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Diss Factsheets

Administrative data

Description of key information

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:
Not applicable
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Secondary literature source (documentation insufficient for assessment)
Principles of method if other than guideline:
The skin sensitization potential of palm oil was evaluated in the Magnusson-Kligman Maximization Test. Induction phase consisted of intradermal injection of 5% palm oil followed by epicutaneous application of 100% palm oil as booster. All the groups were challenged with 0.5 mL 5% palm oil. Reactions were observed 24 and 48 h after patch removal.
GLP compliance:
not specified
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
A valid GMPT study was available before REACH came into force, therefore no additional LLNA study was conducted.
Species:
guinea pig
Strain:
Hartley
Sex:
female
Details on test animals and environmental conditions:
None
Route:
intradermal and epicutaneous
Vehicle:
propylene glycol
Concentration / amount:
5% palm oil in propylene glycol
5% palm oil in 50% aqueous Freund's Complete Adjuvant
50% Freund's Complete Adjuvant
Each material (0.5 mL) was injected intradermally.
Route:
other: epicutaneous
Vehicle:
propylene glycol
Concentration / amount:
0.5 mL 5% palm oil
No. of animals per dose:
10 animals in both control and test groups
Details on study design:
INDUCTION:
During the induction, 3 pairs of sites per animals in the test group were injected with following materials:
5% palm oil in propylene glycol
5% palm oil in 50% aqueous Freund's Complete Adjuvant
50% Freund's Complete Adjuvant
Each material (0.5 mL) was injected intradermally.
In the booster phase, initiated 1 wk after induction, an occlusive dressing pad containing full strength palm oil (0.5 mL) was applied on the induction injection sites on each animal in the test group.

CHALLENGE:
2 wks after the booster phase, animals in first and second test groups were challenged with 0.5 mL 5% palm oil. Patches were applied to previously untreated sites and remained in place for 24 h. Reactions were observed 24 and 48 h after patch removal.

SCORING:
Following scale was used during the observation of skin sensitization:
0 (no evidence of any effects) to 4 (severe, deep red erythema with vesiculation or weeping with or without edema).
Challenge controls:
The three pairs of sites on each control animal were injected intradermally with full strength propylene glycol, 1:1 propylene glycol: 50% aqueous Freund's Complete Adjuvant, 50% aqueous Freund's Complete Adjuvant respectively, during induction. 1 wk after induction, a full strength petrolatum (booster) was applied according to the same procedure as in the test group.
Positive control substance(s):
not specified
Positive control results:
Not applicable
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
5%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No data
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 5%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No data.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
5%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No data
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 5%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No data.
Key result
Reading:
1st reading
Hours after challenge:
72
Group:
positive control
Dose level:
0
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
not measured/tested
Key result
Reading:
1st reading
Hours after challenge:
72
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
not measured/tested
Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, test substance was determined to be a non-sensitizing to guinea pig skin.
Executive summary:

As study was conducted to determine the skin sensitization potential of glycerides, C16-18 and C18-unsatd. (in the form of palm oil) was evaluated in the Magnusson-Kligman Maximization Test using three groups of 10 female guinea pigs of the Hartley strain. In the induction phase, the test group was injected with 5% palm oil in propylene glycol, 5% palm oil in 50% aqueous Freund’s Complete Adjuvant and 50% Freund’s Complete Adjuvant. In the booster phase, full strength palm oil (0.5 mL) was applied occlusively. Two of the groups served as controls. All the groups were challenged with 0.5 mL 5% palm oil. Reactions were observed 24 and 48 h after patch removal. No reactions were observed in any of the tested group. Under the study conditions, the test substance was determined to be non-sensitizing to guinea pig skin (CIR, 2000).

