Registration Dossier

Administrative data

Description of key information

Skin irritation
Not irritating to skin; OECD TG 404, in vivo, rabbit, Type of coverage: semiocclusive, spray dried, 99.4% a.i. (RL1, GLP) read-across: C8-18 and C18 unsatd. AAPB
Not irritating to skin; OECD TG 404, in vivo, rabbit, Type of coverage: semiocclusive, 38.2% a.i. in water (RL1, GLP) read-across: Formamidopropylbetaine
Eye irritation:
irreversible effects on the eye (Category 1); OECD TG 405, in vivo, rabbit (RL1, GLP) read-across: C8-18 and C18 unsatd. AAPB

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No experimental data on skin and eye irritation are available for the target substance Undecylenamidopropyl Betaine. However, in vivo skin and eye irritation studies are available for the closely related source substances C8-18 and C18 unsatd. AAPB (Coco AAPB) and Formamidopropylbetaine. A justification for read-across is given below.

 

Skin irritation/corrosion

In a primary dermal irritation study according to EU Method B.4 (1992) and OECD Guideline 404 (1992), 3 New Zealand White rabbits were dermally patch (2.5 x 2.5 cm²) exposed for 4 hours to 0.5 g of Coco AAPB (99.4 % dry solids) moistened with physiological saline. Test sites were covered with semi-occlusive dressing. Animals were then observed for 72 hours. Irritation was scored according to Draize as stipulated in the OECD guideline.

30 to 60 minutes after patch removal, 3/3 animals showed well defined erythema (score 2) and 1/3 animals each very slight edema (score 1) or slight edema (score 2), 1/3 animals was free of edema at this observation. At the 24 hours scoring, erythema had lessened in 2/3 animals to score 1 and worsened in 1/3 animal to score 3. At the 24 hours scoring 2/3 animals showed an edema score 1. The only skin reaction still present at the 48 hours scoring, was a erythema score 2 in 1/3 animals. Fully reversibility in all animals was reached for erythema at the 72 hours scoring and for edema at the 48 hours scoring.

In this study, Coco AAPB (99.4 % dry solids) was not a dermal irritant.

 

The potential of Formamidopropylbetaine (38.2% a.i.) to cause inflammatory or corrosive changes upon first contact with skin was assessed by semi-occluded application of the test substance for four hours to the shorn skin of two female and one male rabbit, strain New Zealand White according to the OECD Guideline 404. As neither corrosive nor strong irritating effects to the skin have been expected, the test substance was applied to all three animals for four hours at the same time. Dermal reactions at the treated skin sites were assessed 1 hour after removal of the test substance and approximately 24, 48, and 72 hours as well as 7 days later.

Systemic toxic symptoms after application were not observed at any time during the study. Body weight development of the animals was positive and within normal ranges. Only very slight erythema but no oedema was observed in one animal 1 h after removal of the test substance. Especially between 24 and 72 hours no erythema and oedema were observed. The mean scores for erythema and oedema formation for the time period 24 h - 72 h were 0. Under the conditions of this study the test substance is not irritating and does not have to be classified for skin irritation.

 

Eye irritation/corrosion

In a primary eye irritation study according to EU Method B.5 (1992) and OECD Guideline 405 (1987), 100 mg of Coco AAPB (99.4 % dry solids) was instilled into the conjunctival sac of one New Zealand white rabbit. The eye was not rinsed after test substance instillation. After the first scoring one hour after test substance instillation, the test was terminated. Irritation was scored according to Draize as stipulated in the guidelines.

The treated eye showed 1 h after dosing extreme bleeding of conjunctivae and nictating membrane, blood coloured discharge, reddened iris, cornea opacity score 2 of one half of the cornea, iritis score 1, conjunctival erytheme and chemosis score 3. The untreated control eye showed no abnormalities.

After this scoring the animals was humanely killed because of severity of effects.

In this study, Coco AAPB (99.4 % dry solids) caused irreversible effects on the eye.

 

In a primary eye irritation study according to OECD Guideline 405 0.1 mL Formamidopropylbetaine (50% a.i.) was instilled into the conjunctival sac of 3 New Zealand white rabbits. The eyes were rinsed after the 24 h observation.

