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Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was performed on the commercial SAYTEX 8010 Flame Retardant product under international guidelines and GLPS.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2003
Reference Type:
publication
Title:
Unnamed
Year:
2007
Reference Type:
publication
Title:
Allergic Contact Dermatitis in the Guinea Pig
Author:
Magnusson and Kligman
Year:
1970
Bibliographic source:
Charles C. Thomas, Springfield, IL

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The assay was originally run for the US registration.

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1'-(ethane-1,2-diyl)bis[pentabromobenzene]
EC Number:
284-366-9
EC Name:
1,1'-(ethane-1,2-diyl)bis[pentabromobenzene]
Cas Number:
84852-53-9
Molecular formula:
C14H4Br10
IUPAC Name:
1,1'-(ethane-1,2-diyl)bis[pentabromobenzene]
Details on test material:
The commercial SAYTEX 8010 Flame Retardant product was used as test article. The composition was 98.34% DBDPEthane and 1.66% Nonabromodiphenyl ethane.

In vivo test system

Test animals

Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raliegh NC
- Females (if applicable) nulliparous and non-pregnant: 5, Males 5 (4 males, 4 females for preliminary study); 23 males and females for second experiment
- Age at study initiation: 2 months
- Weight at study initiation: males: 263-318 g, females 262-301 g
- Housing: Suspended stainless steel cages, wire mesh floor
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitumn
- Acclimation period: 7 days
- Indication of any skin lesions: no

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 22 deg C
- Humidity (%): 32 to 68%
- Photoperiod (hrs dark / hrs light): 12 h
- IN-LIFE DATES: From: To: Sept. 24 to Oct. 29 2002

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
negative control
Concentration / amount:
O.5% CMC in water : 50% FCA. id induction day 1.
Route:
intradermal
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
positive control
Concentration / amount:
0.5 % CMC in water: 5%, FCA 50%, mixture of 5% HCA in 50% FCA. i.d. induction day 1
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
intradermal
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
Test substance
Concentration / amount:
50% FCA, 5% Test substance in 0.5% CMC in water, test site 3 mixture of 5% test substance in 50% FCA
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
Vehicle control
Concentration / amount:
0.5 % in water on day 8
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Remarks:
positive control
Concentration / amount:
100% HPA on day 8
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Remarks:
Test substance
Concentration / amount:
100% on day 8
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Challengeopen allclose all
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
irritation control
Concentration / amount:
Control animals: left flank 1% Test substance in 0.5% methylcellulose solution in water, right flank 0.5 % methylcellulose. Day 22
Adequacy of challenge:
highest non-irritant concentration
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: mineral oil
Remarks:
positive control
Concentration / amount:
Left Flank: 50% HPA in mineral oil, right flank: mineral oil, Day 22
Adequacy of challenge:
highest non-irritant concentration
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
Test substance
Concentration / amount:
Left flank: 1% testsubstance in 0.5% CMC, right flank 0.5% CMC in water. Day 22
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
10 in each of the control and positive control groups
20 in the test group
Details on study design:
Test group: 1% test article in 0.5% methylcellulose to left flank; 0.5% methylcellulose to right flank.

For the challenge phase, reactions at the test article or positive control treated sites greater than those seen at the vehicle treated sites were considered indicative of a sensitization response. In general, scores of 1 or greater at the test sites indicated sensitization, provided grades of less than 1 were seen at the control sites. If scores of 1 or greater were noted at the control sites; then reactions a test sites that exceeded the most severe control reactions were presumed due to sensitization.

A comparison of the reactions elicited in terms of incidence, severity, and duration between the control, positive control, and test groups was conducted to dtermine whether the test article induced sensitization. In order to interpret the responses, three indices were used: severity index (SI), incidence index (II), and sensistization index (SII). The SI was determine dfor both the 24 and 48 hr scores by dividing the sum of grades in the a group by the total number of animals in that group. The II was the fraction of animals showing a ositive sensitization response at 24 or 48 hours (animals showing a positive response at both observations were counted as one incidence). The SII was the percentage of animals showing a a positive response at 24 or 48 hours (animals showing a positive response at both observations were counted as one incidence). Classification of senzitization potential was determined using the scale below per Magnusson and Kligman (1970).
Challenge controls:
Control: 1% test article in 0.5% methylcellulose) to left flank; 0.5% methylcellulose to right flank.

