Registration Dossier

Administrative data

Description of key information

The conclusion is drawn based on weight-of-evidence. QSAR predictions of the major and minor components were done, which did not result in structural alerts for skin sensitising properties. Two GPMTs are available: one performed with the registered substance and one performed with a substance analogue. Both tests did not show sensitising properties of the test substances.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
September - October 2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
The objective of this study was to obtain predictions on the skin sensitisation of the 4 representative potential C12-alkyl derivatives present in the substance with the DEREK NEXUS programme.
Principles of method if other than guideline:
The objective of this study was to obtain predictions on the skin sensitisation of the 4 representative potential C12-alkyl derivatives present in the substance with the DEREK NEXUS programme. In this assessment version 2.0.0 of DEREK NEXUS was used. DEREK NEXUS is a knowledge-based system that contains over 700 toxicity alerts based on the presence of substructures. The system contains more than 50 alerts specific to skin sensitization. The rules are based on the presence of specific substructures, or chemical classes related to potential mechanisms for skin sensitization.
GLP compliance:
no
Type of study:
other: DEREK assessments
Key result
Parameter:
other: structural alerts
Value:
0
Remarks on result:
other: For all 4 representative potential C12-alkyl derivatives present in the substance, DEREK NEXUS did not find any substructures in its database that fired an alert for sensitisation potential.

For all 4 representative potential C12-alkyl derivatives present in the substance, DEREK NEXUS did not find any substructures in its database that fired an alert for sensitisation potential.

Interpretation of results:
other: DEREK NEXUS did not find any substructures in its database that fired an alert for sensitisation potential for all 4 representative potential C12-alkyl derivatives present in the substance
Conclusions:
The objective of this study was to obtain predictions on the skin sensitisation of 4 representative potential C12-alkyl derivatives present in the substance (monoamphoacetate A and B, and diamphoacetate A and B) with the DEREK NEXUS programme. In this assessment version 2.0.0 of DEREK NEXUS was used. DEREK NEXUS is a knowledge-based system that contains over 700 toxicity alerts based on the presence of substructures. The system contains more than 50 alerts specific to skin sensitization. The rules are based on the presence of specific substructures, or chemical classes related to potential mechanisms for skin sensitization. For all 4 representative potential C12-alkyl derivatives present in the substance, DEREK NEXUS did not find any substructures in its database that fired an alert for sensitisation potential.
Endpoint:
skin sensitisation
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
October 2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
The objective of this study was to obtain predictions on the skin sensitisation of potential minor constituents (by-products) present in the substance with the DEREK NEXUS programme.
Principles of method if other than guideline:
The objective of this study was to obtain predictions on the skin sensitisation of potential minor constituents (by-products) present in the substance with the DEREK NEXUS programme. In this assessment version 2.0.0 of DEREK NEXUS was used. DEREK NEXUS is a knowledge-based system that contains over 700 toxicity alerts based on the presence of substructures. The system contains more than 50 alerts specific to skin sensitization. The rules are based on the presence of specific substructures, or chemical classes related to potential mechanisms for skin sensitization.
GLP compliance:
no
Type of study:
other: DEREK assessments
Key result
Parameter:
other: structural alert
Remarks on result:
other: For all 3 investigated potential minor constituents (by-products) present in the substance, DEREK NEXUS did not find any substructures in its database that fired an alert for sensitisation potential.

For all 3 investigated potential minor constituents (by-products) present in the substance, DEREK NEXUS did not find any substructures in its database that fired an alert for sensitisation potential.

