Poly(oxy-1,2-ethanediyl), α-(carboxymethyl)-ω-hydroxy-, C16-18 (even numbered) and C18-unsatd. alkyl ethers

Endpoint summary

Description of key information

No significant concern can be reliably derived for the registration substance with respect to the endpoint sensitisation.

 

Guinea pig maximisation test (study performed prior to adoption of LLNA guideline): Not sensitising (according to OECD guideline 406 / EU method B.6), Induction: intradermal with 0.5% test substance concentration, epidermal with 10% test substance concentration on day 7; Challenge: topical with 1% (highest non-irritating concentration) and 0.3% test substance concentration; no signs of erythema or oedema in any reading. Read-across:Polyoxyethylene(9) oleyl ether carboxylic acid

Guinea pig maximisation test (study performed prior to adoption of LLNA guideline): Not sensitising (according to OECD guideline 406 / EU method B.6), Induction: intradermal with 0.5% test substance concentration, epidermal with undiluted test substance concentration on day 7; Challenge: topical with 0.01% test substance concentration (highest non-irritating concentration); no signs of erythema or oedema in any reading. Read-across:Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid

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:

weight of evidence

Justification for type of information:

REPORTING FORMAT 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 / identical precursors under similar conditions
• they share structural similarities with common functional groups:
o fatty alcohol ethoxylates with a terminating carboxylic acid group
o a linear alkyl moiety (differing slightly in length and degree of saturation)
o ethylene oxide chain (varying slightly in mean length)

Therefore, read-across from the existing sensitisation studies on 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.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.01%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no skin reactions were evident in the control animals and animals of the test group

Remarks on result:

no indication of skin sensitisation

Remarks:

for Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

0.01%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no skin reactions were evident in the control animals and animals of the test group

Remarks on result:

no indication of skin sensitisation

Remarks:

for Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0,3% and 1%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no skin reactions were evident in the control animals and animals of the test group

Remarks on result:

no indication of skin sensitisation

Remarks:

for Polyoxyethylene(9) oleyl ether carboxylic acid

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

0.3% and 1%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

no skin reactions were evident in the control animals and animals of the test group

Remarks on result:

no indication of skin sensitisation

Remarks:

for Polyoxyethylene(9) oleyl ether carboxylic acid

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the available data Polyoxyethylene(1 to 2.5) oleyl ether carboxylic acid is not be classified as sensitising to the skin according to regulation (EC) 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Data on sensitisation are not available for the target substance Polyoxyethylene(1 to 2.5) oleyl ether carboxylic acid. For the assessment of the skin sensitisation potential of Polyoxyethylene(1 to 2.5) oleyl ether carboxylic acid, results from the following studies are taken into consideration:

- an GMPT according to OECD guideline 406 with the source substance Polyoxyethylene(9) oleyl ether carboxylic acid

- an GPMT according to OECD guideline 406 with the source substance Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid

 

In a dermal sensitisation study according to OECD Guideline 406 (adopted 17th July 1992) with Polyoxyethylene(9) oleyl ether carboxylic acid (90% a.i.) in distilled water, young adult female Albino Hartley guinea pigs (10 in test group, 5 in control group) were tested using the method of Magnusson and Kligman. DNCB (2,4-dinitrochlorobenzene) and formaldehyde were used as historical positive control substances.

Based on the results of a preliminary study, the test substance concentrations selected for the main study were a 0.5% concentration (in 0.9% NaCl solution) for the intradermal induction and a 10% concentration (in distilled water) for the epidermal induction exposure. A 1 and 0.3% test substance concentration (in distilled water) was selected for the challenge phase.

Following a challenge exposure to a 1 and 0.3% test substance concentration, no skin reactions were evident in the control animals and all other experimental animals (24 and 48h readings). The sensitisation rate was 0%.

According to CLP, EU GHS (Regulation (EC) No 1272/2008), a response of at least 30% of the test animals of an adjuvant type guinea pig test method for skin sensitisation is considered as positive.

Polyoxyethylene(9) oleyl ether carboxylic acid is not a dermal sensitiser in this study.

 

In a dermal sensitisation study according to OECD Guideline 406 (adopted 17th July 1992) and EU method B.6 (1992) with Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid (90% a.i.) in hydroxypropyl-methylcellulose gel, young adult male Dunkin-Hartley guinea pigs (10 in test group, 5 in control group) were tested using the method of Magnusson and Kligman. Potassium dichromate was used as positive control.