Positive control: 50% HCA in mineral oil to left flank; mineral oil to right flank.
Positive control substance(s):
yes
Remarks:
50% HCA (alpha-hexylcinnamaldehyde, 85%)

Results and discussion

Positive control results:
During the challenge (maximization) phase of the study, the positive control group responded in a normal manner with approximately 90% of the animals observed with scattered mild erythema (severity score = 1) at the 24 hour observation interval.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
other: irritation control, test substance in uninduced control animals
Dose level:
1% DBDPEthane in CMC; left flank on uninduced control animals
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 1% DBDPEthane in CMC; left flank. No with. + reactions: 9.0. Total no. in groups: 10.0. Clinical observations: scattered mild erythema.
Remarks:
Test substance caused irritation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
CMC; right flank
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: CMC; right flank. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: scattered mild erythema.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
50% HCA in mineral oil; left flank
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. Dose level: 50% HCA in mineral oil; left flank. No with. + reactions: 9.0. Total no. in groups: 10.0. Clinical observations: scattered mild erythema.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
other: posiive control vehicle
Dose level:
mineral oil; right flank
No. with + reactions:
2
Total no. in group:
10
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. Dose level: mineral oil; right flank. No with. + reactions: 2.0. Total no. in groups: 10.0. Clinical observations: scattered mild erythema.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
1% DBDPEthane in CMC; left flank
No. with + reactions:
16
Total no. in group:
20
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 1% DBDPEthane in CMC; left flank. No with. + reactions: 16.0. Total no. in groups: 20.0. Clinical observations: scattered mild erythema.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
other: test chemcial group vehicle control site
Dose level:
CMC; right flank
No. with + reactions:
8
Total no. in group:
20
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: CMC; right flank. No with. + reactions: 8.0. Total no. in groups: 20.0. Clinical observations: scattered mild erythema.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
other: irritation control, test chemical in uninduced animals
Dose level:
1% DBDPEthane in CMC; left flank
No. with + reactions:
2
Total no. in group:
10
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 1% DBDPEthane in CMC; left flank. No with. + reactions: 2.0. Total no. in groups: 10.0. Clinical observations: scattered mild erythema.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
other: test chemical group vehicle control site
Dose level:
CMC, right flank
No. with + reactions:
2
Total no. in group:
10
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: CMC, right flank. No with. + reactions: 2.0. Total no. in groups: 10.0. Clinical observations: scattered mild erythema.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
50% HCA in mineral oil; left flank
No. with + reactions:
5
Total no. in group:
10
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 50% HCA in mineral oil; left flank. No with. + reactions: 5.0. Total no. in groups: 10.0. Clinical observations: scattered mild erythema.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
other: positive control vahicle control site
Dose level:
mineral oil; right flank
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: positive control. Dose level: mineral oil; right flank. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: scattered mild erythema.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
1% DBDPEthane in CMC; left flank
No. with + reactions:
4
Total no. in group:
20
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 1% DBDPEthane in CMC; left flank. No with. + reactions: 4.0. Total no. in groups: 20.0. Clinical observations: scattered mild erythema.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
other: test chemical group vehicle control site
Dose level:
CMC; right flank
No. with + reactions:
5
Total no. in group:
20
Clinical observations:
scattered mild erythema
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: CMC; right flank. No with. + reactions: 5.0. Total no. in groups: 20.0. Clinical observations: scattered mild erythema.