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2000
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other:
Remarks:
Secondary literature source (documentation insufficient for assessment)
Principles of method if other than guideline:
The procedure was based on, and similar to, the method described by Magnusson and Kligman, 1970 (Skin sensitizing: Guinea pig maximization test).Induction phase consisted of intradermal injection of 5% soybean oil followed by epicutaneous application of 100% soybean. 50% soybean oil was applied epicutaneously during challenge phase.
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
A valid GMPT study was available before REACH came into force, therefore no additional LLNA study was conducted.
Species:
guinea pig
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
No data
Route:
intradermal and epicutaneous
Vehicle:
no data
Concentration / amount:
Induction injection: 5%
Induction application: 100%
Challenge application: 50%
Route:
other: epicutaneous
Vehicle:
no data
Concentration / amount:
Induction injection: 5%
Induction application: 100%
Challenge application: 50%
No. of animals per dose:
10
Details on study design:
The procedure was based on, and similar to, the method described by Magnusson and Kligman, 1970.
Challenge controls:
No data
Positive control substance(s):
not specified
Positive control results:
No data
Key result
Reading:
other: Readings after three challenges
Hours after challenge:
72
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Not reported
Remarks on result:
other: Reading: other: Readings after three challenges. Group: test group. Dose level: 50%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: Not reported.
Key result
Reading:
1st reading
Hours after challenge:
72
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
not measured/tested
Key result
Reading:
1st reading
Hours after challenge:
72
Group:
positive control
Dose level:
0
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
not measured/tested
Interpretation of results:
GHS criteria not met
Conclusions:
Under the study conditions, test substance was determined to be a non-sensitizing to guinea pig skin.
Executive summary:

A study was conducted to evaluate the skin sensitisation potential of glycerides, C16-18 and C18-unsatd. (in the form of soybean oil) in guinea pigs. The procedure was based on the method described by Magnusson and Kligman, 1970 (Skin sensitizing: Guinea pig maximization test). The induction phase consisted of an intradermal injection of 5% test substance followed by epicutaneous application of 100% test substance. 50% test substance was applied epicutaneously during the challenge phase. 0/10 guinea pigs were sensitized after 3 challenges. Under the study conditions, the test substance was determined to be a non-sensitizing to guinea pig skin (ECB, 2000).

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
From June 01, 2016 to June 30, 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
2010
Deviations:
yes
Remarks:
no radioactive labelling was used to measure cell proliferation
Qualifier:
according to guideline
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
2012
Deviations:
yes
Remarks:
no radioactive labelling was used to measure cell proliferation
Principles of method if other than guideline:
The study was performed according to OECD 429, however not employing the use of radioactive labelling to measure cell proliferation. The alternative method used for the study employing the lymph node weight and lymph node cell count to assess proliferation has been established by an European interlaboratory validation exercise, as described in the two publications by Ehling et al. 2005a and 2005b. In addition, the acute inflammatory skin reaction is measured by ear weight determination of circular biopsies of the ears and ear thickness measurements on test day 1 and test day 4 to identify skin irritation properties of the test item.

References:
Ehling, G., M. Hecht, A. Heusener, J. Huesler, A. O. Gamer, H. van Loveren, T. Maurer, K. Riecke, L. Ullmann, P. Ulrich, R. Vandebriel, H.-W. Vohr: An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: First round; Toxicology 212, 60-68 (2005a)

Ehling, G., M. Hecht, A. Heusener, J. Huesler, A. O. Gamer, H. van Loveren, T. Maurer, K. Riecke, L. Ullmann, P. Ulrich, R. Vandebriel, H.-W. Vohr: An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: 2nd round; Toxicology 212, 69-79 (2005b)
GLP compliance:
yes (incl. QA statement)
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
NMRI
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 62 days (on test day 1)
- Weight at study initiation: 29 - 34 g (test day 1)
- Housing: animals were kept individually in in MAKROLON cages (type III) supplemented with granulated textured wood as bedding material (Granulat A2, J. Brandenburg, Goldenstedt, Germany)
- Diet: commercial diet ssniff R/M-H V1534 (ssniff Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
acetone/olive oil (4:1 v/v)
Concentration:
50, 75 and 100%
No. of animals per dose:
6
Details on study design:
PRE-SCREEN TESTS
A preliminary experiment was carried out in 4 animals to examine the irritating potential and handling/application of the test substance in order to select the appropriate concentrations. Four concentrations of 25%, 50% and 75% dissolved in acetone / olive oil (4:1, v/v) and the undiluted test substance were examined. Doses were selected according to OECD guideline from the concentration series 100%, 50%, 25%, 10%, 5%, 2.5%, 1%, 0.5% etc. The preliminary experiment was conducted under conditions identical to the main LLNA study, except there was no assessment of lymph node proliferation and only 1 animal per concentration was used. Both ears of each mouse were observed for erythema and scored using following pattern: 0 (no erythema), 1 (very slight erythema), 2 (well-defined erythema) and 4 (moderate to severe erythema).

