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Administrative data

Description of key information

Skin sensitisation (OECD 406, GPMT and Buehler; human repeated insult patch test): not skin sensitising

Read-across from structural analogue source substances Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS No. 68424-31-7), Fatty acids, C5-9 tetraesters with pentaerythritol (CAS No. 67762-53-2), and Dipentaerythritol hexaesters with fatty acids, C5 and C9iso (CAS No. 647028-25-9)

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:
14 Dec 1998-01 February 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
adopted in 1992
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Version / remarks:
draft
GLP compliance:
yes (incl. QA statement)
Remarks:
The Department of Health of the Government of the United Kingdom, UK
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
A non-LLNA test is available that was performed prior to the current data requirements, stipulated in Regulation (EC) No 1907/2006. In accordance with the same Regulation, the data was included to avoid unnecessary testing.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: David Hall Limited, Burton-on-Trent, Staffordshire, United Kingdom
- Age at study initiation: 8–12 weeks
- Weight at study initiation: 335 – 440 g
- Housing: individually or in pairs in solid-floor polypropylene cages furnished with woodflakes.
- Diet: Guinea Pig FD1, Special Diets Services Limited, Witham, United Kingdom; ad libitum
- Water: ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22
- Humidity (%): 44-57
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12

Route:
intradermal and epicutaneous
Vehicle:
other: unchanged and arachis oil BP
Concentration / amount:
intradermal: 25%
epicutaneous: undiluted
Route:
epicutaneous, occlusive
Vehicle:
other: unchanged and arachis oil BP
Concentration / amount:
100% and 75%
No. of animals per dose:
5 (controls), 10 (test group)
Details on study design:
RANGE FINDING TESTS (selection of concentration):
INDUCTION EXPOSURE (INTRADERMAL)
Four guinea pigs were intradermally injected with 1%, 5%, 10% and 25% w/v in arachis oil BP. The grade of erythema at the injection site was assessed approximately 24, 48 and 72 hours and 7 days after injection according to the Draize scale. The highest concentration that caused only mild to moderate skin irritation, and was well tolerated systemically, was selected for the intradermal induction phase of the main study.
INDUCTION EXPOSURE (TOPICAL)
Two guinea pigs, previously injected with Freund’s Complete Adjuvant (eighteen days earlier), were applied to the clipped flanks under occlusive dressing with undiluted test item and 75%, 50% and 25% v/v of the test item in arachis oil BP for 48 hours. The degree of erythema and oedema was assessed approximately 1, 2 and 48 hours after dressing removal. The highest concentration producing only mild to moderate dermal irritation was selected for the topical induction stage of the main study.
CHALLENGE
Two guinea pigs were treated with undiluted test material and 75%, 50% and 25% v/v in arachis oil BP to the clipped flanks under occlusive conditions for an exposure period of 24 hours. Erythema and oedema score were observed approximately 1, 24, and 48 hours after dressing removal. The highest non-irritant concentration of the test material and one lower concentration were selected for the topical challenge phase of the main study.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (intradermal and epicutaneous, respectively)
- Exposure period: single injection (intradermal) and 48 hours
- Test groups:
Intradermal (3 pairs of injections):
Injection 1: a 1:1 mixture (v/v) FCA/water
Injection 2: test substance in arachis oil BP
Injection 3: test substance in a 1:1 mixture (v/v) FCA/water

Epicuteneous: test substance in arachis oil BP

- Control group:
Intradermal (3 pairs of injections)
Injection 1: a 1:1 mixture (v/v) FAC/water
Injection 2: arachis oil BP
Injection 3: arachis oil BP at 50% in a 1:1 mixture (v/v) FCA/water
Epicuteneous: arachis oil BP

- Site: shoulder region (intradermal + epicutaneous)
- Frequency of applications: every 7 days
- Duration: Days 0-7
- Concentrations: intradermal 25%, epicutaneous undiluted