Interpretation of results:
other: DEREK NEXUS did not find any substructures in its database that fired an alert for sensitisation potential for 3 potential minor constituents (by-products) present in the substance
Conclusions:
The objective of this study was to obtain predictions on the skin sensitisation of 3 potential minor constituents (by-products) present in the substance with the DEREK NEXUS programme. In this assessment version 2.0.0 of DEREK NEXUS was used. DEREK NEXUS is a knowledge-based system that contains over 700 toxicity alerts based on the presence of substructures. The system contains more than 50 alerts specific to skin sensitization. The rules are based on the presence of specific substructures, or chemical classes related to potential mechanisms for skin sensitization. For all 3 investigated potential minor constituents (by-products) present in the substance, DEREK NEXUS did not find any substructures in its database that fired an alert for sensitisation potential.
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
Reason / purpose:
read-across source
Key result
Reading:
1st reading
Hours after challenge:
48
Group:
test group
Dose level:
1 % (solid content approx. 0.394%)
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 1 % (solid content approx. 0.394%). No with. + reactions: 0.0. Total no. in groups: 10.0.
Key result
Reading:
2nd reading
Hours after challenge:
72
Group:
test group
Dose level:
1 % (solid content approx. 0.394%)
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 1 % (solid content approx. 0.394%). No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
1 % (solid content approx. 0.394%)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 1 % (solid content approx. 0.394%). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
1 % (solid content approx. 0.394%)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 1 % (solid content approx. 0.394%). No with. + reactions: 0.0. Total no. in groups: 5.0.
Interpretation of results:
GHS criteria not met
Conclusions:
In this adjuvant type guinea pig test method for skin sensitisation conducted with REWOTERIC AM C according to OECD 406 and GLP, positive reactions in 0 of the 20 animals (0%) were observed during challenge. Therefore, based on the results of this study the substance shall not be classified as a skin sensitiser in accordance with the CLP Regulation. This result is read across to the registered substance.
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
February 5, 1990 - March 13, 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Study conducted comparable to OECD 406 and GLP. Deviations: - no data provided about the latest reliability check (however because skin reactions were observed at challenge, the model seemed to be responsive) - the choice for the intradermal induction exposure was based on the minimal irritating exposure in the range finding test, while it should have been the highest exposure to cause mild-to-moderate skin irritation
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
no data about the latest reliability check; the choice for the intradermal induction exposure was based on the minimal irritating exposure in the range finding test, while it should have been the highest exposure to cause mild-to-moderate skin irritation
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The test substance was tested positive in an LLNA test (Sire, 2006). The test substance is a surfactant with irritating effects. As both properties are described in scientific literature as confounding factors for false positives, the LLNA result is considered inconclusive and an alternative test to the LLNA was thus needed.
Species:
guinea pig
Strain:
other: Pirbright white
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Fa. Winkelmann, Borchen, Germany
- Age at study initiation: no data
- Weight at study initiation: Main study: ca. 390 g (average)
- Housing:
Test group: 6 groups with 3 per cage and 1 group with 2 per cage (Makrolon Type IV)
Control group: 2 groups with 3 per cage and 2 groups with 2 per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 20-25 °C
- Humidity (%): ca. 45-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hrs/12 hrs

IN-LIFE DATES: From: February 12, 1990 To: March 9, 1990
Route:
intradermal and epicutaneous
Vehicle:
physiological saline
Concentration / amount:
See section "Details on study design"
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Concentration / amount:
See section "Details on study design"
No. of animals per dose:
Test animals: 20 (7 groups)
Control animals: 10 (4 groups)
Details on study design:
RANGE FINDING TESTS

6 animals were used in total for these tests

For the intradermal induction exposure:
- Concentrations: 0.5; 1; 2 and 3%
- Amount: 0.1 mL
- Scoring: the skin reactions were scored 24 and 48 hours after application
- Result (see also the attached background material): the lowest, the 0.5% concentration, showed to be minimal irritating and was used for the main test (although the highest exposure to cause mild-to-moderate skin irritation should have been choosen)

For the epicutaneous induction and challenge exposure (occlusive):
- Concentrations: (1) 30; 50 and 70% and (2) 10; 30 and 50%
- Amount: 0.1 g
- Scoring: the skin reactions were scored 24 and 48 hours after patch removal
- Exposure period: 48 hours (occlusive)
- Result (see also the attached background material): as at the 24 hours reading in the 1st experiment crusts were observed in almost all animals, the experiment was performed analogue on the other flank (left) with slightly lower concentrations. In this experiment it was shown that 50% can be considered a concentation causing minimal irritation, to use in the main test. As in the second experiment no irritating effects were observed at 10 and 30%, but irritating effects were observed at 30% in the 1st experiment, 20% was chosen as the non-irritating challenge concentration to use in the main test.