MAIN STUDY

ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: Alternative endpoints of the murine local lymph node (measurement of lymph node weight and lymph node cell count, ear weight/thickness measurement to detect skin irritation potential)
- Criteria used to consider a positive response: Stimulation indices were calculated for the lymph node cell count, lymph node weight, ear weight and ear thickness by dividing the average values per group of the test substance treated animals by the vehicle treated ones. Values above 1.4 (lymph node cell count to identify sensitisation) or 1.1 (ear weight to identify irritation) are considered positive (these values were fixed empirically during the interlaboratory validation of this method (Ehling et al. 2005a and 2005b).

TREATMENT PREPARATION AND ADMINISTRATION
The test substance was used undiluted or diluted in acetone / olive oil (4:1, v/v). The vehicle acetone / olive oil (4:1, v/v) was used as negative reference substance. The test substance solution was administered to the dorsum of both animals´ ears at an application volume of 25 µL/ear. Five groups of 6 female animals each were examined. The concentrations (50, 75 and 100%) were chosen based on a preliminary experiment. The study was performed according to OECD 429, however not employing the use of radioactive labelling to measure cell proliferation. The alternative method used for the study employing the lymph node weight and lymph node cell count to assess proliferation has been established by an European interlaboratory validation exercise, as described in the two publications by Ehling et al. 2005a and 2005b. In addition, the acute inflammatory skin reaction is measured by ear weight determination of circular biopsies of the ears and ear thickness measurements on test day 1 and test day 4 to identify skin irritation properties of the test substance. The experimental schedule of the assay was as follows:

- Day 1: The weight of each animal was individually identified and recorded. The weights and any clinical observation were recorded. In addition, ear swelling measurements were carried out at the helical edge of both ears using an Oditest micrometer. Open application of 25 μL of the appropriate dilution of the test substance, the vehicle alone or the positive control (as appropriate) were administered to the dorsum of each ear.

- Days 2 and 3: The application procedure carried out on day 1 was repeated.

