Registration Dossier

Administrative data

Description of key information

Based on the available weight of evidence from HRIPT and studies on substances representative of the main constituents, the test substance, 'mono- and di- C16-18 PSE and C16-18 AE20 PSE' is considered to be a non-sensitising to the skin.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
From April 16, 2001 to May 24, 2001
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
A Human Repeated Insult Patch Test (HRIPT) was conducted to determine the skin sensitivity potential of the test substance, following epicutaneous induction with 5% test substance concentrations to 53 healthy volunteers for 24 h under a semi-occlusive conditions. After a rest period of ca. 2 weeks, the substance was applied under the same conditions to a new site as a challenge. A the end of 24 h, the semi-occluded patch is removed and the site is read for immediate response. Follow-up readings are made 24 and 72 h later. The skin effects are then scored for irriation (erythema, edema as well as other irritation signs).
GLP compliance:
yes
Remarks:
ICH Guideline E6 for Good Clinical Practice (GCP) and 21CFR part 50 and 56 compliant
Type of study:
patch test
Justification for non-LLNA method:
- Human study
Species:
other: Human, healthy volunteers
Sex:
male/female
Route:
epicutaneous, semiocclusive
Vehicle:
not specified
Concentration / amount:
0.2 mL (5% solution)
Day(s)/duration:
application of 24 hours on 3 different days for three weeks
Adequacy of induction:
not specified
Route:
epicutaneous, semiocclusive
Vehicle:
not specified
Concentration / amount:
0.2 mL (5% solution)
Day(s)/duration:
24 hours, then follow-up readings (at 24 and 72 h)
Adequacy of challenge:
other: sensitisation responses on an adjacent virgin test site
No. of animals per dose:
53
Details on study design:
In the induction phase, 0.2 mL test substance preparation (5%) was applied epicutaneously on 53 healthy volunteers for 24 h under an semiocclusive type of coverage. The applications were done daily on Monday, Tuesday and Friday for 3 consecutive weeks. After a rest period of ca. 2 weeks, the test substance was applied with the same conditions on a new site as a challenge. A the end of 24 h, the semi-occluded patch was removed and the site was read for immediate response. Follow-up readings were made 24 and 72 h later. The skin effects were then scored for irriation (erythema, edema as well as other irritation signs).
Challenge controls:
-
Positive control substance(s):
no
Positive control results:
-
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
0.2 mL of a 5% test solution
No. with + reactions:
0
Total no. in group:
53
Clinical observations:
none
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
72
Group:
test group
Dose level:
0.2 mL of a 5% test solution
No. with + reactions:
0
Total no. in group:
53
Clinical observations:
none
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Group:
negative control
Remarks on result:
not measured/tested
Key result
Reading:
1st reading
Group:
positive control
Remarks on result:
not measured/tested
Interpretation of results:
other: not classified based on EU CLP criteria
Conclusions:
Under the study conditions, the test substance was not considered as a human skin sensitizer (semi-occlusive patch test).
Executive summary:

A study was conducted to determine the skin sensitisation potential of the test substance, mono- and di- C16-18 PSE and C16-18 AE20 PSE’ using human repeated insult patch test (HRIPT), in compliance with ICH Guideline E6 for Good Clinical Practice (GCP) and 21CFR part 50 and 56. In the induction phase, a 5% test substance preparation was applied epicutaneously 3 times weekly to 53 healthy volunteers for 24 h under a semi-occlusive conditions. After a rest period of ca. 2 weeks, the substance was applied under the same conditions to a new site as a challenge. At the end of 24 h, the semi-occluded patch was removed and the site was read for immediate response. Follow-up readings were made 24 and 72 h later. The skin effects were then scored for irriation (erythema, edema as well as other irritation signs). No visible irritation was observed in any of the 53 individuals following challenge. Under the study conditions, the test substance was not considered to be sensitising to the human skin at 5% test concentration (CPT, 2001).

