Registration Dossier

Administrative data

Description of key information

skin irritation

Source substance Zinc bis(O,O-diisobutyl dithiophosphate) (CAS 68457 -79 -4): non GLP, similar to OECD Guideline 404, Klimisch 1, rabbit, semiocclusive, skin irritating

Source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8): GLP, similar to OECD Guideline 404, Klimisch 1, rabbit, semiocclusive, not skin irritating

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 404, Klimisch 1, rabbit, semiocclusive, skin irritating

eye irritation

Source substance Zinc bis(O,O-diisobutyl dithiophosphate) (CAS 68457 -79 -4): GLP, similar to OECD Guideline 405, Klimisch 1, rabbit, eye irritating

Source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8): GLP, according to OECD Guideline 405, Klimisch 1, rabbit, eye irritating

source substance Phosphorodithioic acid, mixed O,O-bis(1,3 -dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605 -29 -8): GLP, Klimisch 1, rabbit, eye irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
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
Severe gastrointestinal irritation was observed in oral repeated dose toxicity studies with several ZDDP category members (HPV, 2005). “Repeated dermal exposure to experimental animals resulted in moderate-to-severe dermal irritation, behavioural distress, body weight loss and emaciation, reduction in haematological parameters and adverse effects on male reproductive organs”. The source substances were also irritating to skin and severely irritating to eyes. Thus, it is evident that irritation is a primary hazard of this category.
Since the 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 that are in the range of the established ZDDP category (C3-C12), it is assumed to have the same reactivity to skin and eyes as the source substance. The constituents of the target substance do not possess functional groups associated with other modes of action or toxicity effects. Toxicokinetic behaviour of the constituents of the target substance is expected to be essentially the same as those of the source substances. Due to the molecular weight, water solubilities and logPow values, the target and the source substances are expected to react with the skin proteins to a similar degree. There is no evidence of increasing or decreasing irritating properties of the ZDDP category members that could be correlated with an increase or decrease in carbon chain length or molecular weight. Thus, an enhancement of irritation properties of the target substance is not likely. The impurities of the target substance are considered not to contribute to the irritation 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 associated with irritation properties. Furthermore their amounts are very low. Therefore, it is predicted that the target substance would possess the same irritation potential to skin and eyes as the source substance.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24-72 h
Score:
1
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
0.22
Irritation parameter:
overall irritation score
Remarks on result:
not measured/tested
Irritation parameter:
primary dermal irritation index (PDII)
Remarks on result:
not measured/tested
Irritation parameter:
erythema score
Basis:
animal: 1 - 12
Time point:
24/48/72 h
Remarks on result:
other: no individual scores given
Irritation parameter:
edema score
Basis:
animal: 1 - 12
Time point:
24/48/72 h
Remarks on result:
other: no individual scores given
Interpretation of results:
other: EU GHS criteria not met
Conclusions:
Phosphorodithioic acid, O,O-bis(2-ethylhexyl) ester, zinc salt is not a primary skin irritant.
Executive summary:

Skin irritation was assessed similar to OECD Guideline 404. The test item was not a primary skin irritant.

Endpoint:
skin irritation: in vivo
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
Severe gastrointestinal irritation was observed in oral repeated dose toxicity studies with several ZDDP category members (HPV, 2005). “Repeated dermal exposure to experimental animals resulted in moderate-to-severe dermal irritation, behavioural distress, body weight loss and emaciation, reduction in haematological parameters and adverse effects on male reproductive organs”. The source substances were also irritating to skin and severely irritating to eyes. Thus, it is evident that irritation is a primary hazard of this category.
Since the 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 that are in the range of the established ZDDP category (C3-C12), it is assumed to have the same reactivity to skin and eyes as the source substance. The constituents of the target substance do not possess functional groups associated with other modes of action or toxicity effects. Toxicokinetic behaviour of the constituents of the target substance is expected to be essentially the same as those of the source substances. Due to the molecular weight, water solubility and logPow values, the target and the source substances are expected to react with the skin proteins to a similar degree. There is no evidence of increasing or decreasing irritating properties of the ZDDP category members that could be correlated with an increase or decrease in carbon chain length or molecular weight. Thus, an enhancement of irritation properties of the target substance is not likely. The impurities of the target substance are considered not to contribute to the irritation 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 associated with irritation properties. Furthermore their amounts are very low. Therefore, it is predicted that the target substance would possess the same irritation potential to skin and eyes as the source substance.

Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
2.6
Max. score:
4
Reversibility:
not fully reversible within: 7 d
Remarks on result:
other: sites wiped with water
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
1.8
Max. score:
4
Reversibility:
not fully reversible within: 7 d
Remarks on result:
other: sites wiped with water
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
2.3
Max. score:
4
Reversibility:
not fully reversible within: 7 d
Remarks on result:
other: sites wiped with oil
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
1.7
Max. score:
4
Reversibility:
not fully reversible within: 7 d
Remarks on result:
other: sites wiped with oil
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 24 and 72 h
Score:
4.4
Max. score:
8
Reversibility:
other: not applicable
Remarks on result:
other: sites wiped with water
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 24 and 72 h
Score:
4
Max. score:
8
Reversibility:
other: not applicable
Remarks on result:
other: sites wiped with oil
Irritant / corrosive response data:
At the 60 minute observation, all animals exhibited very slight to well-defined erythema at both dose sites. Edema at this time ranged from very slight to slight for four animals at the right dose site (test article removed with distilled water), while three animals exhibited very slight edema at the left dose site (test article removed with white oil). Erythema and edema scores increased at the 24, 48, and 72 hour observations, with the right dose site exhibiting slightly higher scores than the left dose site. Irritation decreased at both dose sites on Day 7 when all animals displayed very slight to well defined erythema and five animals showed very slight to slight edema. However scores at the right dose site were again slightly higher than the left dose sight.
Interpretation of results:
other: Category 2 (irritant) based on EU GHS criteria
Conclusions:
Based on the results of this study, the test substance would be classified as Category 2 in accordance with CLP Regulation.
Executive summary:

The primary dermal irritation potential of the test material was evaluated in this study with New Zealand White rabbits similar to OECD Guideline 404. The test material was administered to two separate sites (right dorsal thoracic and left dorsal thoracic). At each single site, 0.5 ml doses of undiluted test material were applied under gauze patch which was secured with tape. The patch was loosely held in contact with the skin by means of a semi-occlusive dressing for a four hour exposure period. At completion of exposure the dressing and gauze were removed and the right dorsal thoracic site was removed with paper towels moistened with distilled water; residual test material on the left dorsal thoracic dose site was removed with paper towels saturate in white oil. Application sites were evaluated in accordance with the method of Draize at approximately 60 minutes, 24, 48, and 72 hours and Day 7 after patch removal.

The Primary Irritation Index was calculated to be 4.42 for sites wiped with distilled water.

The Primary Irritation Index was calculated to be 4.0 for sites wiped with white oil.

Based on the results of this study, the test substance as supplied would be classified as Category 2 in accordance with CLP Regulation.
Endpoint:
skin irritation: in vivo
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)
Severe gastrointestinal irritation was observed in oral repeated dose toxicity studies with several ZDDP category members (HPV, 2005). “Repeated dermal exposure to experimental animals resulted in moderate-to-severe dermal irritation, behavioural distress, body weight loss and emaciation, reduction in haematological parameters and adverse effects on male reproductive organs”. The source substances were also irritating to skin and severely irritating to eyes. Thus, it is evident that irritation is a primary hazard of this category.
Since the 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 that are in the range of the established ZDDP category (C3-C12), it is assumed to have the same reactivity to skin and eyes as the source substance. The constituents of the target substance do not possess functional groups associated with other modes of action or toxicity effects. Toxicokinetic behaviour of the constituents of the target substance is expected to be essentially the same as those of the source substances. Due to the molecular weight, water solubilities and logPow values, the target and the source substances are expected to react with the skin proteins to a similar degree. There is no evidence of increasing or decreasing irritating properties of the ZDDP category members that could be correlated with an increase or decrease in carbon chain length or molecular weight. Thus, an enhancement of irritation properties of the target substance is not likely. The impurities of the target substance are considered not to contribute to the irritation 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 associated with irritation properties. Furthermore their amounts are very low. Therefore, it is predicted that the target substance would possess the same irritation potential to skin and eyes as the source substance.

Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 h
Score:
2.7
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: as supplied concentration/undiluted
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 h
Score:
1.7
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: as supplied concentration/undiluted
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 h
Score:
1.4
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 6.25% in mineral oil
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 h
Score:
0.08
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 6.25% in mineral oil
Irritation parameter:
erythema score
Basis:
animal: mean of all animals
Time point:
other: 24 and 72 h
Score:
2.2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 12.5% in mineral oil
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 h
Score:
0.6
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 12.5% in mineral oil
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 h
Score:
2.6
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 25% in mineral oil
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 h
Score:
0.9
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 25% in mineral oil
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 h
Score:
2.83
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 50% in mineral oil
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 h
Score:
1.2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 50% mineral oil
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 24 and 72 h
Score:
1.5
Max. score:
8
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 6.25% in mineral oil
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 24 and 72 h
Score:
2.7
Max. score:
8
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 12.5% in mineral oil
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 24 and 72 h
Score:
3.5
Max. score:
8
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 25% in mineral oil
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 24 and 72 h
Score:
4
Max. score:
8
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: 50% in mineral oil
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 24 and 72 h
Score:
4.25
Max. score:
8
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: as supplied concentration/undiluted
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritant / corrosive response data:
Undiluted test material induced moderate erythema and very slight to slight edema on all rabbits. There were no other dermal findings.

The 6.25% concentration of the test material induced very slight to slight erythema on all rabbits and very slight edema on one rabbit. There were no other dermal findings.
The 12.5 % concentration of the test material induced slight to moderate erythema and very slight edema on all animals. There were no other dermal findings.

The 25 % concentration of the test material induced slight to moderate erythema and very slight to slight edema on all animals. There were no other dermal findings.

The 50 % concentration of the test material induced moderate erythema and very slight to slight edema on all rabbits. There were no other dermal findings.
Interpretation of results:
other: Category 2 (irritant) based on EU GHS criteria
Conclusions:
Based on the results of this study, the test substance would be classified as a Category 2 in accordance with the classification system of EU GHS.
Executive summary:

The primary dermal irritation potential of the test material was evaluated in a study with New Zealand White rabbits similar to OECD Guideline 405 according to GLP. There were two groups of six rabbits. In Group 1, single 0.5 milliliter doses of undiluted test material were applied to a single site on each animal's back. In Group 2, single 0.5 milliliter doses of the test material at concentrations of 6.25, 12.5, 25 and 50% (weight to volume in mineral oil) were applied to four distinct application sites on each animal's back; each animal received a single dose of each concentration. All doses were applied under semi-occlusive dressing for a four hour exposure period. At completion of exposure the bandages were removed and the sites washed with light, white mineral oil and disposable paper towels. Application sites were evaluated in accordance with the method of Draize at approximately 24 and 72 hours after patch removal.

There were no deaths or significant body weight changes during the study period.

In Group 1, the Primary Irritation Index was calculated to be 4.3 for sites treated with undiluted test material.

In Group 2, Primary Irritation Indices of 1.5, 2.8, 3.5 and 4.0 were calculated for 6.25, 12.5, 25 and 50% w/v concentrations of the test material in mineral oil, respectively.

