing functional groups shown to act as potential confounders (Basketter et al., 2009) may necessitate the use of guinea pig tests”.
Consequently, in the evaluation of such surface active substances for sensitising properties, the LLNA is not an appropriate assay and would not represent an optimum use of test animals. The mechanism underlying confounding or false positive result is not fully understood, but it may be that an unspecific, non-immunologically triggered mechanism may be the cause of an increased lymphocyte proliferation.
In contrast to the GPMT, the LLNA focuses on the induction process of skin sensitisation (i.e. lymphocyte proliferation), and does not capture the process of elicitation which checks if the organism had actually been sensitized or not. The design of the LLNA does not allow to assess whether lymphocyte proliferation is a specific response or unspecific (false positive) response.

Species:

guinea pig

Strain:

Hartley

Sex:

female

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.5%, 1%, 3%, 5%, 10%, 30%

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: 0.5%, 1%, 3%, 5%, 10%, 30%. 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:

0.5%, 1%, 3%, 5%, 10%, 30%

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: 0.5%, 1%, 3%, 5%, 10%, 30%. 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:

0.5%, 1%, 3%, 5%, 10%, 30%

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: 0.5%, 1%, 3%, 5%, 10%, 30%. 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:

0.5%, 1%, 3%, 5%, 10%, 30%

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: 0.5%, 1%, 3%, 5%, 10%, 30%. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: No.

Group:

positive control

Remarks on result:

not measured/tested

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results obtained with the source substances, DIMAPDO is not a dermal sensitizer.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Experimental data on the skin sensitisation potential are not available for the target substance DIMAPDO. For the assessment of effects of DIMAPDO to skin sensitisation results from the following studies are taken into consideration:

- a GPMT according to OECD guideline 406 with the source substance DIMAPDO lactate

- a GMPT according to OECD guideline 406 with the source substance Stearic acid 3-(dimethylaminopropyl)amide

A justification for read-across is attached to IUCLID section 13.

 

In a dermal sensitization study with the source substance DIMAPDO lactate 23 young female Albino Hartley guinea pigs (8 preliminary study, 10 in test group, 5 in control group) were tested using the method of Guinea pig maximization test equivalent to OECD 406.

In the main study three samples each consisting of a: FCA and physiological saline in 1:1, b: 0.01% test substance and c: 0.02% test substance and FCA were injected intradermally in the back of guinea pigs and 30% test substance was applied in closed patches on the site of intradermal injection on Day 8 from initiation of sensitization (treated with SDS on Day 7).The control animals were treated similarly using the vehicle. The animals were challenged on Day 21 by applying 24-hour closed patch of the 30%, 10%, 5%, 3%, 1% and 0.5% solutions of the test substance.

There were no signs of erythema or oedema in any dose group 3, 24 and 48 hours after patch removal. Therefore in this study, DIMAPDO lactate is not a dermal sensitizer.

 

There is supporting information available from the structurally related substance Stearic acid 3-(dimethylaminopropyl)amide which also is not sensitising in a dermal sensitisation study according to OECD guideline 406 using the GPMT.

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. Positive control substance was mercaptobenzothiazole with a sensitisation rate of 70 %. In this study, Stearic acid 3-(dimethylaminopropyl)amide (a.i. > 99 %), isnot a dermal sensitiser.

Justification for the Guinea Pig Maximisation Test (GPMT)

Teh target substance DIMAPDO as well as teh source substances are surface active chemicals. In recently published articles in peer reviewed journals (see reference list below, and publications cited in the revised OECD guideline 429 (July 2010)) it is clearly demonstrated that for the realistic assessment of the skin sensitization potential of surfactants the LLNA (OECD 429) is much less suitable than the Magnusson & Kli gman method (OECD 406) and could lead to confounding results.

In particular, the OECD 429 guideline specifies that “In addition, test substance classes or substances containing functional groups shown to act as potential confounders (Basketter et al., 2009) may necessitate the use of guinea pig tests”.

Consequently, in the evaluation of such surface active substances for sensitising properties, the LLNA is not an appropriate assay and would not represent an optimum use of test animals. The mechanism underlying confounding or false positive result is not fully understood, but it may be that an unspecific, non-immunologically triggered mechanism may be the cause of an increased lymphocyte proliferation.

In contrast to the GPMT, the LLNA focuses on the induction process of skin sensitisation (i.e. lymphocyte proliferation), and does not capture the process of elicitation which checks if the organism had actually been sensitized or not. The design of the LLNA does not allow to assess whether lymphocyte proliferation is a specific response or unspecific (false positive) response.

 

References:

Kreiling, R et al., Food and Chemical Toxicology 46 (2008): 1896-1904: Comparison of the skin sensitizing potential of unsaturated compounds as assessed by the local lymph node assay (LLNA) and the guinea pig maximization test (GPMT)

 

Basketter, D et al., Regulatory Toxicology and Pharmacology 55 (2009): 90-96: Application of a weight of evidence approach to assessing discordant sensitisation data sets: Implications for REACH

 

Garcia, C et al., Regulatory Toxicology and Pharmacology 58 (2010): 301-307: Comparative testing for the identification of skin sensitizing potentials of nonionic sugar lipid surfactants

 

Ball, N et al., Regulatory Toxicology and Pharmacology 60 (2011): 389-400: Evaluating the sensitizing potential of surfactants: integrating data from the local lymph node assay, guinea pig maximization test, and in vitro methods in a weight-of-evidence approach

 

 

Conclusion skin sensitisation

There is no data gap for skin sensitisation. Although no human data are available for DIMAPDO there is no reason to believe that results obtained in guinea pigs would not be applicable to humans. 

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on relevant, reliable and adequate data, DIMAPDO does not have to be classified and labelled according to the CLP Regulation (EC) No 1272/2008 with respect to skin sensitisation.