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 20
- Exposure period: 24 h
- Test groups: test substance
- Control group: test substance
- Site: right flank (test substance undiluted) and left flank (test substance 75%)
- Concentrations: undiluted and 75%
- Evaluation (hr after challenge): 24 and 48 h after patch removal

Positive control substance(s):
yes
Remarks:
2-Mercaptobenzothiazole (Intradermal induction concentration of 10% in arachis oil, topical induction concentration of 50% in acetone/PEG400; challenge concentration of 50 and 25% in acetone/PEG400)
Positive control results:
The incidence of sensitisation in the historical positive controls was 70-100 % (based on 6 individual experiments).
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
induction: 0%; challenge: 100%
No. with + reactions:
0
Total no. in group:
5
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
induction: 0%; challenge: 100%
No. with + reactions:
0
Total no. in group:
5
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
induction: 25%; challenge: 75 and 100%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
induction: 25%; challenge: 75 and 100%
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
50%
No. with + reactions:
10
Total no. in group:
10
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008.
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
adopted in 1992
Deviations:
yes
Remarks:
analytical purity not reported
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
A non-LLNA test is available that was performed prior to the current data requirements, stipulated in Regulation (EC) No 1907/2006. In accordance with the same Regulation, the data was included to avoid unnecessary testing.
Species:
guinea pig
Strain:
other: Albino Guinea Pigs
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Convance Research Products Inc., Denver, Pennsylvania; USA
- Age at study initiation: approximately 4-7 weeks at dosing (range-finding study; intradermal); approximately 9-12 weeks (rang-finding study; topical); approximately 5-7 weeks at first dose (sensitisation study)
- Weight at study initiation: 376-428 g
- Housing: individually housed in suspended, stainless steel cages with wire mesh bottoms
- Diet: certified Guinea Pig Diet, No. 5026, ad libitum
- Water: automatic watering system (Municipal water supply), ad libitum
- Acclimation period: 8 days (range-finding animals); 14 days (sensitization animals)

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

Route:
intradermal and epicutaneous
Vehicle:
propylene glycol
Concentration / amount:
intradermal: 5%
epicutaneous: 100%
Route:
epicutaneous, occlusive
Vehicle:
propylene glycol
Concentration / amount:
100% and 50%
No. of animals per dose:
5 (controls), 10 (in test groups)
Details on study design:
RANGE FINDING TESTS:
Intradermal:
Two animals were administered intradermal injections (2 injection / animal) of a 5% v/v concentration of test substance in propylene glycol, one on either side of the spinal column. The concentration tested did not produce extensive tissue damage or severe systemic toxicity.

Topical:
4 animals were tested at 4 different concentrations (25, 50, 75% v/v; 100%) per animal (one concentration/site), two on either side of the spinal column. 24 h and 48 h after removal of the patches no signs of erythema and edema were observed for at any of the concentration tested.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (intradermal and epicutaneous, respectively)
- Exposure period: single injection (intradermal) and
- Test group:
Intradermal (3 pairs of injections)
Injection 1: a 1:1 mixture (v/v) FCA/ water
Injection 2: test substance in propylene glycol
Injection 3: test substance in a 1:1 mixture (v/v) FCA/water
Epicutaneous: test substance in propylene glycol

- Control group:
Intradermal (3 pairs of injections)
Injection 1: a 1:1 mixture (v/v) FCA/ water
Injection 2: propylene glycol
Injection 3: propylene glycol at 50% (v/v) in a 1:1 mixture (v/v) FCA/water
Epicutaneous: propylene glycol

- Site: shoulder region (intradermal + epicutaneous)
- Frequency of applications: every 7 days
- Duration: Days 1-8
- Concentrations: Intradermal 5%, epicutaneous 100%

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 22
- Exposure period: 24 h
- Test groups: test substance
- Control group: test substance
- Site: both flanks (two concentrations were applied for a total of two sites per animal)
- Concentrations: 100% and 50%
- Evaluation (hr after challenge): 24 and 48 h after patch removal