- Day 4 (24 hours after the last application): Ear swelling measurements (immediately before sacrificing the mice) were carried out at the helical edge of both ears using an Oditest micrometer. The animals were euthanized by carbon dioxide (CO2) inhalation and laparotomised. Punch biopsies of 8 mm in diameter of the apical area of both ears were prepared and immediately weighed on an analytical balance. Lateral pairs of auricular lymph nodes draining the ear tissue were excised, carefully separated from remaining fatty tissue and weighed on an analytical balance immediately following preparation. The lymph nodes were then stored on ice in PBS/0.5% BSA and subjected to the preparation of single cell suspensions by mechanical tissue disaggregation. The cells were counted automatically in a cell counter.
Positive control substance(s):
other: 20% solution (v/v) of α-hexyl cinnamic aldehyde in acetone / olive oil (4:1, v/v)
Statistics:
For lymph node weight significance at p ≤0.01 is considered positive (U-test according to MANN and WHITNEY). A possible concentration-response-relationship for the lymph node weight in order to determine a possible sensitising potential was examined by linear regression analysis employing PEARSON's correlation coefficient. U-test was performed for cell count, too. Outliers were determined according to the Nalimov test. Hence, in addition, the acute inflammatory skin reaction (irritating potential) was measured by ear weight determination of circular biopsies of the ears and ear thickness measurements on test day 1 and test day 4 to identify skin irritation properties of the test substance employing the U-test according to MANN and WHITNEY by comparing the test groups to the vehicle control. The stimulation indices were calculated by dividing the average ear weight and average ear thickness on test day 4 per group of the test substance treated animals by the vehicle treated ones. The cut-off threshold value for the ear weight stimulation index was set at 1.1.
Positive control results:
The positive control was dissolved in acetone / olive oil (4:1, v/v). Positive controls were used to demonstrate appropriate performance of the assay and competence of the laboratory to successfully conduct the assay. An index for the lymph node cell count above 1.4 is considered positive. The positive control group caused the expected increases in lymph node cell count and lymph node weight (statistically significant at p ≤0.01). Therefore, the study can be regarded as valid.
Key result
Parameter:
SI
Remarks:
Lymph node cell count
Value:
1.073
Test group / Remarks:
50% test substance
Remarks on result:
other: no indication of skin sensitisation
Key result
Parameter:
SI
Remarks:
Lymph node cell count
Value:
1.062
Test group / Remarks:
75% test substance
Remarks on result:
other: no indication of skin sensitisation
Key result
Parameter:
SI
Remarks:
Lymph node cell count
Value:
1.091
Test group / Remarks:
100% test substance
Remarks on result:
other: no indication of skin sensitisation
Key result
Parameter:
SI
Remarks:
Lymph node cell count
Value:
1.526
Test group / Remarks:
Positive control
Key result
Parameter:
SI
Remarks:
Lymph node weight
Value:
1.137
Test group / Remarks:
50% test substance
Remarks on result:
other: no indication of skin sensitisation
Key result
Parameter:
SI
Remarks:
Lymph node weight
Value:
1.235
Test group / Remarks:
75% test substance
Remarks on result:
other: no indication of skin sensitisation
Key result
Parameter:
SI
Remarks:
Lymph node weight
Value:
1.176
Test group / Remarks:
100% test substance
Remarks on result:
other: no indication of skin sensitisation
Key result
Parameter:
SI
Remarks:
Lymph node weight
Value:
1.471
Test group / Remarks:
Positive control
Key result
Parameter:
SI
Remarks:
Ear weight
Value:
0.98
Test group / Remarks:
50% test substance
Remarks on result:
other: no indication of skin irritation
Key result
Parameter:
SI
Remarks:
Ear weight
Value:
1.005
Test group / Remarks:
75% test substance
Remarks on result:
other: no indication of skin irritation
Key result
Parameter:
SI
Remarks:
Ear weight
Value:
1.061
Test group / Remarks:
100% test substance
Remarks on result:
other: no indication of skin irritation
Key result
Parameter:
SI
Remarks:
Ear weight
Value:
1.097
Test group / Remarks:
Positive control
Key result
Parameter:
SI
Remarks:
Ear thickness
Value:
0.996
Test group / Remarks:
50% test substance
Remarks on result:
other: no indication of skin irritation
Key result
Parameter:
SI
Remarks:
Ear thickness
Value:
1.008
Test group / Remarks:
75% test substance
Remarks on result:
other: no indication of skin irritation
Key result
Parameter:
SI
Remarks:
Ear thickness
Value:
0.988
Test group / Remarks:
100% test substance
Remarks on result:
other: no indication of skin irritation
Key result
Parameter:
SI
Remarks:
Ear thickness
Value:
1.118
Test group / Remarks:
Positive control
Cellular proliferation data / Observations:
PRELIMINARY EXPERIMENT
In a preliminary experiment, concentrations of 25%, 50%, 75%, and 100% of the test substance employing 1 animal per concentration, were examined. No systemic toxicity or excessive local skin irritation were observed in this preliminary experiment at concentrations of 25%, 50%, 75% and 100%.

MAIN STUDY
In the main study treatment with the test substance at concentrations of 50%, 75% or 100% did not reveal any statistical significantly increased values for the lymph node cell count. The stimulation indices calculated for the lymph node cell count did not exceed the threshold level of 1.4. In addition, no statistical significantly increase in the lymph node weight was observed. Hence, the test substance is classified as not sensitising to the skin. The threshold level of 1.1 for the ear weight stimulation index was not exceeded and no increase of ear thickness was observed, thus, no irritating properties were noted.

CLINICAL OBSERVATIONS
No signs of local or systemic intolerance were recorded.

BODY WEIGHTS
The animal body weight was not affected by the treatment.

Table 1: Summary of Stimulation indices (SI)

Parameter

Negative control

50% test substance

75% test substance

100% test substance

Positive control

Lymph node cell count

1.000

1.073

1.062

1.091

1.526**

Lymph node weight

1.000

1.137

1.235

1.176

1.471**

Ear weight

1.000

0.980

1.005

1.061

1.097**

Ear thickness (day 4)

1.000

0.996

1.008

0.988

1.118

**: significantly increased compared to negative control at p ≤0.01

Interpretation of results:
GHS criteria not met
Conclusions:
Under the study conditions, the test substance was identified as non-sensitising to skin.
Executive summary:

A study was conducted to determine the skin sensitising potential of fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol using the modified local lymph node assay (LLNA) according to OECD Guideline 429 and EU Method B.42, in compliance with GLP. In this study, groups of six female NMRI mice were treated with the test substance at concentrations of 50, 75 and 100% (w/w) in acetone/olive oil (4:1 v/v). Topical application of 25 µL of the appropriate test substance concentrations was performed daily at the dorsal surface of each ear for three consecutive days. Four days following the first topical application, ear swelling measurements of all mice (immediately before sacrificing the mice) were carried out at the helical edge of both ears followed by lymph node cell count, lymph node weight and ear weight measurements after animal sacrifice. Positive and negative controls were included in the study and gave the expected results. The calculated stimulation indices (SI) of the substance were 1.073, 1.062, 1.091 (for lymph node cell count), 1.137, 1.235, 1.176 (for lymph node weight), 0.980, 1.005, 1.061 (for ear weight) and 0.996, 1.008, 0.988 (for ear thickness) at concentrations of 50, 75 and 100% (w/w), respectively and therefore <1.4 (lymph node cell count and lymph node weight) and <1.1 (ear weight), respectively. Thus, under the study conditions, the test substance was identified as non-sensitising to skin (Oleon, 2016).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

In the absence of specific studies with the test substance, sensitization was assessed based on data for substances representative of the main constituents, which can be categorised as pentaerythritol esters (PE) and glycerol esters (GE). The results are presented below:

Pentaerythritol esters

Study 1:

A study was conducted to determine the skin sensitising potential of fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, tri- and tetraesters with pentaerythritol using the modified local lymph node assay (LLNA) according to OECD Guideline 429 and EU Method B.42, in compliance with GLP. In this study, groups of six female NMRI mice were treated with the test substance at concentrations of 50, 75 and 100% (w/w) in acetone/olive oil (4:1 v/v). Topical application of 25 µL of the appropriate test substance concentrations was performed daily at the dorsal surface of each ear for three consecutive days. Four days following the first topical application, ear swelling measurements of all mice (immediately before sacrificing the mice) were carried out at the helical edge of both ears followed by lymph node cell count, lymph node weight and ear weight measurements after animal sacrifice. Positive and negative controls were included in the study and gave the expected results. The calculated stimulation indices (SI) of the substance were 1.073, 1.062, 1.091 (for lymph node cell count), 1.137, 1.235, 1.176 (for lymph node weight), 0.980, 1.005, 1.061 (for ear weight) and 0.996, 1.008, 0.988 (for ear thickness) at concentrations of 50, 75 and 100% (w/w), respectively and therefore <1.4 (lymph node cell count and lymph node weight) and <1.1 (ear weight), respectively. Thus, under the study conditions, the test substance was identified as non-sensitising to skin (Oleon, 2016).

Glycerol esters (GE)

Study 1:

A study was conducted to evaluate the skin sensitisation potential of glycerides, C16-18 and C18-unsatd. (in the form of soybean oil) in guinea pigs. The procedure was based on the method described by Magnusson and Kligman, 1970 (Skin sensitizing: Guinea pig maximization test). The induction phase consisted of an intradermal injection of 5% test substance followed by epicutaneous application of 100% test substance. 50% test substance was applied epicutaneously during the challenge phase. 0/10 guinea pigs were sensitized after 3 challenges. Under the study conditions, the test substance was determined to be a non-sensitizing to guinea pig skin (ECB, 2000).

Study 2:

As study was conducted to determine the skin sensitization potential of glycerides, C16-18 and C18-unsatd. (in the form of palm oil) was evaluated in the Magnusson-Kligman Maximization Test using three groups of 10 female guinea pigs of the Hartley strain. In the induction phase, the test group was injected with 5% palm oil in propylene glycol, 5% palm oil in 50% aqueous Freund’s Complete Adjuvant and 50% Freund’s Complete Adjuvant. In the booster phase, full strength palm oil (0.5 mL) was applied occlusively. Two of the groups served as controls. All the groups were challenged with 0.5 mL 5% palm oil. Reactions were observed 24 and 48 h after patch removal. No reactions were observed in any of the tested group. Under the study conditions, the test substance was determined to be non-sensitizing to guinea pig skin (CIR, 2000).

Justification for classification or non-classification

Based on the information available for its main constituents, the test substance is not considered to meet the requirements for sensitization classification according to the EU CLP (Regulation 1272/2008/EC) criteria.