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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2022
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:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
See Section 1. “HYPOTHESIS FOR THE ANALOGUE APPROACH” in the attached reasoning: “7.4.1 – EC 941-225-2 – Direct Black 80 – Reasoning.pdf”
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See Section 2. “SOURCE AND TARGET CHEMICAL(S) – INCLUDING INFORMATION ON PURITY AND IMPURITIES” in the attached reasoning: “7.4.1 – EC 941-225-2 – Direct Black 80 – Reasoning.pdf”
3. ANALOGUE APPROACH JUSTIFICATION
See section 3. “JUSTIFICATION FOR THE ANALOGUE APPROACH” in the attached reasoning: “7.4.1 – EC 941-225-2 – Direct Black 80 – Reasoning.pdf”
4. DATA MATRIX
See section 4. “DATA MATRIX” in the attached reasoning: “7.4.1 – EC 941-225-2 – Direct Black 80 – Reasoning.pdf”
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
other: Data Sharing Dispute
Adequacy of study:
supporting study
Study period:
1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Existing study well reported and performed under GLP.
Species:
guinea pig
Strain:
Himalayan
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: BRL Biological Research laboratory Ltd- number of animals: 30 males / 6
females- Age at study initiation: 5 weeks- Weight at study initiation: Control and test group: 281-33
3 g Pretest:286-307 g- Housing: Individually in Makrolon type-3 cages with standard softwood bedd
ing - Diet : Pelleted standard Kliba 342, Batch 63/91 guinea pig breeding/ maintenance diet, ad libi
tum.- Water: tap water , ad libitum. Once weekly additional supply of ascorbic acid (1 g/l) via the
drinking water. - Acclimation period: One week under test conditions after veterinary examination.EN
VIRONMENTAL CONDITIONS- Temperature (°C):22 ± 3°C- Humidity (%):40-70 % - Photoperiod : 12
hours artificial fluorescent light/12 hours dark, music/light period.
Route:
intradermal
Vehicle:
other: for induction: physiological saline; for epidermal: vaselina album
Concentration / amount:
5% for intradermal injenction5, 10, 15 and 25% for epidermal application The highest non-irritating
test article concentration used for challenge application was 15%.
Adequacy of induction:
not specified
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: for induction: physiological saline; for epidermal: vaselina album
Concentration / amount:
5% for intradermal injenction5, 10, 15 and 25% for epidermal application The highest non-irritating
test article concentration used for challenge application was 15%.
Adequacy of challenge:
not specified
No. of animals per dose:
Main study induction: Control 10 females / Test Group: 20 femalesMain study challenge: Control 10 fe
males / Test Group: 20 females
Details on study design:
MAIN STUDYA. INDUCTION EXPOSURE: injection- Test groups: 20 females- Control group: 10 fem
ales- Site: An area of dorsal skin from the scapular region (approximately 6 x 8 cm) was clipped fre
e of hair. Three pairs of intradermal injections (0.1 ml/site) were made at the border of a 4 x 6 cm
area in the clipped region- Concentrations: 5% with physiological saline, 5% by emulsion in a 50:50
mixture of Freund's colplete adjuvant and physiological salineINDUCTION EXPOSURE: epidermal
application, one week after the injections- Exposure period: 48 h- Test groups: 20 females- Control
group: 10 females- Site: (6 x 8 cm)- Type of coverage: filter paper was saturated with the test article
and placed over the injection sites of the test animais. The patch was covered by aluminum foil and fi
rmly secured by an elastic plaster wrapped around the trunk of the animal and secured with imperviou
s adhesive tape.- Concentrations: 25 % in vaseline albumB. CHALLENGE EXPOSURE: The test and
control guinea-pigs were challenged two weeks after the epidermal induction application.- Exposure
period: approximately 24 hours later- Test groups: 20 females- Control group: 10 females- Site:hair
was clipped and shaved from a 5 x 5 cm area on the left and right flank of each guinea-pig.- Type o
f coverage: Two patches (2 x 2 cm) of filter paper- Concentrations: 15% in vaseline album - Evaluati
on : 24, 48 hrsOTHER OBSERVATION:Mortality/Viability: dailyBody Weights:At acclimatization start,
start of application and end of test.Symptoms (local systemic): dailyNecropsy: noAll animals were
killed at the end of the test period with an intraperitoneal injection of pentobarbital (> 800 mg/kg) and
discarded.
Positive control substance(s):
yes
Remarks:
Formaldheyde solution
Positive control results:
8 guinea pigs in a group of 10 animals showed positive response to the formaldehyde solution.
Reading:
1st reading
Hours after challenge:
28
Group:
test chemical
Dose level:
0
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No systemic symptoms were observed.
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 28.0. Group: test group. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: No systemic symptoms were observed..
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No systemic symptoms were obseved.
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: No systemic symptoms were obseved. .
Interpretation of results:
GHS criteria not met
Conclusions:
According to EEC (European Economie Community) and CLP classification criteria described in
guidelines 83/467, September 16, 1983, the tested substance Direct Red 81 is not a sensitizer.
Executive summary:

The purpose of this skin sensitization study was to assess the allergenic potential of Direct Red 81 when
administered to the skin of albino guinea pigs following OECD 406, Maximization-Test of B. Magnusson
and A.M. Kligman (1969).
Ten animals (10 females) were treated with the vehicle alone (vaseline album) and 20 animals (20
females) were treated with the test article.
Due to the unequivocal findings observed after the first challenge, no second challenge was performed.

Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
other: data sharing dispute
Adequacy of study:
key study
Study period:
1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
not specified
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
not reported
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Company distributed by Anlab s.r.o.
- Weight at study initiation: 302-364 g
- Housing: Guinea pigs were housed in separate cages in plastic cages type T4. The group of 5 an
imals were housed in one cage.
- Diet : Experimantal animals were fed with a standard granulated feed mixture TM produced
commercially in Kocanda. Animals were fed ad libitum. Raw material composition provided full biol
ogical and nutritional diet for experimental animals
- Water: guinea pigs were supplied with safe drinking water, according to CSN 757111 and ogni ani
mal additionaly received 20 mg of sorbic acid per day.
- Acclimation period: at least 1 week
Regular cleaning and disinfection of cages was performed to prevent contamination of pathogens a
ccording to standard operating procedure.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22° C ± 3°C
- Humidity (%): 50% ± 15%
- Photoperiod: 12-hour light cycle
Route:
intradermal and epicutaneous
Vehicle:
water
Concentration / amount:
0,5 % of the tested substance in water solution
Adequacy of induction:
not specified
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
water
Concentration / amount:
0,5 % of the tested substance in water solution
Adequacy of challenge:
not specified
No. of animals per dose:
Exterimental group: 20 females x dose (0,5% )
Control group: 10 females x dose
Details on study design:
A. INDUCTION: INTRADERMAL INJECTION
Day 0- treated group:
Three pairs of intradermal injections of 0,1 ml volume were applied to the shaved area .
injection 1: a 1:1 mixture FCA/water
injection 2: 0,5 % of the test substance in water solution
injection 3: 0,5 % of the test substance in water solution formulated in a 1:1 mixture FCA/
water
Day 0- control group:
Three pairs of intradermal injections of 0,1 ml volume were applied to the shaved area .
injection 1: a 1:1 mixture FCA/water
injection 2: water for injection
injection 3: a 50 % w/v formulation of the vehicle in a 1:1 mixture (v/v) FCA/water
INDUCTION: TOPICAL APPLICATION
Day 7- treated group:
Tested area on the neck was again shaved. On the identical site of intradermal injection was
applied a filter paper (2x4cm) which was loaded with 25% of tested substance in white vaseline and
held in contact by an occlusive dressing for 48 hours.
Day 7- control group:
Tested area on the neck was again shaved. White vaseline was applied to an identical area
of intradermal injection on filter paper (2x4 cm) in occlusive dressing for 48 hours.
B. CHALLENGE: TOPICAL APPLICATION
Day 21- treated and control group:
On the right side of the animals was applied a filter paper (2x2 cm) impregnated with 0.5%
solution of the tested substance in water for injections, occlusive dressing covered a period of 24hrs.
Skin reaction were evaluted on 1, 24, 48 and 72 hours after removal of the patch and cleaning of the
challenge area with water. Clinical trials were performed, focusing on the intensity of erythema and
edema .
Day 28- treated and control group second exposure is recommended to avoid false negative results. On the left side of anim
als was applied a filter paper (2x2 cm) impregnated with 0.5% solution of the tested substance in water for injections, occlusive dressing covered a period of 24hrs. After 1,24,48 and 72 hours was removed the patch and the challenge area was cleaned with water and was carried out a evaluation of the skin reactions.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0,5 % of the tested substance in water
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: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
1
Group:
test chemical
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
4
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 1.0. Group: test group. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 4.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0,5 % of the tested substance in water
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: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 72.0. Group: test group. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
1
Group:
negative control
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 1.0. Group: negative control. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0,5 % of the tested substance in water
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: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
72
Group:
negative control
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: test group. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0,5 % of the tested substance in water
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: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
1
Group:
negative control
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 1.0. Group: negative control. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
24
Group:
negative control
Dose level:
0,5 % of the tested substance in water
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 0,5 % of the tested substance in water. No with. + reactions: 0.0. Total no. in groups: 10.0.
Interpretation of results:
GHS criteria not met
Conclusions:
The substance was tested following OECD 406 for skin sensitisation. No positive skin reactions were
observed in the first or in repeated experiments.
Executive summary:

The substance was tested following OECD 406 for skin sensitisation (GMPT). The skin was exposed
to maximal concentration of the tested substance and the allergenic potential was determined using the
known factors for confirmed contact allergy, such as penetration, skin irritation, and high concentrations.
Induction was performed by intradermal and topical application. Clinical sign (edhema and erythema)
were evaluated and no animal showed any important skin reactions after 1, 24, 48 and 72h and it can
be concluded that the substance has no allergenic potential.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2022

Materials and methods

Test material

Constituent 1
Reference substance name:
hexasodium 6-amino-3-[(1E)-2-{7-[(1E)-2-{4-[(1E)-2-(4-amino-2-hydroxy-6-sulfonatonaphthalen-1-yl)diazen-1-yl]phenyl}diazen-1-yl]-8-hydroxy-6-sulfonatonaphthalen-2-yl}diazen-1-yl]-4-hydroxynaphthalene-2-sulfonate 6-amino-3-[(1E)-2-{7-[(1E)-2-{4-[(1E)-2-(4-amino-6-sulfonatonaphthalen-1-yl)diazen-1-yl]phenyl}diazen-1-yl]-8-hydroxy-6-sulfonatonaphthalen-2-yl}diazen-1-yl]-4-hydroxynaphthalene-2-sulfonate
EC Number:
941-225-2
Molecular formula:
not applicable
IUPAC Name:
hexasodium 6-amino-3-[(1E)-2-{7-[(1E)-2-{4-[(1E)-2-(4-amino-2-hydroxy-6-sulfonatonaphthalen-1-yl)diazen-1-yl]phenyl}diazen-1-yl]-8-hydroxy-6-sulfonatonaphthalen-2-yl}diazen-1-yl]-4-hydroxynaphthalene-2-sulfonate 6-amino-3-[(1E)-2-{7-[(1E)-2-{4-[(1E)-2-(4-amino-6-sulfonatonaphthalen-1-yl)diazen-1-yl]phenyl}diazen-1-yl]-8-hydroxy-6-sulfonatonaphthalen-2-yl}diazen-1-yl]-4-hydroxynaphthalene-2-sulfonate

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Group:
negative control
Remarks on result:
not measured/tested
Group:
positive control
Remarks on result:
not measured/tested
Group:
test chemical
Remarks on result:
not measured/tested

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the available information and the reasoning explained above, it should be possible to infer that the target substance Direct Black 80 (EC: 941-225-2) is not a skin sensitizer, based on reliable data and no more experimental test is needed for the endpoint 7.4.1.
Executive summary:

In conclusion, the target substance can be predicted as not a skin sensitizer. The values of the similarity index between the target and sources selected ranges between 0.871 and 0.764 (in a range between 0 and 1). An analysis of the structures and of the profilers was made increasing the evidence that a qualitative read-across can be made to classify the compound of interest. In accordance with the scenario N°2 of the RAAF document [1] (different compounds having the same type of effects); on the basis of a reliable and robust read-across with sources Direct Blue 71-151 (EC: 911-640-3) and Direct Red 81 (EC: 220-028-9), it is possible to classify the target compound as not sensitizing to the skin with a good reliability.