Positive control substance(s):
yes
Remarks:
hexylcinnamic aldehyde (HCA)
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
4
Clinical observations:
one animal was sacrificed on Day 10 at the end of topical induction exposure, due to dosing trauma (humane reasons).
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
4
Clinical observations:
one animal was sacrificed on Day 10 at the end of topical induction exposure, due to dosing trauma (humane reasons)
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
4
Clinical observations:
one animal was sacrificed on Day 10 at the end of topical induction exposure, due to dosing trauma (humane reasons)
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
4
Clinical observations:
one animal was sacrificed on Day 10 at the end of topical induction exposure, due to dosing trauma (humane reasons)
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
100%
No. with + reactions:
5
Total no. in group:
9
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
100%
No. with + reactions:
1
Total no. in group:
9
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008.
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
no information on purity of the test material; both flanks were exposed during challenge, no reliability check done, no positive control used. Method given in very summarized form.
GLP compliance:
not specified
Type of study:
Buehler test
Justification for non-LLNA method:
A non-LLNA test is available that was performed prior to the current data requirements, stipulated in Regulation (EC) No 1907/2006. In accordance with the same Regulation, the data was included to avoid unnecessary testing.
Species:
guinea pig
Strain:
other: Albino
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 344 - 441 g
Route:
epicutaneous, occlusive
Vehicle:
corn oil
Concentration / amount:
100%
Route:
epicutaneous, occlusive
Vehicle:
corn oil
Concentration / amount:
30% and 100%
No. of animals per dose:
20 (10 for the controls)
Details on study design:
RANGE FINDING TESTS: No Data

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: 6 h
- Test groups: Undiluted test sample
- Control group: not stated
- Site: scapular region
- Frequency of applications: 7 d interval
- Duration: 14 d
- Concentrations: undiluted

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: day 28, 14 d after final induction
- Exposure period: 6 h
- Test groups: undiluted (100%) and 30% (w/v in corn oil)
- Control group: undiluted (100%) and 30% (w/v in corn oil)
- Site: undiluted (100%) on left flank and 30% on right flank
- Concentrations: undiluted (100%) and 30% (w/v in corn oil)
- Evaluation (hr after challenge): 24 h and 48 h
Challenge controls:
No
Positive control substance(s):
no
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100%
No. with + reactions:
0
Total no. in group:
20
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100%
No. with + reactions:
0
Total no. in group:
20
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
10
Group:
positive control
Remarks on result:
other: No information regarding positive control group available

No information on positive control group included in study report.

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Justification for grouping of substances and read-across

The read-across from analogue source substances approach comprises aliphatic esters of poly-functional alcohols containing two to six reactive hydroxyl groups and one to six fatty acid chains. The analogue approach contains mono constituent, multi-constituent and UVCB substances with fatty acid carbon chain lengths ranging from C5 - C28, which are mainly saturated but also mono unsaturated C16 and C18, polyunsaturated C18, branched C5 and C9, branched C14 - C22 building mono-, di-, tri-, and tetra esters with an alcohol (i.e. the polyol).

The available data allows for an accurate hazard and risk assessment of the target substance and the read-across concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substances within the group by interpolation to the target substance applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 7.1 and 13).

Skin sensitisation potential

There are several reliable animal studies and one repeated insult patch test with humans available for structural analogue source substances investigating the skin sensitisation potential. All studies are accounted for in a Weight-of-Evidence approach.

The skin sensitisation potential of Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS No. 68424-31-7) was evaluated in guinea pigs with a Buehler test for (WoE, RA-A, 68424-31-7, 1991d). 20 male albino guinea pigs were treated with the test substance and compared with 10 control animals. Three epidermal inductions were performed with 100 % test substance in weekly intervals for 6 hours under occlusive conditions. 14 days after the last induction treatment, all animals were challenged for 6 hours epicutaneously with 100% (left shorn flank) and 30% (right shorn flank) test substance (diluted in corn oil) under occlusive conditions. Animals were evaluated for skin reactions 24 h and 48 h after challenge. No signs for irritation or sensitisation were observed during induction and challenge of the animals.