 

Based on the results of this study, the test substance is classified as a Category 2 in accordance with the classification system of GHS. 
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
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
Severe gastrointestinal irritation was observed in oral repeated dose toxicity studies with several ZDDP category members (HPV, 2005). “Repeated dermal exposure to experimental animals resulted in moderate-to-severe dermal irritation, behavioral distress, body weight loss and emaciation, reduction in hematological parameters and adverse effects on male reproductive organs”. The source substances were also irritating to skin and severely irritating to eyes. Thus, it is evident that irritation is a primary hazard of this category.
Since the 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 that are in the range of the established ZDDP category (C3-C12), it is assumed to have the same reactivity to skin and eyes as the source substance.
The constituents of the target substance do not possess functional groups associated with other mode of actions or toxicity effects. Toxicokinetic behavior of the constituents of the target substance is expected to be essentially the same as those of the source substances. Due to the molecular weight, water solubility and logPow values, the target and the source substances are expected to react with the skin proteins to a similar degree. There is no evidence of increasing or decreasing irritating properties of the ZDDP category members that could be correlated with an increase or decrease in carbon chain length or molecular weight. Thus, an enhancement of irritation properties of the target substance is not likely. The impurities of the target substance are considered not to contribute to the irritation 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 associated with irritation properties. Furthermore their amounts are very low. Therefore, it is predicted that the target substance would possess the same irritation potential to skin and eyes as the source substance.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
1.17
Reversibility:
not reversible
Remarks on result:
other: Non-rinsed
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
0.6
Reversibility:
not fully reversible within: 14 d
Remarks on result:
other: Non-rinsed
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
2.17
Reversibility:
not reversible
Remarks on result:
other: Non-rinsed
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
2.67
Reversibility:
not reversible
Remarks on result:
other: Non-rinsed
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
0.33
Reversibility:
fully reversible
Remarks on result:
other: Rinsed
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
0
Reversibility:
fully reversible
Remarks on result:
other: Rinsed
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
1.55
Reversibility:
fully reversible within: 21 d
Remarks on result:
other: Rinsed
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
1.44
Reversibility:
fully reversible within: 21 d
Remarks on result:
other: Rinsed
Irritation parameter:
overall irritation score
Remarks on result:
not measured/tested
Irritation parameter:
maximum mean total score (MMTS)
Remarks on result:
not measured/tested
Irritation parameter:
cornea opacity score
Basis:
animal: 1, 2, 3, 4, 5, 6, 7, 8, 9
Time point:
24/48/72 h
Remarks on result:
other: no individual scores given
Irritation parameter:
conjunctivae score
Basis:
animal: 1, 2, 3, 4, 5, 6, 7, 8, 9
Time point:
24/48/72 h
Remarks on result:
other: no individual scores given
Irritation parameter:
iris score
Basis:
animal: 1, 2, 3, 4, 5, 6, 7, 8, 9
Time point:
24/48/72 h
Remarks on result:
other: no individual scores given
Irritation parameter:
chemosis score
Basis:
animal: 1, 2, 3, 4, 5, 6, 7, 8, 9
Time point:
24/48/72 h
Remarks on result:
other: no individual scores given
Interpretation of results:
other: Category 1 (irreversible effects on the eye) based on EU GHS criteria
Conclusions:
According to the study conducted, Phosphorodithioic acid, O,O-bis(2-ethylhexyl) ester, zinc salt causes persistent eye irritation through 21 days. Rinsing the test material out of the eyes 30 seconds after the exposure resulted in eye irrtation that was reversible within 21 days.
Executive summary:

Eye irritation was tested according to OECD Guideline 405. According to the study conducted, Phosphorodithioic acid, O,O-bis(2-ethylhexyl) ester, zinc salt causes persistent eye irritation through 21 days. Rinsing the test material out of the eyes 30 seconds after the exposure resulted in eye irrtation that was reversible within 21 days.