Based on the results of a preliminary study, the test substance concentrations selected for the main study were a 0.5% concentration (in 0.9% NaCl solution) for the intradermal induction and a 100% concentration for the epidermal induction exposure. A 0.01% test substance concentration (in 0.8% aqueous hydroxypropyl-methylcellulose gel) was selected for the challenge phase.

After epidermal induction all animals of the experimental group showed signs of irritation. Following a challenge exposure to a 0.01% test substance concentration, no skin reactions were evident in the control animals and animals of the test group (24, 48 and 72 h readings). The sensitisation rate was 0%.

According to CLP, EU GHS (Regulation (EC) No 1272/2008), a response of at least 30% of the test animals of an adjuvant type guinea pig test method for skin sensitisation is considered as positive.

Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid is not a dermal sensitiser in this study.

 

Justification for read-across

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 / identical precursors under similar conditions

·        they share structuralsimilarities with common functional groups:

o   fatty alcohol ethoxylates with a terminating carboxylic acid group

o   a linear alkyl moiety (differing slightly in length and degree of saturation)

o   ethylene oxidechain (varying slightly in mean length)

Therefore, read-across from the existing sensitisation studies on 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.

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

 

1. Substance Identities

The target and source substances are manufactured by the reaction of fatty alcohol ethoxylates with sodium chloroacetate under alkaline conditions. The main components can be described as fatty alcohol ethoxylate linked via ether bond to the acetic acid. The general structure of the alkyl polyglycol ether carboxylic acidis:

 

 R-O-(CH₂CH₂O-)_nCH₂COOH

 

with R = linear alkyl chain, C12 – C18, C18:1

and n = 1 - 9

 

The target substance Polyoxyethylene(1 to 2.5) oleyl ether carboxylic acid contains mainly 9-octadecenyl chains (=C18 unsaturated) and a mean number of 2.5 EO units.

 

The source substances vary in thecarbon chain length of the alkyl chain as well as in the number of EO units:

 

The source substance Polyoxyethylene(9) oleyl ether carboxylic acid contains a 9-octadecenyl chain (=C18 unsaturated) and a mean number of 9 EO units.

The source substance Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid contains lauryl and myristyl chains (C12, C14, saturated) and a mean number of 4.5 EO units.

 

 

Table 1: Substance identities

	Target substance	Source substances
	Polyoxyethylene(1 to 2.5) oleyl ether carboxylic acid	Polyoxyethylene(9) oleyl ether carboxylic acid	Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid
CAS number	57635-48-0	57635-48-0	27306-90-7
Moles EO (mean)	2.5	9	4.5
Chain length distribution	C12: < 5% C14: < 10% C16: 2 - 25% C18 1 - 15 % C18:1(oleyl):60- 95%	C12: < 5% C14: < 10% C16: 2 - 25% C18 1 - 15 % C18:1(oleyl):60- 95%	C12: 70% C14: 30%
Composition	Alkylethercarboxylic acid: 60-90%   Alkylethoxylate < 2.5 EO: 5-30%   Ester: 0-25%	n.a.	Fatty alcohol: 8%
Minor constituents	Alkylethercarboxylic acid: 30-80%   Alkylethoxylate <2.5EO: 5-40%   Esterification products ofAlkylethercarboxylic acidand Alkylethoxylate: 1-35%   Fatty alcohol: < 1%	Alkylethercarboxylic acid: 30-80%   Alkylethoxylate:0-40%   Esterification products of Alkylethercarboxylic acid and Alkylethoxylate: 1-35%   Fatty alcohol: < 1%	Alkylethercarboxylic acid: 30-80%   Alkylethoxylate: 0-40%   Esterification products of Alkylethercarboxylic acid and Alkylethoxylate: 1-35%   Fatty alcohol: < 10 %

 

2. Impurities

The target and source substances belong to the group of alkyl polyglycol ether carboxylic acid, which are manufactured from different fatty alcohol ethoxylates as raw material. Since the impurities in the fatty alcohol ethoxylates are considered to be comparable, the impurities of the registration substance and of other alkyl polyglycol ether carboxylic acid are expected to be comparable. A difference in irritation or sensitisation potential due to different impurity profiles is not likely.

 

3. Analogue approach justification

The read-across hypothesis is based on structural similarity of target and source substances. The respective reliable data (RL 1 or 2) are summarized in the data matrix; robust study summaries are included in the Technical Dossier in the respective sections.

