Registration Dossier

Administrative data

Description of key information

Skin sensitisation:

guinea pig maximization test (according to OECD 406): not sensitising (read- across from disodium dihydrogen EDTA EDTA)

guinea pig repeated insult patch test (no guideline): not sensitising

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 from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Refer to analogue justification provided in IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Key result
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:
no indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
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:
no indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
30%
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
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:
no indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
dryness of skin in 1/5 animals
Remarks on result:
no indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
other: negative control group 2
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
other: negative control group 2
Dose level:
0
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
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:
positive indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Key result
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:
positive indication of skin sensitisation
Remarks:
source: CAS 139-33-3, BASF SE, 2000, GPMT
Interpretation of results:
other: CLP/GHS criteria not met; no classification required according to Regulation (EC) No. 1272/2008
Conclusions:
A Guinea Pig maximization Test according to OECD 406 performed with the source substance disodium hydrogen EDTA (CAS 139-33-3) was selected as key result for reasons of structural similarity and data reliability. The read across approach is justified in the analogue justification. The target and source substances are considered unlikely to differ in their skin sensitisation potential. 3/10 guinea pigs showed a patch erythema after the first challenge and 1/10 after the re-challenge. However, overall these results do not warrant a labeling according to CLP 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). Therefore, no skin sensitisation potential is expected for the target substance trisodium hydrogen EDTA (CAS 150-38-9).

CLP: not classified
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline available
Principles of method if other than guideline:
Repeated insult patch test
GLP compliance:
no
Type of study:
other: Repeated insult patch test
Justification for non-LLNA method:
The existing data from this study not only being acceptable but of good quality, precludes the need for an additional LLNA study. In addition, a supplementary LLNA study would violate the ECHA objectives with regards to animal welfare.
Species:
guinea pig
Strain:
Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Buckberg Lab Animals, Inc., New York, USA
- Weight at study initiation: 250 - 325 g
- Housing: 5 animals per cage in wire-bottom cages
- Diet: Ralston Purina, guinea pig chow, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 2 weeks

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

Route:
other: topically to the clipped and depilated skin
Vehicle:
other: 9:1 solution of dipropylene glycol methyl ether and polyethylene sorbitan monooleate
Concentration / amount:
0.1 mL of a 10% solution
Day(s)/duration:
4 times in 10 days
Adequacy of induction:
not specified
No.:
#1
Route:
epicutaneous, open
Vehicle:
other: 9:1 solution of dipropylene glycol methyl ether and polyethylene sorbitan monooleate
Concentration / amount:
0.1 ml of a 10% solution
Day(s)/duration:
1
Adequacy of challenge:
not specified
No. of animals per dose:
10
Details on study design:
Induction:
4 topical treatments (0.1 mL) with test substance, at the third time 0.2 mL Freud`s adjuvant was injected additionally.
Challenge:
2 weeks after the last treatment animals were challenged topically.
Positive control substance(s):
yes
Remarks:
diglycidyl ether of 2,2-di(p,p-hydroxyphenyl)propane (DER® 331 epoxy resin (Dow Chemical))
Positive control results:
The positive control sensitized 9/10 animals, producing a slight to marked erythema (9/10 animals) and a slight to moderate edema (9/10 animals).
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
10%
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
slight to marked erythema, slight to moderate edema
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
10%
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation

Evaluation criteria: A test material is considered a skin sensitiser if at least 3 of 10 guinea pigs exhibit slight erythema on the challenge application site.

- None of the animals treated with trisodium hydrogen EDTA showed positive reactions

- 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 EDA did not respond to a challenge by trisodium hydrogen EDTA. Therefore, it can be concluded that there is no cross sensitisation between EDA and trisodium hydrogen EDTA.

Interpretation of results:
other: CLP/GHS criteria not met; no classification required according to Regulation (EC) No. 1272/2008
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Justification for read-across

A repeated insult patch test in the guinea pig is available for trisodium hydrogen EDTA (CAS 150 -38 -9). In order to corroborate this data read-across from an appropriate source substance, disodium dihydrogen EDTA (CAS 139-33-3), is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5 in order to fulfil the standard information requirements defined in Regulation (EC) No 1907/2006, Annex VII, 8.3. (Bio)transformation to common compounds of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

The Magnusson Klingman Test according to OECD Test Guideline 406 using the source substance disodium hydrogen EDTA (CAS 139 -33 -3) was chosen as key study. This test was performed under GLP by BASF (2000). 10 test animal and 5 control animals were used. A 0.5% concentration of the test substance in corn oil was used for intradermal induction and a 30% test concentration for topical induction. Control animals were treated with corn oil as vehicle control. The challenge was conducted with 30% Na2EDTA in corn oil. 3/10 test animals showed a discrete patchy erythema 24 h after patch removal, after 48 h 0/10 showed a patchy erythema. 7 days later a rechallenge was conducted using 30% substance in corn oil. 1/10 test animals exhibited a discrete patchy erythema after 24 h, which was reversible within 48 h. Control animals did not exhibit skin reaction after challenge or rechallenge. The positive control group using 20% mercaptobenzodiazol induced positive skin sensitisation reactions in 7/10 animals at the 24 and 48 h reading.

Also a supporting Repeated Insult Patch Test with trisodium hydrogen EDTA gave a negative result (0/10 animals) (Henck 1980). Within 10 days the animals received 4 topical treatments (0.1 mL) of 10% test item in a 9:1 solution of dipropylene glycol methyl ether and polyethylene sorbitan monooleatee. Two weeks after the last treatment animals were challenged topically. Within the same test the authors also tested for cross-sensitisation between the known skin sensitizer ethylenediamine (EDA) and the test item. Animals were sensitized with EDA and challenged topically with the test item on the one flank and trisodium hydrogen EDTA on the other. None of the animals reacted positive after the challenge with the test item, trisodium hydrogen EDTA, but all of the animals which were challenge with EDA showed a slight to marked erythema and slight edema. Therefore, it was concluded that the test item does not cross-sensitize with EDA.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The available data on skin sensitisation do not meet the classification criteria according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.