Endpoint:
eye irritation: in vivo
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
Severe gastrointestinal irritation was observed in oral repeated dose toxicity studies with several ZDDP category members (HPV, 2005). “Repeated dermal exposure to experimental animals resulted in moderate-to-severe dermal irritation, behavioral distress, body weight loss and emaciation, reduction in hematological parameters and adverse effects on male reproductive organs”. The source substances were also irritating to skin and severely irritating to eyes. Thus, it is evident that irritation is a primary hazard of this category.
Since the 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 that are in the range of the established ZDDP category (C3-C12), it is assumed to have the same reactivity to skin and eyes as the source substance.
The constituents of the target substance do not possess functional groups associated with other mode of actions or toxicity effects. Toxicokinetic behavior of the constituents of the target substance is expected to be essentially the same as those of the source substances. Due to the molecular weight, water solubility and logPow values, the target and the source substances are expected to react with the skin proteins to a similar degree. There is no evidence of increasing or decreasing irritating properties of the ZDDP category members that could be correlated with an increase or decrease in carbon chain length or molecular weight. Thus, an enhancement of irritation properties of the target substance is not likely. The impurities of the target substance are considered not to contribute to the irritation 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 associated with irritation properties. Furthermore their amounts are very low. Therefore, it is predicted that the target substance would possess the same irritation potential to skin and eyes as the source substance.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 21 d
Remarks on result:
other: not reversible in 3/3 animals
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.2
Max. score:
2
Reversibility:
fully reversible within: 7 d
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
2.9
Max. score:
3
Reversibility:
fully reversible within: 14 d
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 7 d
Irritation parameter:
overall irritation score
Remarks on result:
not measured/tested
Irritation parameter:
maximum mean total score (MMTS)
Remarks on result:
not measured/tested
Irritant / corrosive response data:
The test material elicited moderate to severe ocular irritation that included corneal opacity, iritis, and conjunctival effects. Corneal opacity persisted in all three rabbits to Day 21.
Interpretation of results:
other: Category 1 (irreversible effects on the eye) based on EU GHS criteria
Conclusions:
Under the conditions of this study, the test material causes irreversible effects on the eye
Executive summary:

In a primary eye irritation study similar to OECD Guideline 405, 0.1 ml of undiluted test substance was placed into conjuctival sac of one eye of each of the New Zealand White rabbits (3 animals).The test material elicited moderate to severe ocular irritation that included corneal opacity, iritis, and conjunctival effects. Corneal opacity persisted in all three rabbits to Day 21.

 

The test substance is classified as Category 1 in accordance with CLP Regulation.

