Registration Dossier

Administrative data

Description of key information

oral route:

source substance Zinc bis(O,O-diisobutyl dithiophosphate) (CAS 68457 -79 -4): non GLP, similar to OECD Guideline 401, Klimisch 1, rat, oral (gavage), LD50 = 3600 mg/kg bw

source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8): non GLP, similar to OECD Guideline 401, Klimisch 2, rat, oral (gavage), LD50 = 3100 mg/kg bw

source substance Phosphorodithioic acid, mixed O,O-bis(1,3 -dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605 -29 -8): non GLP, similar to OECD 401, Klimisch 1, rat, oral (gavage), LD50 = 3100 mg/kg bw

inhalative route:

source substance Phosphorodithioic acid, mixed O,O-bis(1,3 -dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605 -29 -8): non GLP, similar to OECD 403, Klimisch 2, rat, inhalation (vapour) - whole body, 4 h, LD50 > 2.3 mg/L air (nominal)

dermal route:

source substance Zinc bis(O,O-diisobutyl dithiophosphate) (CAS 68457 -79 -4): GLP, similar to OECD 402 - according to 16CFR1500.3, Klimisch 2, rabbit, dermal - occlusive, 25 h, LD50 > 20000 mg/kg bw

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 402, Klimisch 2, rat, dermal - semiocclusive, 25 h, LD50 > 2002 mg/kg bw

source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8): non GLP, similar to OECD 402, Klimisch 2, rabbit, dermal - occlusive, 24 h, LD50 > 5000 mg/kg bw

Based on the available data and based on the performed studies for CSA as key value the lowest value of all category members was choosen. Differences in the values of each category-member are obvious, but this is in range with the category approach, where nevertheless the members of one category may have different values, because all results show, that no substance has to be classified according to CLP (Regulation (EC) No 1272/2008).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
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 acute toxicity potential of the ZDDP category members is reported to be low (HPV, 2005). The source substances were practically non-toxic in the acute toxicity study with rats (LD50 >3000 mg/kg bw).
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 mode of actions or toxicity effects. Toxicokinetic behavior of the constituents of the target substance is expected to be essentially the same as that of the source substance. Based on the results of the oral acute toxicity studies with the source substances and other ZDDP category members, it is evident that the structural dissimilarities – the chain lengths of the alkyl rests – did not result in different strength of the toxicity effects. Even if absorption through GI tract of the category members with shorter alkyl rests and theoretically higher absorption rates (due to the increased water solubility and decreased molecular weights favouring absorption) is higher, their intrinsic properties are essentially the same as the findings in the acute toxicity studies are very similar. The impurities of the target substance are considered not to contribute to the toxicity effects 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. Furthermore, their amounts are very low. Therefore, it is predicted that the target substance would possess the same toxicity potential by acute oral exposure as the source substance.
Sex:
male
Dose descriptor:
LD50
Effect level:
3 100 mg/kg bw
Based on:
not specified
95% CL:
>= 1 800 - <= 5 100
Mortality:
7500 mg/kg: 10/10 rats died 1-2 days after exposure
5000 mg/kg: 9/10 rats died between 1-9 days after exposure
3300 mg/kg: 6/10 rats died 1-2 days after exposure
2200 mg/kg: 2/10 rats died between 1-8 days after exposure
Clinical signs:
Depresson, diarrhea, reduced food intake
Gross pathology:
Survivors had less than normal amounts of body fat. No other changes observed.
Other findings:
not specified
Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
The rat oral LD50 is 3100 mg/kg in male rats. Sublethal effects of depression, diarrhea, and reduced food intake were observed. Necropsy observations included reduction of body fat, no specific organ toxicity is evident.
Executive summary:

The substance was tested simiar to OECD Guideline 401. The rat oral LD50 is 3100 mg/kg in male rats. Sublethal effects of depression, diarrhea, and reduced food intake were observed. Necropsy observations included reduction of body fat, no specific organ toxicity is evident.  