A guinea pig maximisation test (GPMT) was performed with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS No. 67762-53-2) comparable to the OECD Guideline 406 (Exxon, 1999e). A range-finding study was performed for dose selection. 10 albino guinea pigs were treated with the test substance at 5% for intra- and 100% for epidermal induction on days 1 and 7, respectively. 5 animals served as negative controls. A positive control group was not included in the study but information is given on periodical testing of strain sensitivity using hexylcinnamic aldehyde (HCA). 14 days after the epidermal induction, epidermal challenging was performed with 50 and 100% test material dilution in propylene glycol. 24 h and 48 hours after challenging skin examination revealed no irritation in the test group and control group. Thus, the test material was found to be not sensitising to the skin of guinea pigs, under the conditions of this test.

The skin sensitisation potential of Dipentaerythritol hexaesters with fatty acids, C5 and C9iso (CAS No. 647028-25-9) was tested in a guinea pig maximisation test (GPMT) equivalent to OECD Guideline 406 and under GLP conditions (WoE, RA-A, 647028-25-9, 1999e). Suitable doses were investigated by means of a range finding study prior to the main test. 10 male Dunkin-Hartley guinea pigs were treated with the test substance at 25% (diluted in arachis oil BP) for intra- and 100% for epidermal induction on days 1 and 7, respectively. 5 animals served as negative controls. There was no positive control group included in the study but information was given that the incidence of sensitisation in the historical positive controls using 2-Mercaptobenzothiazole was 70-100 %. Epicutaneous challenge was performed on Day 20 with undiluted (right flank) and 75% (diluted in arachis oil BP, left flank) test material under occlusive conditions for 24 h and skin reactions were evaluated 24 h and 48 h after removal of the patches. No animal in either the test or control groups exhibited skin reactions at any reading time point. Therefore, the test substance was considered not to be skin sensitising.

The analogue substance Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester (CAS No. 7299-99-2) was tested in a repeated insult patch test (RIPT) with 113 volunteers between 18 and 65 years old (Stearinerie, 1997). The 29 male and 84 female subjects received a series of nine induction patches on the identical site, which were completed over a period of three weeks. With every patch, 0.2 mL of the pure substance was applied. If a subject was unable to make up a missed patching during the same week, the subject was either patched four days the following week or was repatched at the end of the induction phase. The patches remained in place and kept dry for approximately 24 hours, at which time the patch was to be removed by the subject. After a rest phase of two weeks after the last induction, the challenge patch with 0.2 mL of the substance was applied to a virgin skin site and was removed 24 h later. At this time the skin site was evaluated as well as 48, 72 and 96 h after patching. 1 subject showed faint, minimal erythema 24 h after the challenge, but not at later time points. None of the remaining 97 subjects that completed the study showed any signs of skin effects after the induction or challenge applications. Thus, the test substance is considered to be not sensitising.

Conclusion on skin sensitisation

Several reliable studies performed with analogue source substances are available investigating the skin sensitisation potential both in animals as well as in humans. All data indicate no potential for skin sensitisation in adequate GPMT, Buehler and human repeated insult patch tests. Thus, no hazard for skin sensitisation is identified for the target substance Monopentaerythritol tetraesters and dipentaerythritol hexaesters of 2-ethylhexanoic and n-valeric acids either.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 information on intrinsic properties of substances may be generated by means other than tests, e.g. using information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the read-across concept is applied to the target substance Monopentaerythritol tetraesters and dipentaerythritol hexaesters of 2-ethylhexanoic and n-valeric acids from representative structural analogue source substances to avoid unnecessary animal testing.

The read-across concept is also used to derive the classification of the target substance taking the properties of the source substances into account. Based on the read-across concept, all available data on skin sensitisation in animals and humans do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP) and are therefore conclusive but not sufficient for classification.