MAIN STUDY

Test animals: 20 (7 groups)
Control animals: 10 (4 groups)

A. INDUCTION EXPOSURE
- No. of exposures: 2
1) Intradermal injections on day 0:
- Concentration: 0.5% in physiol. saline
- Site: shoulder/back
Three pairs of intradermal injections:
1) 0.1 mL: FCA (50% in physiol. Saline)
2) 0.1 mL: 0.5% of the substance in physiol. saline
3) 0.1 mL: 50% with 0.5% of the substance in physiol. Saline + 50% FCA (50% in physiol. Saline)
-Readings: scores were rated 1 hour and 24 hours after injection
2)Topical application on day 7:
- Concentration: 50% in physiol. Saline
- Amount: 0.5 g (control animals: 0.5 mL of physiol. Saline)
- Area: approximately 6 cm^2
- Exposure period: 48 hours (occlusive)
- Readings: scores were rated 1 hour and 24 hours after patch removal
B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day of challenge: day 21 (14 days after the start of the 2nd induction)
- Exposure period: 24 hours (occlusive)
- Site: one flank, not specified which
- Concentration: 20% in physiol. saline
- Amount: 0.1 g
- Readings: scores were rated 24 and 48 hours after patch removal
Challenge controls:
Not applicable
Positive control substance(s):
not specified
Positive control results:
No data
Key result
Reading:
1st reading
Hours after challenge:
48
Group:
test group
Dose level:
20% (solid content approx. 7%)
No. with + reactions:
5
Total no. in group:
20
Clinical observations:
No data
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 20% (solid content approx. 7%). No with. + reactions: 5.0. Total no. in groups: 20.0. Clinical observations: No data.
Key result
Reading:
2nd reading
Hours after challenge:
72
Group:
test group
Dose level:
20% (solid content approx. 7%)
No. with + reactions:
4
Total no. in group:
20
Clinical observations:
No data
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 20% (solid content approx. 7%). No with. + reactions: 4.0. Total no. in groups: 20.0. Clinical observations: No data.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
20% (solid content approx. 7%)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No data
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 20% (solid content approx. 7%). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No data.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
20% (solid content approx. 7%)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No data
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 20% (solid content approx. 7%). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No data.

Animal No. / Animal Group No.

Intradermal induction

 

With 0.5% of the test material (solid content approximately 0.18%)

Epicutaneous induction

 

With 50% of the test material (solid content approximately 17.5%)

Challenge exposure

 

With 20% of the test material (solid content approximately 7%)

Scoring after 1 hour

Scoring after 24 hours

Scoring 1 hour after patch removal

Scoring 24 hours after patch removal

Scoring 24 hours after patch removal

Scoring 48 hours after patch removal

1/1

0

0

1

1

0

0

2/1

0

0

2

2

0

0

3/1

0

0

1

1

1

0

1/2

0

0

2

1

0

0

2/2

0

0

2

1

0

0

3/2

0

0

1

1

0

0

1/3

0

0

1

2

1

1

2/3

0

1

2

1

2

3/3

0

0

1

2

0

0

1/4

0

0

2

1

0

0

2/4

0

0

1

2

0

0

3/4

0

0

1

1

0

0

1/5

0

0

2

2

0

0

2/5

0

0

2

2

0

0

3/5

0

1

1

0

0

1/6

0

0

2

2

0

0

2/6

0

2

1

0

0

3/6

0

0

2

2

1

1

1/7

0

0

1

1

0

0

2/7

0

0

1

1

1

2; crust forming

- See the attached background material for the results of the Range finding tests

Other information:

- No mortalities

- No significant difference between the average body weight of the control and test animals during the study

Interpretation of results:
GHS criteria not met
Conclusions:
In this adjuvant type guinea pig test method for skin sensitisation conducted comparable to OECD 406 and GLP, positive reactions in 5 of the 20 animals (25%) were observed during challenge. Therefore, based on the results of this study the substance is not classified as a skin sensitiser in accordance with the CLP Regulation.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Local Lymph Node Assay (LLNA)