Endpoint:
eye irritation: in vivo
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
Severe gastrointestinal irritation was observed in oral repeated dose toxicity studies with several ZDDP category members (HPV, 2005). “Repeated dermal exposure to experimental animals resulted in moderate-to-severe dermal irritation, behavioral distress, body weight loss and emaciation, reduction in hematological parameters and adverse effects on male reproductive organs”. The source substances were also irritating to skin and severely irritating to eyes. Thus, it is evident that irritation is a primary hazard of this category.
Since the 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 that are in the range of the established ZDDP category (C3-C12), it is assumed to have the same reactivity to skin and eyes as the source substance.
The constituents of the target substance do not possess functional groups associated with other mode of actions or toxicity effects. Toxicokinetic behavior of the constituents of the target substance is expected to be essentially the same as those of the source substances. Due to the molecular weight, water solubility and logPow values, the target and the source substances are expected to react with the skin proteins to a similar degree. There is no evidence of increasing or decreasing irritating properties of the ZDDP category members that could be correlated with an increase or decrease in carbon chain length or molecular weight. Thus, an enhancement of irritation properties of the target substance is not likely. The impurities of the target substance are considered not to contribute to the irritation 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 associated with irritation properties. Furthermore their amounts are very low. Therefore, it is predicted that the target substance would possess the same irritation potential to skin and eyes as the source substance.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
1.2
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: at 25% effects did not clear in 1/6 animals at 21 days
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.6
Max. score:
2
Reversibility:
fully reversible within: 10 d
Remarks on result:
other: at 25% effects were clear in all animals by day 10
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
2.6
Max. score:
3
Reversibility:
not reversible
Remarks on result:
other: at 25% all effects clear in all animals by day 16
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
2.2
Max. score:
4
Reversibility:
not fully reversible within: 10 d
Remarks on result:
other: at 25% all effects were clear by day 10
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.6
Max. score:
4
Reversibility:
fully reversible within: 10 d
Remarks on result:
other: at 12.5% effects were clear in all animals by day 10
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.3
Max. score:
2
Reversibility:
fully reversible within: 10 d
Remarks on result:
other: at 12.5% effects were clear in all animals by day 10
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
2.2
Max. score:
3
Reversibility:
fully reversible within: 21 d
Remarks on result:
other: at 12.5% all effects clear in all animals by day 21
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 16 d
Remarks on result:
other: at 12.5% all effects were clear by day 16
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.1
Max. score:
4
Reversibility:
fully reversible within: 2 d
Remarks on result:
other: at 10% all effects clear by day 2
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.1
Max. score:
2
Reversibility:
fully reversible within: 2 d
Remarks on result:
other: at 10% effects were clear in all animals by day 2
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
1.3
Max. score:
3
Reversibility:
not fully reversible within: 3 d
Remarks on result:
other: at 10% effects were not clear in 6/6 animals by day 3
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.1
Max. score:
4
Reversibility:
not fully reversible within: 3 d
Remarks on result:
other: at 10% effects were not clear in 5/6 animals by day 3
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
other: at 7.5% no effects noted on cornea
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible
Remarks on result:
other: at 7.5% no effects noted on iris
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0.9
Max. score:
3
Reversibility:
not fully reversible within: 3 d
Remarks on result:
other: at 7.5% effects were not clear in 1/6 animals by day 3
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.1
Max. score:
4
Reversibility:
fully reversible within: 2 d
Remarks on result:
other: at 6.25% all effects clear by day 2
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.1
Max. score:
2
Reversibility:
fully reversible within: 2 d
Remarks on result:
other: at 6.25% all effects clear by day 2
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
not fully reversible within: 3 d
Remarks on result:
other: at 6.25% effects were not clear in 5/6 animals by day 3
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0.4
Max. score:
4
Reversibility:
not fully reversible within: 3 d
Remarks on result:
other: at 6.25% effects were not clear in 1/6 animals by day 3
Interpretation of results:
other: Category 1 at 25% concentration only; Category 2A at 12.5% and not classified at 10% or less
Conclusions:
Under the conditions of this study, the test material caused ocular irritation that persisted through Day 21 when tested as a 25% concentration in mineral oil. At a concentration of 12.5% it caused moderate irritation which fully resolved by day 21. At a concentration of 10, 7.5, and 6.25% in mineral oil the test material was not an eye irritant according to EU GHS classification system.
Executive summary:

In a primary eye irritation study, 0.1 ml ofthe test substance at either 25, 12.5, 10, 7.5, or 6.25% in mineral oilwas placed into one eye of each of the New Zealand White rabbits (6 animals per concentration). The test substance produced ocular irritation up to 21 days at a concentration of 25% and moderate irritation at a concentration of 12.5%.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

skin irritation

source substance Zinc bis(O,O-diisobutyl dithiophosphate) (CAS 68457 -79 -4):

The primary dermal irritation potential of the test material was evaluated in this study with New Zealand White rabbits similar to OECD Guideline 404. The test material was administered to two separate sites (right dorsal thoracic and left dorsal thoracic). At each single site, 0.5 ml doses of undiluted test material were applied under gauze patch which was secured with tape. The patch was loosely held in contact with the skin by means of a semi-occlusive dressing for a four hour exposure period. At completion of exposure the dressing and gauze were removed and the right dorsal thoracic site was removed with paper towels moistened with distilled water; residual test material on the left dorsal thoracic dose site was removed with paper towels saturate in white oil. Application sites were evaluated in accordance with the method of Draize at approximately 60 minutes, 24, 48, and 72 hours and Day 7 after patch removal.