Ocular reactions were assessed 1, 24, 48, 72 hours and 7 days after application of the test substance. At 24 hours post application the eyes of all animals were further examined with fluorescein to look for cornea damage. Systemic toxic symptoms after application were not observed at any time during the study. Body weight development was positive and within normal ranges. All 3 animals showed slight ocular reaction (conjunctivae redness 1 score, conjunctivae chemosis 1 or 2 scores and conjunctivae discharge 1 score) 1 h after application of the test substance. In one animal a slight conjunctivae redness and chemosis was still observed 24 h after application. 24 hours later (48 h after application) all three animals were without any sign of ocular irritation. Cornea damage or iris irritation was not observed at any time during the study. Under the conditions of this study the test substance Formamidopropylbetaine (50% a.i.) was graded as non-irritating to eyes.

 

Summary

Based on interpolation of the results from the available studies on skin irritation conducted with the closely related source substances C8-18 and C18 unsatd. AAPB and Formamidopropylbetaine, the target substance Undecylenamidopropyl Betaine is considered to be not irritating to skin.

 

Based on the available data obtained with the source substance C8-18 and C18 unsatd. AAPB, the target substance Undecylenamidopropyl Betaine is considered to cause irreversible effects on the eye. As the structural relationship of the target substance is closer to the source substance C8-18 and C18 unsatd. AAPB than to the source substance Formamidopropylbetaine, the results of C8-18 and C18 unsatd. AAPB are considered to be more relevant for the target substance.

 

There are no data gaps for the endpoint irritation/corrosion. No human data are available. However, there is no reason to believe that these results from rabbit would not be applicable to humans.

 

Justification for read-across

For details on substance identity and detailed toxicological profiles, please refer also to the general justification for read-across given at the beginning of the CSR and attached as pdf document to IUCLID section 13.

This read-across approach is justified based on structural similarities. The target and source substances contain the same functional groups. Thus a common mode of action can be assumed.

 

a. Structural similarity and functional groups

The target substance Undecylenamidopropyl Betaine is a monoconstituent substance manufactured from undecylenic acid and N, N-dimethylpropylenediamine (DMAPA) and further reacted with monochloroacetic acid.

 

The source substance C8-18 and C18 unsatd. AAPB is aUVCB substance manufactured from natural fatty acids or oils and  N, N-dimethylpropylenediamine (DMAPA) and further reacted with sodium monochloroacetate. As their origin is from natural sources, the used fatty acids may have a mixed slightly varying composition with an even numbered chain length from C8 to C18. Unsaturated C18 amounts may be included.

 

The source substance Formamidopropylbetaine is a monoconstituent substance manufactured from formic acid and N, N-dimethylpropylenediamine (DMAPA) and further reacted with sodium monochloroacetate.

 

b. Differences

Differences in chemical and other intrinsic properties of the target and source substances could potentially arise from the following facts:

-Different amounts of different carbon chain lengths (carbon chain length distribution):

Higher amounts of higher chain lengths and corresponding lower amounts of lower chain length lead to a rising average lipophilicity as can be seen from the increasing log Kow from Formamidopropylbetaine (log Kow: -3.3), Undecylenamidopropyl Betaine (log Kow: -1.38), C8-18 and C18 unsatd. AAPB (log Kow:4.23).

 

- Different amounts of unsaturated fatty ester moieties:

The source substance C8-18 and C18 unsatd. AAPB contains considerable amounts of unsaturated C18 chains, which represents a worst case with respect to some toxicological endpoints, mainly local effects (e.g. irritation, sensitisation) (HERA, 2002; Stillman, 1975; Aungst, 1989).

 

The provided structural similarities and impurity profiles support the proposed read-across hypothesis with high confidence.

 

Comparison of irritation data

 

Endpoints

Target substance

Source substances

 

Undecylenamidopropyl Betaine

C8-18 and C18 unsatd. AAPB

Formamidopropyl-betaine

Skin irritation, in vivo

No data, read-across

WoE_RA_99.4% dry solids_Skin irritation / corrosion: 61789-40-0_8.1.1_HOECHST_1995_OECD404


OECD TG 404, in vivo, rabbit, Type of coverage: semiocclusive, spray dried, 99.4% a.i.


not irritating

 

Reliability: 1 (reliable without restriction), GLP

WoE_RA_LTOE 16399 Skin irritation / corrosion

 

OECD TG 404, in vivo, rabbit, Type of coverage: semiocclusive, 38.2% a.i. in water


not irritating

 

Reliability: 1 (reliable without restriction), GLP

Eye irritation, in vivo

No data, read-across

sup_RA_99.4% dry solids_Eye irritation: 61789-40-0_8.2.1_HOECHST_1995_OECD_405

 

OECD TG 405, in vivo, rabbit, spray dried, 99.4% a.i.

