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Diss Factsheets

Administrative data

Description of key information

Based on the available weight of evidence from studies on substances representative of the main constituents, the test substance, 'mono- and di- C16-18 PSE and C16-18 AE10 PSE', is considered to be 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 (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.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
Qualifier:
according to guideline
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-sensitiser 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 AE10 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.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
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 chemical
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 chemical
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 AE10 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:
2004
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Refer to section 13 of IUCLID for details on the read-across justification.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: Internal Human repeat insult patch test (HRIPT) Protocol No. 1.01 (at CPTC)
Deviations:
not specified
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 10% test substance concentrations (in distilled water; pH 6.49) to 48 healthy volunteers for 1 to 4 d 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 followed by reading the sites for immediate and delayed responses after 24 and 72 h.
GLP compliance:
not specified
Type of study:
patch test
Justification for non-LLNA method:
- Human study
Species:
other: Human
Sex:
male/female
Details on test animals and environmental conditions:
48 healthy volunteers
Route:
epicutaneous, semiocclusive
Vehicle:
water
Concentration / amount:
10%
Day(s)/duration:
1 - 4 d
Adequacy of induction:
not specified
Route:
epicutaneous, semiocclusive
Vehicle:
water
Concentration / amount:
10%
Day(s)/duration:
1
Adequacy of challenge:
other: two weeks after last induction
No. of animals per dose:
48
Challenge controls:
-
Positive control substance(s):
no
Positive control results:
-
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10% in water
No. with + reactions:
0
Total no. in group:
48
Clinical observations:
none
Remarks on result:
other: see 'Any other information on results incl. tables'
Key result
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
10% in water
No. with + reactions:
1
Total no. in group:
48
Clinical observations:
none
Remarks on result:
other: see 'Any other information on results incl. tables'
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
not tested
Clinical observations:
not tested
Remarks on result:
not measured/tested
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
not tested
Clinical observations:
not tested
Remarks on result:
not measured/tested

Results: details

- Subject #12 developed moderate erythema and mild edema during Days 1 and 2 of induction. Patching was continued on Day 3. Subject #12 had a barely perceptible response. While on Day 4 it was noted that Subject #12 had mild erythema covering the patch site. Two weeks later subject #12 was challenged with the the test substance and there was no response indicating that the initial response was not clinically relevant.

 - Subject # 13 developed spotty erythema on Days 2, 3, and 7. Two weeks later subject #13 was challenged and 24 h later they developed moderate erythema and mild edema. By 72 h post-challenge only spotty erythema was noted (Subject # 13). This pattern of skin reactivity is suggestive of a pre-existing hypersensitivity. No evidence of induced allergic contact sensitization was recorded.

Interpretation of results:
other: not classified based on EU CLP criteria
Conclusions:
Based on the results of the read across study, a similar absenc of skin sensitisation in HRIPT can be expected for the test substance, 'mono- and di- C16-18 PSE and C16-18 AE10 PSE'.
Executive summary:

A study was conducted to determine the skin sensitivity potential of the read across substance, ‘mono- and di- C18-unsatd. PSE and C18-unsatd. AE5 PSE’, according to the Human Repeated Insult Patch Test (HRIPT). In the induction phase, a 10% test substance preparation (in distilled water; pH 6.49) was applied epicutaneously to 48 healthy volunteers for 1 to 4 d 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 occluded patch was removed and the site was read for immediate response. Follow-up readings were made 72 h after challenge. Subject #12 developed moderate erythema and mild edema during Day 1 and 2 of induction, barely perceptible response on Day 3 and mild erythema on Day 4. However, two weeks later the subject #12 was challenged with the test substance and there was no response indicating that the initial response was not clinically relevant. Subject # 13 developed spotty erythema on Days 2, 3, and 7. Two weeks later subject #13 was challenged and 24 h later they developed moderate erythema and mild edema. By 72 h post-challenge only spotty erythema was noted (Subject # 13). This pattern of skin reactivity is suggestive of a pre-existing hypersensitivity. No evidence of induced allergic contact sensitisation was recorded in any other volunteers. Under the study conditions, the read across substance did not indicate a potential for dermal irritation or allergic contact sensitization in human volunteers at 10% test concentrations (Croda, 2004). Based on the results of the read across study, a similar absenc of skin sensitisation in HRIPT can be expected for the test substance, 'mono- and di- C16-18 PSE and C16-18 AE10 PSE'.

Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

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), ethoxylated phosphate ester (AE PSE) and/or free ethoxylated alcohol (AE). 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. This is further supported with the HRIPT availanle for the read across substance, 'mono- and di- C18-unsatd. PSE and C18-unsatd. AE5 PSE'. The results are presented below:

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-sensitising 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-sensitising to the skin (Eisele, 1995).

Further, 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.

HRIPT with read across substance

A study was conducted to determine the skin sensitivity potential of the read across substance, ‘mono- and di- C18-unsatd. PSE and C18-unsatd. AE5 PSE’, according to the Human Repeated Insult Patch Test (HRIPT). In the induction phase, a 10% test substance preparation (in distilled water; pH 6.49) was applied epicutaneously to 48 healthy volunteers for 1 to 4 d 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 occluded patch was removed and the site was read for immediate response. Follow-up readings were made 72 h after challenge. Subject #12 developed moderate erythema and mild edema during Day 1 and 2 of induction, barely perceptible response on Day 3 and mild erythema on Day 4. However, two weeks later the subject #12 was challenged with the test substance and there was no response indicating that the initial response was not clinically relevant. Subject # 13 developed spotty erythema on Days 2, 3, and 7. Two weeks later subject #13 was challenged and 24 h later they developed moderate erythema and mild edema. By 72 h post-challenge only spotty erythema was noted (Subject # 13). This pattern of skin reactivity is suggestive of a pre-existing hypersensitivity. No evidence of induced allergic contact sensitisation was recorded in any other volunteers. Under the study conditions, the read across substance did not indicate a potential for dermal irritation or allergic contact sensitization in human volunteers at 10% test concentrations (Croda, 2004). Based on the results of the read across study, a similar absenc of skin sensitisation in HRIPT can be expected for the test substance, 'mono- and di- C16-18 PSE and C16-18 AE10 PSE'.

Overall, based on the available weight of evidence from studies on the main constituents, the test substance, ‘mono- and di- C16 -18 PSE and C16-18 AE10 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 studies on substances representative of the main constituents, the test substance, 'mono- and di- C16-18 PSE and C16-18 AE10 PSE' is concluded not to warrant classification for skin sensitisation, according to the EU CLP criteria (Regulation 1272/2008/EC).