The Primary Irritation Index was calculated to be 4.42 for sites wiped with distilled water.

The Primary Irritation Index was calculated to be 4.0 for sites wiped with white oil (Plutnick 1986).

source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8):

Skin irritation was assessed similar to OECD Guideline 404. Phosphorodithioic acid, O,O-bis(2-ethylhexyl) ester, zinc salt caused no skin irritation (Cooper 1986).

source substance Phosphorodithioic acid, mixed O,O-bis(1,3 -dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605 -29 -8)

The primary dermal irritation potential of the test material was evaluated in a study with New Zealand White rabbits similar to OECD Guideline 405 according to GLP. There were two groups of six rabbits. In Group 1, single 0.5 milliliter doses of undiluted test material were applied to a single site on each animal's back. In Group 2, single 0.5 milliliter doses of the test material at concentrations of 6.25, 12.5, 25 and 50% (weight to volume in mineral oil) were applied to four distinct application sites on each animal's back; each animal received a single dose of each concentration. All doses were applied under semi-occlusive dressing for a four hour exposure period. At completion of exposure the bandages were removed and the sites washed with light, white mineral oil and disposable paper towels. Application sites were evaluated in accordance with the method of Draize at approximately 24 and 72 hours after patch removal.

There were no deaths or significant body weight changes during the study period.

In Group 1, the Primary Irritation Index was calculated to be 4.3 for sites treated with undiluted test material.

In Group 2, Primary Irritation Indices of 1.5, 2.8, 3.5 and 4.0 were calculated for 6.25, 12.5, 25 and 50% w/v concentrations of the test material in mineral oil, respectively.

eye irritation

source substance Zinc bis(O,O-diisobutyl dithiophosphate) (CAS 68457 -79 -4):

In a primary eye irritation study similar to OECD Guideline 405, 0.1 ml of undiluted test substance was placed into conjuctival sac of one eye of each of the New Zealand White rabbits (3 animals).The test material elicited moderate to severe ocular irritation that included corneal opacity, iritis, and conjunctival effects. Corneal opacity persisted in all three rabbits to Day 21 (Turck 1994).

source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8):

Eye irritation was tested according to OECD Guideline 405. In this study Phosphorodithioic acid, O,O-bis(2-ethylhexyl) ester, zinc salt caused persistent eye irritation through 21 days. Rinsing the test material out of the eyes 30 seconds after the exposure resulted in eye irrtation that was reversible within 21 days (Morris 1996).

source substance Phosphorodithioic acid, mixed O,O-bis(1,3 -dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605 -29 -8)

In a GLP-compliant primary eye irritation study, 0.1 ml of the test substance at either 25, 12.5, 10, 7.5, or 6.25% in mineral oilwas placed into one eye of each of the New Zealand White rabbits (6 animals per concentration). The test substance produced ocular irritation up to 21 days at a concentration of 25% and moderate irritation at a concentration of 12.5%.

Justification for classification or non-classification

Based on the presented studies the source substances are classified as follows

source substance Zinc bis(O,O-diisobutyl dithiophosphate) (CAS 68457 -79 -4): skin irritating Cat. 2 (Plutnick 1986)

source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8): not skin irritating (Cooper 1986)

source substance Phosphorodithioic acid, mixed O,O-bis(1,3 -dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605 -29 -8): skin irritating Cat. 2

source substance Zinc bis(O,O-diisobutyl dithiophosphate) (CAS 68457 -79 -4): eye irritation Cat. 1 (Turck 1994)

source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8): eye irritation Cat. 1 (Morris 1996)

source substance Phosphorodithioic acid, mixed O,O-bis(1,3 -dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605 -29 -8): eye irritating Cat. 1

Based on the results for the three source substances, the registered substance is classified as skin irritant, Cat. 2 (H315) and eye irritant Cat. 1 (H318).


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