Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Data on sensitisation are not available for the target substance MDEA Esterquat C18 satd.. For the assessment of effects of MDEA Esterquat C18 satd. to skin sensitisation results from the following studies are taken into consideration:

- 3 HRIPT with a total of 283 volunteers with the source substance MDEA-Esterquat C16-18 and C28 unsatd.

-2 GPMT according to OECD guideline 406 with the source substanceMDEA-Esterquat C16-18 and C28 unsatd.

Human Data

According to “Guidance on information requirements and chemical safety assessment Chapter R.7.3.4.2” reliable and relevant human data should be used for hazard identification and are even preferable to animal data.

Ethical considerations

“The material under registration is for use in the manufacture of commercial fabric softener products that are used by millions of consumers on a daily basis. Because of this, and after having established the material’s lack of contact sensitization potential in the Guinea Pig, it was thought prudent to conduct confirmatory studies in a limited number of volunteers. The objective was to confirm that, as expected, no unforeseen reactions would occur when the material is in contact with people’s skin under consumer relevant conditions. To that end, three separate standard Human Result Insult Patch Tests (HRIPT) were conducted as described below”.

Data are generated in accordance with ethical considerations outlined in the Procter & Gamble policy “company policy for research involving human subjects”. This policy includes the principles of the ICH-GCP Regulation and the Declaration of Helsinki.

Human Repeat Insult Patch Tests

Data from three Human Repeat Insult Patch Test (HRIPT) studies with the structurally similar source substance MDEA-Esterquat C16-18 and C18 unsatd. are available. Dermal sensitisation studies were conducted according to the publications of Griffith, J.F., (1969), Predictive and Diagnostic Testing for Contact Sensitisation, Toxicol. Appl. Pharmacol., Suppl.3:90 and Stotts, J., (1980), Planning, Conduct and Interpretation Human Predictive Sensitisation Patch Test, Current Concepts in Cutaneous Toxicity, pp 41-53. During a three week period, volunteers were exposed under occlusive dressing in 9 successive occasions to induction patches containing 0.5 mL w/v aqueous solution of test substance. In each of the 9 occasions, the test substance was removed 24 hours after application of the patch. 14 days after exposure to the final induction patch, volunteers were challenged using the same concentration and the same procedure adopted for induction. The concentration for induction was chosen to cause mild to moderate irritation. Results were graded using a scoring system from 1 - 6 for erythema and edema, at 48 and 96 hours after challenge.

In the first study MDEA-Esterquat C16-18 and C18 unsatd. was tested as 1.5 % aqueous dilution. 90 volunteers took part in this study, six dropped out due to personal reason and a total of 84 volunteers were challenged. Acceptable irritation with mild (score 1) to particular moderate (score 2) erythema was observed throughout the study. No edema, which would be indicative for sensitisation was observed neither during induction nor during elicitation.

In two additional studies with MDEA-Esterquat C16-18 and C18 unsatd., a total of 210 volunteers were exposed to a 2.0 % aqueous dilution of test substance. 11 volunteers dropped out due to personal reason. Therefore a total of 199 study participants were challenged, using the same concentration of 2.0 % substance in aqueous dilution as for induction. A steady, acceptable irritation with mild (score 1) to particular moderate (score 2) erythema was observed throughout the study. As in the first study, no edema, which would be indicative for sensitisation was observed during induction or challenge.

Animal data

Data from two Bühler studies and three Human Repeat Insult Patch Test studies with the structurally similar source substance MDEA-Esterquat C16-18 and C18 unsatd. are available:

In two dermal sensitisation studies according to OECD Guideline 406 (12 May 1981) with MDEA-Esterquat C16-18 and C18 unsatd.  (80 % a.i.) in isopropanol, Pirbright-Hartley guinea pigs (10 male and 10 female in each study) were tested using the method of Bühler.

In the first study no skin alterations were observed during the induction period with 15 % test substance in 96 % ethanol. At challenge with 15 % test substance in acetone, slight erythema was observed in 1/20 test animals. No skin reactions were observed in the control animals. Both test and control animals were re-challenged with 15 % and 7.5 % MDEA-Esterquat C16-18 and C18 unsatd.  in acetone. No skin responses were observed upon re-challenge.

In the second study no skin alterations were observed during the induction period with 15 % test substance in 96 % ethanol. 48 hours after challenge with 7.5 % test article, partly slight, patchy erythema (score 0.5) was observed in the test group in 3/20 animals. No skin reactions were observed in the control animals. There was a very slight intergroup difference in the skin alterations between test- and control group.

RIPTAccording to “Guidance on information requirements and chemical safety assessment Chapter R.7.3.4.2” reliable and relevant human data should be used for hazard identification and are even preferable to animal data. The human repeat insult patch test (HRIPT) is considered to be a good predictor for the sensitisation potential (Bannan et al 1991).

Justification for read-across

For details on substance identity, toxicokinetics and detailed toxicological profiles, please refer also to the general justification for read-across given in chapter 5 of the CSR and attached as pdf document to section 7 of the IUCLID file.

a. Structural similarity and functional groups

The target substance, MDEA Esterquat C18 satd., consists of an amine backbone (MDEA = Methyldiethanol amine) esterified with the long chain fatty acid stearic acid (C18 satd.; IV (iodine value) < 1). The main reaction product is the dialkylester compound, next to that small amounts of the monoalkylester may be formed. The amine function is quaternised with two methyl groups. The counter ion is Chloride.

