Registration Dossier

Administrative data

Description of key information

Source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8): GLP, similar to OECD Guideline 406, Klimisch 2, guinea pig maximisation test, not skin sensitising

Source substance Phosphorodithioic acid, mixed O,O-bis(1,3 -dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605 -29 -8): GLP, similar to OECD Guideline 406, Klimisch 2, Buehler test, not skin 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 based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Justification for type of information:
REPORTING FORMAT FOR THE CATEGORY APPROACH
Please refer also to the read-across statement attached in section 13

1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
The target and the source substances are structurally similar substances that share the common organometallic core structure consisting of a central zinc metal bonded to four alkyldithiophosphate esters (ligands) by coordinate covalent bonds -Zn[(S2P(OR)2]2. Structural variations between the target and the source substances are related only to the alkyl (R) groups of the alkyldithiophosphate ligands. The substances in this category give thus rise to an (identical) common compound Phosphorodithioic acid moiety that can be released by the breakage of ester bonds and dissociation from the Zinc complex to which the organism would be exposed if the target substance was tested in the toxicity studies. Exposure to the parent compounds (non-transformed constituents) and to the counter alkyl alcohols, possibly released by hydrolysis of P-O bonds – non-common compounds – would not influence the prediction of the (eco)toxicological properties because they are considered to have the same biological targets and to cause the same type of effects through a common underlying mechanism due to the same functional groups (zinc cation, phosphorodithioic cation and aliphatic alcohol anionic moieties). The impurities of the target and the source substances are not expected to impact the prediction because they are identical or, if slightly structural different, belong to the same class of compounds with the same functional groups and their percentages are very low.

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL )
The source substances were non-sensitising in skin sensitisation studies.
Since the main constituents of the target substance are structurally similar to the constituents of the source substances with the same functional groups and the alkyl chain lengths of phosphoroditioate moieties are in the range of the established ZDDP category (C3-C12), the same mode of toxicological action is expected for the target and the source substances. The constituents of the target substance do not possess functional groups associated with other deviating modes of action or toxicity effects from the source substances. Toxicokinetic behavior of the constituents of the target substance is expected to be essentially the same as that of the source substance. Thus, it is not likely that the structurally dissimilar alerts i.e. alkyl chain rests of the target substance would result in protein binding leading to hypersensitivity reactions. Therefore, a skin sensitisation of the target substance is not likely. The impurities of the target substance are considered not to contribute to sensitisation potential because they are also structurally similar to the impurities of the source substances and consist of substances of simple structure without specific mode of action and do not contain functional groups leading to protein binding and subsequently to a hapten formation and eliciting skin sensitisation.
Therefore, it is predicted that the target substance would not possess skin sensitisation potential if it was tested in a skin sensitisation study.
Positive control results:
n/a
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
5 % (w/v)
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
none
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
5 % (w/v)
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
none
Group:
positive control
Remarks on result:
not measured/tested
Group:
negative control
Remarks on result:
not measured/tested
Interpretation of results:
other: EU GHS criteria not met
Conclusions:
The test material does not appear to be a sensitiser in the albino guinea pig.
Executive summary:

In a Magnusson-Kligman Guinea Pig maximization test similar to OECD Guideline 406, 20 Dunkin-Hartley strain albino Guinea Pigs were treated with 5.0 % w/v test substance. Scores of zero in all test animals were obtained at all time points examined. The test material does not appear to be a sensitiser in the albino guinea pig.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Justification for type of information:
REPORTING FORMAT FOR THE CATEGORY APPROACH
Please refer also to the read-across statement attached in section 13

1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
The target and the source substances are structurally similar substances that share the common organometallic core structure consisting of a central zinc metal bonded to four alkyldithiophosphate esters (ligands) by coordinate covalent bonds -Zn[(S2P(OR)2]2. Structural variations between the target and the source substances are related only to the alkyl (R) groups of the alkyldithiophosphate ligands. The substances in this category give thus rise to an (identical) common compound Phosphorodithioic acid moiety that can be released by the breakage of ester bonds and dissociation from the Zinc complex to which the organism would be exposed if the target substance was tested in the toxicity studies. Exposure to the parent compounds (non-transformed constituents) and to the counter alkyl alcohols, possibly released by hydrolysis of P-O bonds – non-common compounds – would not influence the prediction of the (eco)toxicological properties because they are considered to have the same biological targets and to cause the same type of effects through a common underlying mechanism due to the same functional groups (zinc cation, phosphorodithioic cation and aliphatic alcohol anionic moieties). The impurities of the target and the source substances are not expected to impact the prediction because they are identical or, if slightly structural different, belong to the same class of compounds with the same functional groups and their percentages are very low.

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL
)
The source substances were non-sensitising in skin sensitisation studies.
Since the main constituents of the target substance are structurally similar to the constituents of the source substances with the same functional groups and the alkyl chain lengths of phosphoroditioate moieties are in the range of the established ZDDP category (C3-C12), the same mode of toxicological action is expected for the target and the source substances. The constituents of the target substance do not possess functional groups associated with other deviating modes of action or toxicity effects from the source substances. Toxicokinetic behavior of the constituents of the target substance is expected to be essentially the same as that of the source substance. Thus, it is not likely that the structurally dissimilar alerts i.e. alkyl chain rests of the target substance would result in protein binding leading to hypersensitivity reactions. Therefore, a skin sensitisation of the target substance is not likely. The impurities of the target substance are considered not to contribute to sensitisation potential because they are also structurally similar to the impurities of the source substances and consist of substances of simple structure without specific mode of action and do not contain functional groups leading to protein binding and subsequently to a hapten formation and eliciting skin sensitisation.
Therefore, it is predicted that the target substance would not possess skin sensitisation potential if it was tested in a skin sensitisation study.
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
1 %
No. with + reactions:
3
Total no. in group:
20
Clinical observations:
not specified
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
1 %
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
not specified
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
1 %
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
not specified
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
1 %
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
not specified
Group:
positive control
Remarks on result:
no indication of skin sensitisation
Interpretation of results:
other: EU GHS criteria not met
Conclusions:
The irritation in 3/20 animals in the challenge phase scored after 24 hours did not persist to 48 hours, indicating an irritation response rather than a skin sensitisation response.
Executive summary:

Skin sensitisation was tested in a study similar to OECD Guideline 406 (Buehler assay). The irritation in 3/20 animals in the challenge phase scored after 24 hours did not persist to 48 hours, indicating an irritation response rather than a skin sensitisation response.

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

The source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8) was tested in a Magnusson-Kligman Guinea Pig maximization test similar to OECD Guideline 406. 20 Dunkin-Hartley strain albino Guinea Pigs were treated with 5.0 % w/v test substance. Scores of zero in all test animals were obtained at all time points examined. The test material does not appear to be a sensitiser in the albino guinea pig (Costello 1982).

The source substance Phosphorodithioic acid, mixed O,O-bis(1,3 -dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605 -29 -8) was tested in a study similar to OECD Guideline 406 (Buehler assay) according to GLP. The test item was not sensitising (Morris 1997).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the results for the source substances (no adverse effect observed) the registered substance does not have to be classified according to Regulation (EC) No 1272/2008.


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