Registration Dossier

Diss Factsheets

Administrative data

Description of key information

HEDTA-Na3 is not expected to be a skin sensitizer based on read across.

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:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study (OECD 406) For read-across justification refer to section 13.
Remarks:
Read across study
Justification for type of information:
Justification for type of information: See read across document in section 13.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
Total amount of TS applied is not stated
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Species:
guinea pig
Strain:
Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River France, 76410 Saint-Aubin-16s-Elbeuf, France
- Age at study initiation: 3 months
- Weight at study initiation: 374 ± 22 g
- Housing: individually in polycarbonate cages with stainless steel lid
- Diet: "106 pelleted diet" ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature : 21 ± 2°C
- Relative humidity : 30 to 70%
- Light/dark cycle: 12 h/12 h
- Ventilation: approximately 12 cycles/hour of filtered, non-recycled air
Route:
intradermal and epicutaneous
Vehicle:
corn oil
Concentration / amount:
intradermal injections: TRILON BD at the concentration of 0.5% (w/w) in corn oil,
topical application: TRILON BD at the concentration of 30% (w/w) in corn oil
Route:
epicutaneous, occlusive
Vehicle:
corn oil
Concentration / amount:
intradermal injections: TRILON BD at the concentration of 0.5% (w/w) in corn oil,
topical application: TRILON BD at the concentration of 30% (w/w) in corn oil
No. of animals per dose:
5 females/control group
10 females/treated group
Details on study design:
RANGE FINDING TESTS:
In order to determine the concentration of the TS in the main study one range finding test were performed on two animals (1 male and 1 female).
By intradermal route (tested concentrations: 1 % and 0.1 % (w/w):
24 hours before treatment, the dorsal region of the animals was clipped, intradermal injections of the dosage form preparations (0.1 ml) were performed in the interscapular region , cutaneous reactions were evaluated approximately 24, 48 hours and 6 days after the injections.
By cutaneous route (tested concentrations: 30% and 10% (w/w):
24 hours before treatment, both flank regions of the animals were clipped, the filter paper of a chamber was fully-loaded with one dosage form preparation. The chamber was then applied to the clipped area of the skin (one concentration per flank) . The chamber was held in place by means of an occlusive dressing for 24 hours, cutaneous reactions were evaluated approximately 24 and 48 hours after removal of the dressings.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: once intradermal (day 1) and additionally once cutanenously (day 8)
- Test groups: 1
- Control group: 2

INTRADERMAL EXPOSURE
- Site: six injections as pairs in the interscapular area
- Treatment:
Test group: A) front row: Freund's complete adjuvant (FCA) at 50% (v/v) in 0.9% NaCl; B) middle row: 0.1 ml TS at 0.5% (w/w) in corn oil; C) test substance at 0.5% (w/w) in the mixture FCA/0.9% NaCl (50/50)
Control groups: The animals were given the same injections (A, B, C) but without test substance, only with the formulating agent.

CUTANEOUS EXPOSURE
- Site: interscapular area
- Treatment:
Test group: a pad of filter paper (approximately 8 cm2) was fully-loaded with the test substance at the concentration of 30% (w/w) and was then applied to the interscapular region of the animals. The pad was held in place for 48 hours by means of an adhesive hypoallergenic dressing and an adhesive anallergenic waterproof plaster
Control groups: received an application of the vehicle alone under the same experimental conditions.

B. CHALLENGE EXPOSURE
Challenge:
- Day of challenge: day 22 (21 days after intradermal induction)
- Exposure period: 24 h
- Site: interscapular
- Treatment:
Test groups: received an application of the test substance and vehicle. The filter paper of a chamber (Finn Chambero) was fully-loaded with the test substance at the concentration of 30% (w/w) and was then applied to a clipped area of the skin of the posterior right flank of all animals. The vehicle was applied under the same experimental conditions to the skin of the posterior left flank. The chambers were held in contact with the skin for 24 hours by means of an adhesive an allergenic waterproof plaster. On removal of the dressing, any residual test substance was removed by means of a moistened
gauze pad.
Control groups: Control group one was treated like the treatment group; control group 2 remained untreated
- Evaluation (hr after challenge): 24, 48 h