 

The read-across from the source substances is justified:

 

a)    Based on the information given in section 1, it can be concluded that the substances are similar in structure, since they are manufactured from similar or identical precursors under similar conditions and all contain the same functional groups. Thus a common mode of action can be assumed.

b)   The content of minor constituents in all products are comparable and differ to an irrelevant amount.

c)    The only deviations within this group of substances is a variety in their alkyl chain length as well as in the number of EO units, which is not expected to have a relevant impact on intrinsic toxic activity.

 

 

3.1. Structural similarity and functional groups (Table 1)

The general structure of the alkyl polyglycol ether carboxylic acidis:

 

 R-O-(CH₂CH₂O-)_nCH₂COOH

 

with R = linear alkyl chain, C12 – C18, C18:1

and n = 1 - 9

 

target substance:

Polyoxyethylene(2.5) oleyl ether carboxylic acid: R = C18:1, n =2.5.

 

source substances:

Polyoxyethylene(9) oleyl ether carboxylic acid: R = C18:1, n =9

Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid: R = C12-14, n =4.5

 

 

3.2. Differences

 

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

 

-      Differences in C-chain length and unsaturated moieties:

The source substance Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid contains mainly shorter chain lengths (C12 - 14, saturated) compared to the target substance (mainly C18:1).

The presence of unsaturated C18 chains may be considered as a worst case with respect with respect to local effects (irritation, sensitisation) (HERA, 2002; Stillman, 1975; Aungst, 1989). As also data on skin irritation and sensitisation are available for the source substance Polyoxyethylene(9) oleyl ether carboxylic acid (containing C18:1 chains like the target substance), it is demonstrated based on experimental data, that the small difference in C-chain length and degree of unsaturation is not relevant for this read-across approach.

 

-      Differences in number of EO units:

The degree of ethoxylation may influence the irritation potential: longer EO chains may exhibit a slightly lower irritation potential (HERA, 2009). However, the difference in number of EO units is rather small between the target and source substances (ranging from 2.5 to 9). Ethoxylation is generally not associated with sensitisation (HERA, 2009). Thus, difference in the number of EO units is of no concern for this endpoint.

 

The target and source substances belong to the group of alkyl polyglycol ether carboxylic acid, the structural difference being only different alkyl moieties and number of ethylene glycol units. Based on the incremental change in the chemical structures among the members, the read-across is justified with high confidence.

 

4. Data matrix

	Polyoxyethylene(2.5) oleyl ether carboxylic acid	Source chemicals: Alkyl polyglycol ether carboxylic acid
Endpoints	Hazard profile/ Hazard assessment method	Hazard profile
Irritation
Skin	read-across	Not irritating	C12-14/4.5EO/27306-90-7   C12-14/2.5EO/NA Salt/33939-64-9   Oleyl/9EO/57635-48-0   C12-14/4.5EO Na Salt/33939-64-9
Eye	read-across	corrosive	C12-14/4.5EO/27306-90-7
Skin Sensitization
	read-across	not sensitizing	Oleyl/9EO/57635-48-0   C12-14/4.5EO/27306-90-7

 

 

Schematic overview sensitisation 

		Target substance
	Polyoxyethylene(9) oleyl ether carboxylic acid	Polyoxyethylene(1 to 2.5) oleyl ether carboxylic acid	Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid
Moles EO (mean)	9	2.5	4.5
Main alkyl chain	C18:1	C18:1	C12 / C14
Na salt / free acid	Acid	Acid	Acid

 

Based on interpolation from the results obtained with the source substances Polyoxyethylene(9) oleyl ether carboxylic acid and Polyoxyethylene(4.5) lauryl miristyl ether carboxylic acid, which were both not sensitizing, the target substance Polyoxyethylene(1 to 2.5) oleyl ether carboxylic acid is considered to be not sensitizing.

 

5. Quality of the experimental data of the analogues

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

The studies were conducted according to OECD Guideline 406 (GPMT) and are reliable without restrictions (RL1).

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

 

6. 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; http://www.heraproject.com/files/5-HH-04-HERA%20Fatty%20acid%20salts%20HH%20web%20wd.pdf

 

HERA, 2009: Alcohol Ethoxylates; http://www.heraproject.com/files/34-F-09%20HERA%20AE%20Report%20Version%202%20-%203%20Sept%2009.pdf

 

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

 

Conclusion skin sensitisation

There is no data gap for skin sensitisation. Although no human data are available for Polyoxyethylene(1 to 2.5) oleyl ether carboxylic acid, 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

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, Polyoxyethylene(1 to 2.5) oleyl ether carboxylic aciddoes not have to be classified and labelled according to the CLP Regulation (EC) No 1272/2008 with respect to skin sensitisation.