An aqueous solution of the substance (containing approx. 37%) was found to induce proliferation of lymphocytes in the murine Local Lymph Node Assay at a concentration of 50% (v/v) only (SI = 3.44). This may be a false-positive result, taking into account:

- that significant irritation was observed starting from this concentration, as shown by an increase in ear thickness (11.34% at the 50% concentration and ≥56% at 100% in the preliminary test)

- that the proliferation response was only marginally increased above the cut-off level (SI of 3), indicating a weak response in the presence of irritation

- that there have been several literature publications, reporting apparent false positive results from the LLNA for certain groups of chemicals, including surfactants (as also recognized in the OECD Guideline revised in 2010). Based on these publications it is considered justified to not conclude on the sensitisation potential of a surfactant only on the LLNA result (when more information is available)

As it is not clear whether a false-positive result was obtained and there is more information available, it is not considered justified to conclude on the sensitizing potential of this substance only on the results of this LLNA study. Therefore the conclusion of this study is assessed to be inconclusive.

Guinea Pig Maximization Test (GPMT)

In an adjuvant type guinea pig test method for skin sensitisation conducted similar to OECD 406 and GLP, positive reactions in 5 of the 20 animals (25%) were observed during challenge. Although a deviation of the study was to base the choice for the intradermal induction exposure on the minimal irritating exposure instead of on the highest exposure to cause mild-to-moderate skin irritation, the concentrations selected for the other phases of the study (topic applications for the induction and challenge phases) were in compliance with the guidelines. Based on the results of this study the substance does not need to be classified for skin sensitising in accordance with the CLP Regulation.

Human Repeated Insult Patch Test (HRIPT)

Under the conditions of a human repeated insult (occlusive) patch test procedure, a 0.5% aqueous dilution of the aqueous solution of the substance (at 0.15%) did not induce clinically significant skin irritation nor show any evidence of induced allergic contact dermatitis in human subjects. This concentration is likely representative of in-use conditions for most consumer formulations.

DEREK assessments

Predictions on the skin sensitisation potential of the 4 representative potential C12-alkyl derivatives and of 3 potential minor constituents (by-products) present in the substance were obtained with the DEREK NEXUS programme. In this assessment version 2.0.0 of DEREK NEXUS was used. DEREK NEXUS is a knowledge-based system that contains over 700 toxicity alerts based on the presence of substructures. The system contains more than 50 alerts specific to skin sensitization. The rules are based on the presence of specific substructures, or chemical classes related to potential mechanisms for skin sensitization. For all 7 investigated structures (potentially) present in the substance, DEREK NEXUS did not find any substructures in its database that fired an alert for sensitisation potential.

Additional supporting considerations

The main potential surfactant structures present did not trigger any structural alerts in a second sensitization assessment model, ToxTree v.2.1.0, i.e. no alert for nucleophilic aromatic substitution, Schiff Base formation, Michael acceptor, acyl transfer agents, or nucleophilic aliphatic substitution.

Despite a long history of use in consumer products, there are only rare occurrences of in-use sensitization reports with surfactants in general, and with alkylamphoacetates more specifically.

Read across data

In an adjuvant type guinea pig test method for skin sensitisation conducted according to OECD 406 and GLP, positive reactions in 0 of the 20 animals (0%) were observed during challenge with an aqueous solution of the read across substance AMPHOACETATES C8-C18 (common name). See also the document with the read across rationale, attached in Section 13.

Conclusion

Based on a weight-of-evidence approach it is considered justified to conclude that the substance has a low potential to cause skin sensitisation in humans.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Skin sensitisation

Based on a weight-of-evidence approach, the substance is considered to be not classified for skin sensitisation in accordance with the CLP Regulation.

Respiratory sensitisation

Due to the lack of data, the substance is not classified. In addition, given the physical-chemical properties of the substance and its use pattern, a potential for causing respiratory sensitisation is unlikely.