The source substance, MDEA Esterquat C16-18 and C18 unsatd., consists of the same amine backbone (MDEA = Methyldiethanol amine) but esterified with a mixture of the long chain fatty acids C16, C18 and C18 unsaturated (IV < 25). The main reaction product is the dialkylester compound, next to that small amounts of the monoalkylester may be formed. The amine function is quaternised with two methyl groups. The counter ion is Chloride.

The source and the target substance share structural similarities with common functional groups (quaternary amines, esters, and fatty acid chains with comparable length and degree of saturation).

b. Common breakdown products

The metabolism expected to occur is hydrolysis of the ester-bond by esterases. However, the rate of hydrolysis is assumed to be low. The fraction of metabolised molecules would result in free fatty acids and Dimethyl-DEA (DEA = Diethanolamine). The carboxylic acids 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 quaternary ammonium ions are not expected to be further metabolised, but excreted unchanged via the urine. 

c. Differences

The differences in fatty acid chain length (higher percentage of C16 in the source substance MDEA Esterquat C16 -18 and C18 unsatd.) and degree of saturation (higher degree of unsaturation of the C18 fatty acid chains in the source substance substance MDEA Esterquat C16-18 and C18 unsatd.) could be relevant for local toxicity (skin and eye irritation) but arebut are not considered to be of relevance for sensitisation.

Based on these available reliable, relevant and adequate datait can be concludedthat MDEA is not a dermal sensitizer.

 

Molecular structures and sensitization data of MDEA Esterquat C18 satd. and MDEA-Esterquat C16-18 and C18 unsatd.

 

 

Source substances

Target substance

 

Endpoints

 

MDEA-Esterquat C16-18 and C18 unsatd.

 

MDEA Esterquat C18 satd.

Skin Sensitisation

OECD 406 (GPMT), RL 2, GLP

 

Induction: occlusive epicutanous, 15% in ethanol

Challenge: occlusive epicutanous 15% in acetone

Rechallenge: occlusive epicutanous 7,5 and 15% in acetone

 

negative (not sensitizing)

read-across from MDEA-Esterquat C16-18 and C18 unsatd.

 

OECD 406 (GPMT), RL 2, GLP

 

Induction: occlusive epicutanous, 15% in ethanol

Challenge: occlusive epicutanous 7.5% in acetone

 

Negative (not sensitizing)

Human Repeat Insult Patch Tests, RL 2, GLP

 

3 Tests, including a total of 283 evaluated volunteers

 

Test substance concentration: 1.5-2% aqueous dilution

 

Negative (not sensitizing)

Respiratory sensitisation

No data available

No data available

Fatty acids

<C16      <7%                                            

C16, 16‘  26-35%

C18         42-52%

C18‘        15-20%

C18‘‘,18‘‘‘ ≤ 1.5%

>C18       ≤ 2%

C16 8%

C18 92%

IV

< 25

< 1

Headgroup

MDEA

MDEA

Anion

Chloride

Chloride

 

 

Quality of the experimental data of the analogues:

The source substance MDEA-Esterquat C16-18 and C18 unsatd. has been tested two a reliable GLP-compliant studies according to OECD 406 and three HRIPTwhichmeets generally accepted scientific standards and are described in sufficient detail (study conducted according to good clinical practices guideline 21CFR parts 50 and 56 and proposed ICH guidelines).

Therefore these data have no uncertainties and can be used in an analogue approach. The available data from the source chemical are sufficiently reliable to justify the read-across approach.

 

Classification and labelling (Human Health)

The source substance MDEA-Esterquat C16-18 and C18 unsatd. not classified for any human health effects similar to the target substance MDEA Esterquat C18 satd. which is also not classified regarding human health hazards.

 

 

Conclusion skin sensitisation

There is no data gap for skin sensitisation. Although there are no data available for MDEA Esterquat C18 satd. there is no reason to believe that results obtained with the structurally similar source substance MDEA-Esterquat C16 -18 and C18 unstad. in humans and guinea pigs would not be applicable.

 


Migrated from Short description of key information:
3 Human Repeat Insult Patch Tests, including a total of 283 evaluated volunteers;
Test substance concentration: 1.5-2% aqueous dilution; the observed irritation scores of 1 and 2 (of an overall scale of up to 6) were judged to be acceptable due to the nine extended exposures of 24 hours and due to the occlusive dressing. Edema, which would be indicative for a sensitising reaction was not observed in any of the challenged volunteers; read-across MDEA-Esterquat C16-18 and C18 unsatd.

2 Guinea pig maximisation tests: Not sensitising (according to OECD guideline 406, GLP), Induction: epicutanous with 15% test substance concentration, Challenge/rechallenge: epicutanous with 7.5%-15% test substance concentration; At challenge, slight erythema was observed in 4/40 test animals, no skin responses were observed at rechallenge; read-across MDEA-Esterquat C16-18 and C18 unsatd.

Justification for selection of skin sensitisation endpoint:
No single key study has been selected, since all available data have been considered in a weight of evidence approach

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

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 classification or non-classification

Based on relevant, reliable and adequate data, MDEA Esterquat C18 satd. does not have to be classified and labelled according to the CLP Regulation (EC) No 1272/2008 and Directive 67/548/EEC with respect to skin sensitisation.