Any other information on results incl. tables

Summary of Dermal Scores (Challenge) – Male and Female

Group

# GP

Total 24 Hr Score

Total 48 Hr Score

# w/scores ≥1 at 24 or 48 hr

Severity Index (SI)

Incidence Index (II)

Sensitization Index (SII)

24 Hr

48 Hr

Control

 L Flank

10

9

2

9

0.9

0.2

9/10

90%

 R Flank*

10

1

2

2

0.1

0.2

2/10

20%

Positive Control

 L Flank

10

9

5

9

0.9

0.5

9/10

90%

 R Flank

10

2

1

2

0.2

0.1

2/10

20%

Test

 L Flank

20

18

4

16

0.9

0.2

16/20

80%

 R Flank

20

8

5

9

0.4

0.25

9/20

45%

* Right flank treated with vehicle only (control & test vehicle = CMC; positive control vehicle = mineral oil). In the irritation control groups it does not make sense to calculate the sensitization index. The results indicate that the test substance caused irritaiton in particular in the 24 h reading, that disappeared after 48 h. The severity and incidence was comparble in the control animals that were not induced with the test substance and in the iduced group. This demonstrates that the reactions are not a skin sensitization reaction, but an irritation.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
DBDPEthane was not a skin sensitizer when tested in the guinea pig maximization test. Upon challenge, the responses in the test animals were similar to those in the control group.
Executive summary:

DBDPEthane was not a skin sensitizer when tested in the guinea pig maximization test. Upon challenge, the responses in the test animals were similar to those in the control group.

No test-article-related mortalities occurred. Body weights were normal for the age and species. Group mean body weights increased during the study.

During the intradermal irritation screen, scattered mild erythema was observed at the 4 and 5% concentration sites in all animals at both observation intervals. Scattered mild erythema was observed at the 0.5, 1 and 2% concentration sites in two of four animals at one or both observation intervals. Two animals did not exhibit any erythema at the 0.5 and 1% concentration sites. During the topical patch irritation screen, scattered mild erythema was observed in one of four animals at the 50% concentration site (24 hours only) and in two of four animals at the 75% concentration site (24 hours only). Therefore, based on the irritation screen results, the test article was used at 5% in 0.5% methylcellulose for the intradermal injection induction, 100% for the topical patch induction, and 1% in 0.5% methylcellulose for the challenge exposure.

During the challenge (maximization) phase of the study, the positive control group responded in a normal manner with approximately 90% of the animals observed with scattered mild erythema (severity score = 1) at the 24 hour observation interval. In the control group, scattered mild erythema was observed at the test article sites in nine of ten animals at 24 hours (90%) and two of ten animals (20%) at 48 hours. In the test group, scattered mild erythema (severity score = 1) was observed in fourteen of twenty animals at 24 hourspostdose (70%) and in four of twenty animals at 48 hours postdose (20%). Moderate and diffuse erythema (severity score = 2) was observed in two of twenty animals at 24 hours postdose (10%). Test group dermal observations of the vehicle sites (right flank) were similar to those seen in the control group.

No other clinical signs were observed in any animal.

Under the conditions of this study, because the severity and sensitization indices were approximately the same for the control and test groups, it was concluded that the test article was not a sensistizer in guinea pigs.

Summary of Dermal Scores (Challenge) – Male and Female

Group

# GP

Total 24 Hr Score

Total 48 Hr Score

# w/scores ≥1 at 24 or 48 hr

Severity Index (SI)

Incidence Index (II)

Sensitization Index (SII)

24 Hr

48 Hr

Control

 L Flank

10

9

2

9

0.9

0.2

9/10

90%

 R Flank*

10

1

2

2

0.1

0.2

2/10

20%

Positive Control

 L Flank

10

9

5

9

0.9

0.5

9/10

90%

 R Flank

10

2

1

2

0.2

0.1

2/10

20%

Test

 L Flank

20

18

4

16

0.9

0.2

16/20

80%

 R Flank

20

8

5

9

0.4

0.25

9/20

45%

* Right flank treated with vehicle only (control & test vehicle = CMC; positive control vehicle = mineral oil).