 

Category 1 (irreversible effects on the eye)

 

Reliability: 1 (reliable without restriction), GLP

sup_RA_LTOE 16433 Eye irritation.001

 

OECD TG 405, in vivo, rabbit, 50% as manufactured

 

not irritating

 

Reliability: 1 (reliable without restriction), GLP

 

The source substances C8-18 and C18 unsatd. AAPB and Formamidopropylbetaine were not irritating to skin: In the study with C8-18 and C18 unsatd. AAPB, mean values of skin reactions at 24, 48 and 72 h were less than the cut-off values for classification i. e. < 2.3 (CLP) for erythema/eschar and edema in each individual animal. Also, all findings were fully reversible.

Formamidopropylbetaine was tested at 38.2% a.i.; the scores for erythema and edema were zero in all three animals.

The source substance C8-18 and C18 unsatd. AAPB caused irreversible effects to the eye, whereas the source substance Formamidopropylbetaine caused only minimal irritating effects not leading to classification.

 

Quality of the experimental data of the analogues:

The available data are adequate and sufficiently reliable to justify the read-across approach.

The source substances were tested in reliable (RL1) GLP-compliant studies according to OECD TG 404 and 405.

The test materials used in the respective studies represent the source substance as described in the hypothesis in terms of substance identity and minor constituents.

Overall, the study results are adequate for the purpose of classification and labelling and risk assessment.

 

Conclusion

Based on structural similarities of the target and source substances as presented above and in more detail in the general justification for read across, it can be concluded that the available data on skin irritation from the source substances C8-18 and C18 unsatd. AAPB and Formamidopropylbetaine are also valid for the target substance Undecylenamidopropyl Betaine.

C8-18 and C18 unsatd. AAPB is a worst case model substance, as it contains short chain fatty acid moieties as well as unsaturated moieties, fatty acid amounts which might have some increasing influence on the irritating potential. However, both source substances, C8-18 and C18 unsatd. AAPB and Formamidopropylbetaine were not irritating to skin. Thus, by interpolation also the target substance Undecylenamidopropyl Betaine is considered to be not irritating to skin.

 

The source substance C8-18 and C18 unsatd. AAPB caused irreversible effects to the eye, whereas the source substance Formamidopropylbetaine was not irritating to the eyes. As the structural relationship of the target substance is closer to the source substance C8-18 and C18 unsatd. AAPB than to the source substance Formamidopropylbetaine based on chain length and the presence of unsaturated C chains, the results of C8-18 and C18 unsatd. AAPB are considered to be more relevant for the target substance.

Based on the available data, the target substance Undecylenamidopropyl Betaine is considered to cause irreversible effects on the eye.

 

References

Aungst, 1989.Structure/Effect Studies of Fatty Acid Isomers as Skin Penetration Enhancers and Skin Irritants. Pharmaceutical Research, March 1989, Volume 6, Issue 3, pp 244-247

 

HERA, 2002: Fatty Acid Salts – Human Health Risk Assessment

Stillman et al., 1975. Relative irritancy of free fatty acids of different chain length. Contact Dermatitis. 1975;1(2):65-9.


Justification for selection of skin irritation / corrosion endpoint:
No single study has been selected as key study, since all available data are considered together in a weight of evidence approach.

Justification for selection of eye irritation endpoint:
No single study has been selected as key study, since all available data are considered together in a weight of evidence approach.

Effects on eye irritation: corrosive

Justification for classification or non-classification

Skin irritation

Based on reliable, adequate and relevant data, Undecylenamidopropyl Betaine does not need to be classified for skin irritation according to regulation (EC) 1272/2008.

 

Eye irritation

Based on reliable, adequate and relevant data, Undecylenamidopropyl Betaine is classified as Category 1 (Irreversible effects on the eye) according to regulation (EC) 1272/2008 and labelled with H318: Causes serious eye damage and the signal word “Danger”.