Registration Dossier

Administrative data

Description of key information

Skin sensitisation (OECD 406, GPMT and Buehler): not skin sensitising

Read-across from structural analogue source substances Fatty acids, C5-9 tetraesters with pentaerythritol (CAS No. 67762-53-2), Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS No. 189200-42-8), and Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS No. 68424-31-7)

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (use of an irritating dose for challenge exposure; lack of data on test substance)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
(use of an irritating dose for challenge exposure; lack of data on test substance)
GLP compliance:
yes
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 were included to avoid unnecessary testing.
Species:
guinea pig
Strain:
other: Hartley Albino
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC, USA
- Age at study initiation: ca. 5 weeks
- Weight at study initiation: 286 - 342 g
- Housing: animals were housed separately in suspended stainless steel and wire mesh cages with absorbent paper below the cages.
- Diet: Agway PROLAB Certified Guinea Pig Chow, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 9 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 22
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
From: 14 Sep 1995
To: 16 Oct 1995
Route:
intradermal and epicutaneous
Vehicle:
other: peanut oil, FCA
Concentration / amount:
intradermal induction: 5%
topical induction: 100%
Route:
epicutaneous, occlusive
Vehicle:
other: peanut oil, FCA
Concentration / amount:
50%
No. of animals per dose:
10 irritation control animals, 10 positive control animals, 20 animals in test groups
Details on study design:
RANGE FINDING TESTS:
A primary irritation test (PIT) was performed to determine suitable concentrations for intradermal and epicutaneous induction. Therefore, three concentrations of the test substance (0.1, 1.0 and 5.0% v/v in peanut oil) were administered intradermally to 2 animals per concentration. The injection sites were evaluated 24 and 48 h after injection. None of the injection sites for the 5.0% animals showed skin corrosion or irritation at either the 24 or 48 h observations. Therefore, 5% of the test substance was chosen for intradermal induction. The PIT also indicated that 100% of the test substance applied topically produced mild to moderate irritation whereas 50% of the test substance was non-irritating. Therefore, concentrations of 100% of the test substance were chosen for the topical induction dose and 50% for the challenge dose, respectively.

MAIN STUDY
A. INDUCTION EXPOSURE
On Day 0, 3 pairs of intradermal injections (0.1 mL) were made in the shoulder region of the test animals. On Day 7, 100% of the test substance (0.5 mL) was applied topically under occlusive conditions for 48 h on the shoulder region of the test animals.
- Exposure period: 3 single injections (intradermal) and 48 h (epicutaneous)
- Test groups:
Intradermal (3 pairs of injections):
Injection 1: a 1:1 mixture (v/v) FCA/water
Injection 2: 5% (v/v) test substance in peanut oil
Injection 3: 5% (v/v) test substance in a 1:1 mixture (v/v) FCA/water

Epicutaneous: test substance (0.5 mL, occlusive conditions)

Evaluation: 1 and 24 h after each induction

- Control group:
Injection 1: a 1:1 mixture (v/v) FCA/water
Injection 2: peanut oil
Injection 3: peanut oil in a 1:1 mixture (v/v) FCA/water

Epicutaneous: peanut oil (0.5 mL, occlusive conditions)

Evaluation: 1 and 24 h after each induction

B. CHALLENGE EXPOSURE
On Day 21, the test substance in peanut oil (50% (v/v, 0.4 mL) was applied topically under occlusive conditions for 24 h to all animals.
- No. of exposures: 1
- Exposure period: 24 h
- Test groups: test substance in peanut oil (left flank) and peanut oil only (right flank)
- Control group: test substance in peanut oil (left flank) and peanut oil only (right flank)
- Evaluation (hr after challenge): 24 and 48 h

Due to the fact that the challenge dosing with 50% test substance was more irritating than is ideal for the challenge and rechallenge phases, the concentration for rechallenge dosing was lowered to 10% of the test substance.