Rechallenge:
- Day of challenge: day 29
- Exposure period: 24 h
- Treatment: the animals of all groups received an application of the test substance at the concentration of 30% (w/w) to the anterior left flank and the vehicle to the anterior right flank, under the same experimental conditions as for the first challenge application.
- Evaluation (hr after challenge): 24, 48 h
Challenge controls:
Yes, 2 groups
Positive control substance(s):
yes
Remarks:
Mercaptobenzothiazole
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
30%
No. with + reactions:
3
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 30%. No with. + reactions: 3.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
30%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 30%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
other: Negative control group 1
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: other: Negative control group 1. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
other: Negative control group 1
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: Negative control group 1. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
30%
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 30%. No with. + reactions: 1.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
30%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
Dryness of skin in 3/10 animals
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 30%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: Dryness of skin in 3/10 animals.
Reading:
rechallenge
Hours after challenge:
24
Group:
other: Negative control group 1
Dose level:
30%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: other: Negative control group 1. Dose level: 30%. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
other: 1egative control group 1
Dose level:
30%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
Dryness of skin was observed in 1/5 animals
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: other: 1egative control group 1. Dose level: 30%. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: Dryness of skin was observed in 1/5 animals.
Reading:
rechallenge
Hours after challenge:
24
Group:
other: Negative control group 2
Dose level:
30%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: other: Negative control group 2. Dose level: 30%. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
other: negative control group 2
Dose level:
30%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: other: negative control group 2. Dose level: 30%. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
20%
No. with + reactions:
7
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. Dose level: 20%. No with. + reactions: 7.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
20%
No. with + reactions:
7
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 20%. No with. + reactions: 7.0. Total no. in groups: 10.0.

One animal of the control group 1 was found dead on day 13. Hypoactivity and dyspnea were observed prior to death. The authors stated that such spontaneous clinical signs and mortality are sometimes observed in this species.

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the test there was no evidence for skin sensitization
Executive summary:

Under the conditions of the test there was no evidence for skin sensitization

Endpoint:
skin sensitisation
Remarks:
in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets generally accepted scientific principles For read-across justification refer to section 13.
Qualifier:
no guideline available
Principles of method if other than guideline:
Insult patch test
GLP compliance:
no
Type of study:
other: Insult patch test
Species:
guinea pig
Strain:
Hartley
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Buckberg Lab Animals, Inc., New York, USA
- Housing: 5/ animals per cage in wire-bottom cages
- Diet: Ralston Purina, guinea pig chow
- Water: tap water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23°C
- Humidity (%): 45%
- Photoperiod (hrs dark / hrs light): 12

Positive control results:
The epoxy resin sensitized 9/10 animals, producing a slight to marked erythema (9/10 animals) and a slight to moderate edema (9/10 animals).

- None of the animals treated with Na3EDTA showed positive reactions (see table).

- All animals treated with EDA were sensitized and displayed a slight to marked edema and erythema after challenge with EDA.

- Animals which were sensitized to EDTA did not respond to a challenge by Na3EDTA. Therefore it can be concluded that there is no cross sensitisation between EDA and Na3EDTA.

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
Under the conditions of the test, the substance is not sensitizing and does not cross react with EDA.
Executive summary:

Under the conditions of the test, the substance is not sensitizing and does not cross react with EDA.

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

No skin sensitisation studies on HEDTA-Na3 or HEDTA-H3 are available. However the structural analogue, EDTA-H4 and its various Na salts, are expected to exhibit similar properties and therefore studies using Na2-EDTA and Na3-EDTA have been used for read across. (For read-across justification also refer to section 13). In the OECD 406 guideline study with Na2-EDTA 3/10 guinea pigs showed a patch erythema after the first challenge and 1/10 after the second challenge. The reports on humans are conflicting and in case of positive results it was concluded that the reactions reflected irritation rather than sensitisation. Moreover, animals treated with Na3-EDTA did not show positive reactions. Overall, these results do not warrant classification and labeling according to EU or GHS critieria, which was also confirmed by the independent evaluation of the MAK Commission for the Investigation of Health Hazards of Chemical Compounds in the work area (MAK, 46. Lieferung, 2009).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The available information indicate that the substance should not be classified as skin sensitising according to Regulation 1272/2008/EC (CLP).