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
From May 25, 2005 to June 13, 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
KL2 due to RA
Justification for type of information:
Refer to section 13 of IUCLID for details on the read-across justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA:J
Sex:
female
Details on test animals and environmental conditions:
Source: Jackson Laboratories
Acclimation: 5 days
Number of animals: 37 females (nulliparous and non-pregnant)
Body weight: 16 - 21g
Body weight variation was within +/- 20% of the sex mean.
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle.
Diet: Fresh PMI (Diet #5001)
Water: free access to tap water.
Vehicle:
other: Ultrapure liquid petrolatum
Concentration:
0, 2.5, 5, 10 and 25% w/w
No. of animals per dose:
5
Details on study design:
The test substance concentrations selected for the main study were based on the results of a pre-screen test. In the main study, four experimental groups of five female CBA/J mice were treated with test substance concentrations of 2.5, 5, 10 or 25% w/w for three consecutive days, by topical application on the ears. Five vehicle control animals were similarly treated, but with the vehicle alone (Liquid petrolatum). A positive control group with a-hexylcinnamaldehyde (HCA - 50%) was also included in the experiment. Five days after the last exposure, all animals were injected with 5-bromo-2'-deoxy-uridine (BrdU) and the draining (auricular) lymph nodes were then isolated and pooled for each animal. Cells were fixed using 70% ethanol and used for the measurement of the cell number and the BrdU determination (percentage of proliferating cells in "S" phase). Flow cytometry was conducted for analysis and stimulation index (SI) was recorded
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Statistics:
SI
Positive control results:
The SI value calculated for the positive control was 9.6 and ear swelling was observed in this group.
Key result
Parameter:
SI
Value:
ca. 0.9
Variability:
+/- 0.7
Test group / Remarks:
2.5%
Key result
Parameter:
SI
Value:
ca. 0.9
Variability:
+/- 0.6
Test group / Remarks:
5%
Key result
Parameter:
SI
Value:
ca. 0.7
Variability:
+/- 0.3
Test group / Remarks:
10%
Key result
Parameter:
SI
Value:
ca. 0.3
Variability:
+/- 0.1
Test group / Remarks:
25%
Cellular proliferation data / Observations:
- SI values were similar among the control and test groups and were below 3. Three concentrations (i.e.2.5, 5 and 25%) induced ear swelling.
- No mortality occurred and no clinical signs of systemic toxicity were observed in the animals of the main study. Body weights and body weight gain of experimental animals remained in the same range as controls over the study period.
Interpretation of results:
other: not classified based on EU CLP criteria
Conclusions:
Based on the results of the read across study, the test substance, is considered to be non-sensitising to the skin.
Executive summary:

A study was conducted to determine the skin sensitisation potential of the read across substance, 'mono- and di- C16 PSE and H3PO4' (98.5%) according to OECD Guideline 429 and US EPA OPPTS 870.2600 (LLNA), in compliance with GLP. The read across substance concentrations selected for the main study were based on the results of a pre-screen test. In the main study, four experimental groups of five female CBA/J mice were treated with read across substance concentrations of 2.5, 5, 10 or 25% w/w for three consecutive days, by topical application on the ears. Five vehicle control animals were similarly treated, but with the vehicle alone (Liquid petrolatum). A positive control group with a-hexylcinnamaldehyde (HCA - 50%) was also included in the experiment. Five days after the last exposure, all animals were injected with 5-bromo-2'-deoxy-uridine (BrdU) and the draining (auricular) lymph nodes were then isolated and pooled for each animal. Cells were fixed using 70% ethanol and used for the measurement of the cell number and the BrdU determination (percentage of proliferating cells in "S" phase). Flow cytometry was conducted for analysis and stimulation index (SI) was recorded. Mortality/viability, body weights, clinical signs, ear size and irritation (and other local effects) were recorded as well. SI values were similar among the control and test groups and were below 3. Three concentrations (i.e. 2.5, 5 and 25%) induced ear swelling. No mortality occurred and no clinical signs of systemic toxicity were observed in the animals of the main study. Body weights and body weight gain of experimental animals remained in the same range as controls over the study period (MBRL, 2005). Based on the results of the read across study, the test substance, 'mono- and di- C16-18 PSE and C16-18 AE20 PSE' is considered to be non-sensitising to the skin.

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
Study period:
1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
KL2 due to RA
Justification for type of information:
Refer to section 13 of IUCLID for details on the read-across justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of study:
Buehler test
Justification for non-LLNA method:
LLNA study is already covered in the dossier
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
Accoding to Guideline.
Route:
epicutaneous, occlusive
Vehicle:
maize oil
Concentration / amount:
100%
Day(s)/duration:
Exposure for 6 h on Day 0, 7 and 14
Adequacy of induction:
not specified
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
maize oil
Concentration / amount:
100%
Day(s)/duration:
Exposure for 6 h to 100% test substance after 2 weeks of last induction
Adequacy of challenge:
not specified
No. of animals per dose:
Test group: 20
Control: 10
Positive control substance(s):
no
Remarks:
historical data
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
100%
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 20.0.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
100%
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 20.0.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
not tested
Clinical observations:
not tested
Remarks on result:
not measured/tested
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
not tested
Clinical observations:
not tested
Remarks on result:
not measured/tested
Interpretation of results:
other: not classified based on EU CLP Criteria
Conclusions:
Based on the results of the read across study, the test substance, is considered to be non-sensitiser to the skin.
Executive summary:

A study was conducted to determine the skin sensitivity potential of the read across substance, 'C16-18 AE1 -2.5' (purity not specified),using Buehler test method,according to OECD Guideline 406, in compliance with GLP. In this study 20 female guinea pigs were induced by an epicutaneous occlusive dressing with 100% test substance (in maize oil) for 6 h on Day 0, 7 and 14. Two weeks after the last induction animals were challenged by epicutaneous occlusive exposure for 6 h to 100% test substance (in maize oil). 24 and 48 h after patch removal the application site was assessed for signs of local irritation or sensitisation. No dermal reactions were observed in any test animal at any time point (Eisele, 1995). Based on the results of the read across study, the test substance, 'mono- and di- C16-18 PSE and C16-18 AE20 PSE' is considered to be non-sensitising to the skin.

Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reason / purpose:
data waiving: supporting information
Reason / purpose:
data waiving: supporting information
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Only a human repeat insult patch test (HRIPT) is available with the test substance. In absence of skin sensitisation study with the test substance, the endpoint can be assessed based on studies for substances representative of the main constituents, which can be categorised as phosphate esters (PSE) and ethoxylated phosphate ester (AE PSE). As, representative studies are not available for the constituent, AE PSE, the endpoint assessment has been based on representative studies available on PSE and AE only, under the assumption that AE PSE is likely to hydrolyse to AE and PSE. The results are presented below:

HRIPT with test substance:

A study was conducted to determine the skin sensitisation potential of the test substance, mono- and di- C16-18 PSE and C16-18 AE20 PSE’ using human repeated insult patch test (HRIPT), in compliance with ICH Guideline E6 for Good Clinical Practice (GCP) and 21CFR part 50 and 56. In the induction phase, a 5% test substance preparation was applied epicutaneously 3 times weekly to 53 healthy volunteers for 24 h under a semi-occlusive conditions. After a rest period of ca. 2 weeks, the substance was applied under the same conditions to a new site as a challenge. At the end of 24 h, the semi-occluded patch was removed and the site was read for immediate response. Follow-up readings were made 24 and 72 h later. The skin effects were then scored for irriation (erythema, edema as well as other irritation signs). No visible irritation was observed in any of the 53 individuals following challenge. Under the study conditions, the test substance was not considered to be sensitising to the human skin at 5% test concentration (CPT, 2001).

Constituent: PSE - read across study:

A study was conducted to determine the skin sensitisation potential of the read across substance, ‘mono- and di- C16 PSE, K+ and H3PO4’ (98.5%) according to OECD Guideline 429 and US EPA OPPTS 870.2600 (LLNA), in compliance with GLP. The read across substance concentrations selected for the main study were based on the results of a pre-screen test. In the main study, four experimental groups of five female CBA/J mice were treated with read across substance concentrations of 2.5, 5, 10 or 25% w/w for three consecutive days, by topical application on the ears. Five vehicle control animals were similarly treated, but with the vehicle alone (Liquid petrolatum). A positive control group with a-hexylcinnamaldehyde (HCA - 50%) was also included in the experiment. Five days after the last exposure, all animals were injected with 5-bromo-2’-deoxy-uridine (BrdU) and the draining (auricular) lymph nodes were then isolated and pooled for each animal. Cells were fixed using 70% ethanol and used for the measurement of the cell number and the BrdU determination (percentage of proliferating cells in “S” phase). Flow cytometry was conducted for analysis and stimulation index (SI) was recorded. Mortality/viability, body weights, clinical signs, ear size and irritation (and other local effects) were recorded as well. SI values were similar among the control and test groups and were below 3. Three concentrations (i.e.2.5, 5 and 25%) induced ear swelling. No mortality occurred and no clinical signs of systemic toxicity were observed in the animals of the main study. Body weights and body weight gain of experimental animals remained in the same range as controls over the study period. Under the study conditions, the read across substance, was considered to be non-sensitiser to the skin (MBRL, 2005).

Constituent: AE - read across study:

A study was conducted to determine the skin sensitivity potential of the read across substance, C16 -18 AE (1 -2.5 EO) (purity not specified), using Buehler test method, according to OECD Guideline 406, in compliance with GLP. In this study 20 female guinea pigs were induced by an epicutaneous occlusive dressing with 100% test substance (in maize oil) for 6 h on Day 0, 7 and 14. Two weeks after the last induction animals were challenged by epicutaneous occlusive exposure for 6 h to 100% test substance (in maize oil). 24 and 48 h after patch removal the application site was assessed for signs of local irritation or sensitisation. No dermal reactions were observed in any test animal at any time point. Under the study conditions, the read across substance was considered to be non-sensitiser to the skin (Eisele, 1995).

A HERA 2009 review report on AEs, reported that overwhelming majority of available guinea pig studies in which AEs were tested for skin sensitisation properties demonstrated the absence of skin sensitisation potential with both the Magnusson and Kligman and Buehler protocol. Only one study following the Magnusson and Kligman protocol indicated a weak sensitisation potential of selected AE. No follow-up work was conducted to further investigate the relevance of the observation. However, for structurally similar products the sensitisation reaction was not seen and therefore it was considered that the observed reactions may have been confounded with irritation reactions.

Overall, bsed on the available weight of evidence, the test substance, ‘mono- and di- C16-8 PSE and C16 -18 AE20 PSE’, is considered to be non-sensitising to skin.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available weight of evidence from HRIPT and studies on substances representative of the main constituents, the test substance, 'mono- and di- C16 -18 PSE and C16-18 AE20 PSE' does not warrant classification for skin sensitisation, according to the EU CLP criteria (Regulation 1272/2008/EC).