C. RECHALLENGE EXPOSURE
On Day 28, the test substance in peanut oil (10% (v/v, 0.4 mL) was applied topically under occlusive conditions for 24 h to all animals.
- No. of exposures: 1
- Exposure period: 24 h
- Test groups: test substance in peanut oil (right flank) and peanut oil only (left flank)
- Control group: test substance in peanut oil (right flank) and peanut oil only (left flank)
- Evaluation (hr after rechallenge): 24 and 48 h after patch removal
Challenge controls:
The control group is actually a challenge control.
Positive control substance(s):
yes
Remarks:
2-Mercaptobenzothiazole (MBT): intradermal induction: 3%, epicutaneous induction: 25%, challenge: 0.5%; no rechallenge was done
Positive control results:
The positive control substance (0.4% 2-Mercaptobenzothiazole in peanut oil) induced positive reactions in 10/10 animals (100%), thus meeting the reliability criteria.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
5%
No. with + reactions:
9
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
5%
No. with + reactions:
18
Total no. in group:
20
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
3%
No. with + reactions:
10
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
5%
No. with + reactions:
7
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
5%
No. with + reactions:
7
Total no. in group:
20
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
3%
No. with + reactions:
10
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
5%
No. with + reactions:
5
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
5%
No. with + reactions:
4
Total no. in group:
20
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
5%
No. with + reactions:
0
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
48
Group:
test group
Dose level:
5%
No. with + reactions:
0
Total no. in group:
20
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:
other: Guideline study with acceptable restrictions (no analytical purity reported)
Qualifier:
equivalent or similar to
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:
5% (intradermal), 100% (epicutaneous)
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 group
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 group
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 group
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 group
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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (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).
Qualifier:
equivalent or similar to
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 were 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 group
Dose level:
100%
No. with + reactions:
0
Total no. in group:
20
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
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 on positive control group included in study report.

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 analogue approach comprises aliphatic esters of poly-functional alcohols containing four to six reactive hydroxyl groups and one to six fatty acid chains. The read-across analogue approach contains mono constituent, multi-constituent and UVCB substances with fatty acid carbon chain lengths ranging from C5 - C20, which are mainly saturated but also mono unsaturated C16 and C18, polyunsaturated C18 and branched C5, C7 and C9, building mono-, di-, tri-, and tetra esters with the polyol. The available data allow for an accurate hazard and risk assessment of the target substance and the source substances 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 read-across analogue approach by interpolation to the target substances in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006 (REACH). In particular, for each specific endpoint the source substance or substances 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 substance and target substances are the basis of read-across.

A detailed justification for the read-across applied is provided in the technical dossier (see IUCLID Section 7.1 and 13) and within Chapter 5.1 of the CSR.

Skin sensitisation potential

There are several reliable studies available for structural analogue source substances investigating the skin sensitisation potential.

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, 1999d). 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 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.

A guinea pig maximisation test (GPMT) was performed with Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS No. 189200-42-8) according to a protocol comparable to the OECD Guideline 406 (Exxon, 1995c). A range-finding study was performed for dose selection. 20 female Hartley albino guinea pigs were treated with the test substance at 5% for intra- and 100% for epidermal induction on days 1 and 7, respectively. 10 animals served as negative controls. A positive control group treated with 2-Mercaptobenzothiazole (MBT) (intradermal induction: 3%, epicutaneous induction: 25%, challenge: 0.5%; no rechallenge) was included in the study which showed 100% sensitising reactions. 14 days after the epidermal induction, epidermal challenging was performed with a 50% test material dilution in peanut oil. At the first reading, 24 hours after challenge, skin examination revealed irritation reactions in the test group for 18 of 20 animals and in the control group for 9 of 10 animals. 48 hours after challenge, 7 animals in test and control group each showed skin irritation reactions. Since the 50% challenge concentration resulted in skin irritation, a rechallenge was done using 10% test substance. 5 of 10 control animals (50%) and 4 of 20 (20%) test group animals showed skin irritation 24 hours after rechallenge. All skin reactions were completely reversed 48 hours after rechallenge in both groups. Thus, the test material was found to be not sensitising to the skin of guinea pigs, when used as 5% solution for induction and 10% solution for challenge.

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 and 48 h after challenge. No signs for irritation or sensitisation were observed during induction and challenge of the animals.

In addition to the animal-derived data, a repeated insult human patch test (RIPT) was conducted to assess the sensitizing potential of 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl (CAS No. 62125-22-8) in 55 human volunteers from the general population (Key, RA-A, 62125-22-8, 1985). Induction was carried out by 10 repeated semiocclusive applications of the unchanged test substance. Patches were placed on the back of volunteers for 24 hours, followed by a 24 hour rest period (48 hours on weekends). The 10 induction patches were applied to the same site. The induction phase was followed by a resting period of 14 days. Challenge patches were applied to the same site on the back and to a naïve site. Skin reactions were assessed 24 and 48 hours after patch removal. None of the human volunteers showed any skin reactions at the end of the study period. Thus, the test material is not considered sensitising to humans.

Conclusion on skin sensitisation

All data indicate no potential for skin sensitisation in adequate GPMT and Buehler tests. Thus, no hazard for skin sensitisation is identified for the target substance Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid.

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 (REACH) 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 physico-chemical, 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 Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid, data gaps can be filled by interpolation 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 do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP) and are therefore conclusive but not sufficient for classification.