Endpoint:
acute toxicity: oral
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 acute toxicity potential of the ZDDP category members is reported to be low (HPV, 2005). The source substances were practically non-toxic in the acute toxicity study with rats (LD50 >3000 mg/kg bw).
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 mode of actions or toxicity effects. Toxicokinetic behavior of the constituents of the target substance is expected to be essentially the same as that of the source substance. Based on the results of the oral acute toxicity studies with the source substances and other ZDDP category members, it is evident that the structural dissimilarities – the chain lengths of the alkyl rests – did not result in different strength of the toxicity effects. Even if absorption through GI tract of the category members with shorter alkyl rests and theoretically higher absorption rates (due to the increased water solubility and decreased molecular weights favouring absorption) is higher, their intrinsic properties are essentially the same as the findings in the acute toxicity studies are very similar. The impurities of the target substance are considered not to contribute to the toxicity effects 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. Furthermore, their amounts are very low. Therefore, it is predicted that the target substance would possess the same toxicity potential by acute oral exposure as the source substance.
Preliminary study:
Conducted at 10 g/kg, however details from this study are not available in this report.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
3 600 mg/kg bw
Based on:
not specified
95% CL:
>= 2.7 - <= 4.8
Mortality:
Deaths occured at the 3.5, 5.0 and 8.75 g/kg dose levels. Most deaths occurred within the first two days.
Clinical signs:
Lethargy, diarrhea, piloerection, chromodacryorrhea, chromorhinorrhea and ptosis. These findings were no longer evident in the two lowest groups by the middle of week two. Tremors and spasms were noted at the 5.0 g/kg dose level.
Body weight:
Body weight changes were within expected ranges for the surviving animals.
Gross pathology:
Lung congestion, gastrointestinal findings and staining around the mouth, nose and anus were common necropsy findings for the animals that died. All surviving animals were normal at necropsy.
Interpretation of results:
other: not classified according to CLP
Conclusions:
The test article, when administered as received to male Wistar rats, had an acute oral LD 50 of 3.6 g/kg.
Executive summary:

In an acute oral toxicity study similar to OECD Guideline 401, male Wistar rats were exposed to test substance at doses of 2.0, 3.5, 5.0 and 8.75 g/kg. The oral LD50 is 3.6 g/kg. Sublethal effects of lethargy, diarrhea, piloerection, chromodacryorrhea, chromorhinorrhea and ptosis were observed. Necropsy observations included lung and gastrointestinal abnormalities. Based on the results of this study, the test substance would be classified as Category 5 in accordance with the classification system of GHS. This toxicity study is classified as acceptable and satisfies the guideline requirement for acute oral toxicity in rats.

Endpoint:
acute toxicity: oral
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 acute toxicity potential of the ZDDP category members is reported to be low (HPV, 2005). The source substances were practically non-toxic in the acute toxicity study with rats (LD50 >3000 mg/kg bw).
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 mode of actions or toxicity effects. Toxicokinetic behavior of the constituents of the target substance is expected to be essentially the same as that of the source substance. Based on the results of the oral acute toxicity studies with the source substances and other ZDDP category members, it is evident that the structural dissimilarities – the chain lengths of the alkyl rests – did not result in different strength of the toxicity effects. Even if absorption through GI tract of the category members with shorter alkyl rests and theoretically higher absorption rates (due to the increased water solubility and decreased molecular weights favouring absorption) is higher, their intrinsic properties are essentially the same as the findings in the acute toxicity studies are very similar. The impurities of the target substance are considered not to contribute to the toxicity effects 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. Furthermore, their amounts are very low. Therefore, it is predicted that the target substance would possess the same toxicity potential by acute oral exposure as the source substance.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
3 100 mg/kg bw
Based on:
not specified
95% CL:
> 2 600 - < 3 800
Sex:
male
Dose descriptor:
LD50
Effect level:
3 200 mg/kg bw
Based on:
not specified
95% CL:
> 3 600 - < 4 000
Mortality:
Deaths occurred in all groups greater than 1825 mg/kg within 93 hours of dosing.
Clinical signs:
Signs of toxicity included hypokinesia at all dose levels, ataxia at doses above 1825 mg/kg and diarrhea in almost all animals in all dose groups.
Body weight:
All surviving animals gained weight.
Gross pathology:
Necropsy findings in animals that died on test were limited to findings suggestive of post mortem changes. No treatment related necropsy findings were observed. Surviving animals had no remarkable necropsy findings.
Other findings:
None reported.
Interpretation of results:
other: not classified according to EU GHS
Conclusions:
The test article, when administered as received in corn oil to male and female Sprague-Dawley rats, had an acute oral LD50 of 3.2 (2.6-4.0) g/kg (males); 3.1 (2.6-3.8) g/kg (females).
Executive summary:

The substance does not show any evidence of toxicity via the oral route of exposure in animals when tested in accordance with OECD Guideline 401. The rat oral LD50 is3,200 mg/kg in male and 3,100 mg/kg in female rats. Sublethal effects included hypokinesia and diarrhea; necropsy observations were unremarkable; no specific organ toxicity is evident; all animals showed expected bodyweight gain during the course of study. 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 100 mg/kg bw
Quality of whole database:
High due to high quality guideline studies

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
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 acute toxicity potential of the ZDDP category members is reported to be low (HPV, 2005). The source substances were practically non-toxic in the acute toxicity study with rats (LD50 >3000 mg/kg bw).
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 mode of actions or toxicity effects. Toxicokinetic behavior of the constituents of the target substance is expected to be essentially the same as that of the source substance. Based on the results of the oral acute toxicity studies with the source substances and other ZDDP category members, it is evident that the structural dissimilarities – the chain lengths of the alkyl rests – did not result in different strength of the toxicity effects. Even if absorption through GI tract of the category members with shorter alkyl rests and theoretically higher absorption rates (due to the increased water solubility and decreased molecular weights favouring absorption) is higher, their intrinsic properties are essentially the same as the findings in the acute toxicity studies are very similar. The impurities of the target substance are considered not to contribute to the toxicity effects 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. Furthermore, their amounts are very low. Therefore, it is predicted that the target substance would possess the same toxicity potential by acute oral exposure as the source substance.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.3 mg/L air (nominal)
Exp. duration:
4 h
Mortality:
No animals died following exposure to the test article.
Clinical signs:
other: Diarrhea was noted in one rat following exposure. All remaining rats appeared normal.
Body weight:
All test rats were weighed immediately prior to exposure. Body weights were not recorded following the observation period for comparison.
Gross pathology:
Gross necropsy findings for nine rats were within normal limits. The remaining rat had red foci throughout the liver.
Other findings:
Tan livers and kidneys were observed at necropsy, however, these were not deemed to be treatment related.
Interpretation of results:
study cannot be used for classification
Conclusions:
Under the conditions of this study, the test material did not produce significant toxicity at the nominal concentration of 2.3 mg/l in male or female Sprague Dawley rats.
Executive summary:

In an acute inhalation toxicity study similar to OECD guideline 403 (no GLP conditions), male and female rats were exposed to test substance at a nominal concentration of 2.3 mg/l (vapour) under continuous air flow conditions for 4 h. The LC50 is >2.3 mg/l. Diarrhea was noted in one animal, all other animals appeared normal. Based on the results of this study, the test substance would be unclassifiable in accordance with the classification system of GHS. The LC50 only eliminates Category 1 or 2 classification.This toxicity study is classified as acceptable and satisfies the guideline requirement for acute inhalation toxicity in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
2 300 mg/m³
Quality of whole database:
Good due to well documented study comparable to guideline study

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
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 acute toxicity potential of the ZDDP category members is reported to be low (HPV, 2005). The source substances were practically non-toxic in the acute oral and dermal toxicity study with rats (LD50 >2000 mg/kg bw).
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 modes of action or toxicity effects. Toxicokinetic behaviour of the constituents of the target substance is expected to be essentially the same as that of the source substances. Based on the results of the acute toxicity studies with the source substances and other ZDDP category members it is evident that the structural dissimilarities – the chain lengths of the alkyl rests – did not result in different strength of the toxicity effects. Even if absorption through GI tract or skin of the category members may differ due to different molecular weight and water solubility, their intrinsic properties are essentially the same as the findings in the acute toxicity studies are very similar. The impurities of the target substance are considered not to contribute to the toxicity effects 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. Furthermore their amounts are very low. Therefore, it is predicted that the target substance would possess the same toxicity potential by acute oral and dermal exposure as the source substance.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
One animal with abraded skin died 13 days after dosing
Clinical signs:
Severe erythema and edema noted at 24 hours. By seven days treated sites were thick and escharotic.
Body weight:
Treated animals weighed significantly less than controls.
Average body weight during study
Control: 2.47 kg (start), 2.49 kg (day 7), 2.85 kg (day 14
Treated: 2.44 kg (start), 2.15 kg (day 7), 2.15 kg (day 14)
Note: Values are an average of 6 rabbits except for day 14 treated, which is the mean of 5 animals
Gross pathology:
Liver-like or necrotic-appearing areas of lung tissue observed in five rabbits. Further histology of the lungs revealed confluent bronchipnuemonia or chronic interstitial pneumonia. Two rabbits had small white liver abcesses that were determined to be of parasitic origin after histological examination.
Interpretation of results:
other: EU GHS criteria not met
Remarks:
Based on the low level of toxicity and no mortality observed at 2002 mg/kg, material is not classified for acute dermal toxicity.
Conclusions:
The rat dermal LD50 is greater than 5000 mg/kg in male rabbits.
Executive summary:

This substance does not show any evidence of toxicity via the dermal route of exposure in animals when tested in accordance with OECD Guideline 402. The rat dermal LD50 is greater than 5000 mg/kg in male rabbits. Severe erythema and edema noted at 24 hours. Necrotic-appearing areas of lung tissue observed in five rabbits. Further histology of the lungs revealed confluent bronchopneumonia or chronic interstitial pneumonia.

Endpoint:
acute toxicity: dermal
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 acute toxicity potential of the ZDDP category members is reported to be low (HPV, 2005). The source substances were practically non-toxic in the acute oral and dermal toxicity study with rats (LD50 >2000 mg/kg bw).
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 modes of action or toxicity effects. Toxicokinetic behaviour of the constituents of the target substance is expected to be essentially the same as that of the source substances. Based on the results of the acute toxicity studies with the source substances and other ZDDP category members it is evident that the structural dissimilarities – the chain lengths of the alkyl rests – did not result in different strength of the toxicity effects. Even if absorption through GI tract or skin of the category members may differ due to different molecular weight and water solubility, their intrinsic properties are essentially the same as the findings in the acute toxicity studies are very similar. The impurities of the target substance are considered not to contribute to the toxicity effects 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. Furthermore their amounts are very low. Therefore, it is predicted that the target substance would possess the same toxicity potential by acute oral and dermal exposure as the source substance.
Doses:
20 g/kg
No. of animals per sex per dose:
2
Control animals:
no
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 20 000 mg/kg bw
Based on:
not specified
Mortality:
All animals survived the test.
Clinical signs:
Lethargy, diarrhea, ataxia, ptosis, alopecia, emaciation, yellow nasal discharge and sensitivity to touch were noted during the second week of observation. Well defined erythema and slight edema were noted at 24 h.
Body weight:
All treated animals lost weight during the study.
Gross pathology:
No data.
Other findings:
No data.
Interpretation of results:
GHS criteria not met
Remarks:
Based on the low level of toxicity and no mortality observed at 2002 mg/kg, material is not classified for acute dermal toxicity.
Conclusions:
The test article, when administered dermally as received to 2 male and 2 female New Zealand white rabbits had an acute dermal LD50 of greater than 20.0 g/kg
Executive summary:

In an acute dermal toxicity study similar to OECD Guideline 402, New Zealand White rabbits were exposed to 20 g/kg of the test substance. The LD50 on Day 14 post-exposure was greater than 20 g/kg. Toxic signs observed included lethargy, diarrhea, ataxia, ptosis, alopecia, emaciation, and yellow nasal discharge. Based on the results of this study, the test substance would not be classified in accordance with CLP. This toxicity study is classified as acceptable and satisfies the guideline requirement for acute dermal toxicity in rabbits.

Endpoint:
acute toxicity: dermal
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 acute toxicity potential of the ZDDP category members is reported to be low (HPV, 2005). The source substances were practically non-toxic in the acute oral and dermal toxicity study with rats (LD50 >2000 mg/kg bw).
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 modes of action or toxicity effects. Toxicokinetic behaviour of the constituents of the target substance is expected to be essentially the same as that of the source substances. Based on the results of the acute toxicity studies with the source substances and other ZDDP category members it is evident that the structural dissimilarities – the chain lengths of the alkyl rests – did not result in different strength of the toxicity effects. Even if absorption through GI tract or skin of the category members may differ due to different molecular weight and water solubility, their intrinsic properties are essentially the same as the findings in the acute toxicity studies are very similar. The impurities of the target substance are considered not to contribute to the toxicity effects 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. Furthermore their amounts are very low. Therefore, it is predicted that the target substance would possess the same toxicity potential by acute oral and dermal exposure as the source substance.
Sex:
male/female
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 002 mg/kg bw
Mortality:
0 mg/kg: 0/10 dead
2002 mg/kg: 0/10 dead
Clinical signs:
Prostration in one animal. No other behavioral anomalies. Desquamation of the skin noted on test day 11.
Interpretation of results:
other: EU GHS criteria not met
Remarks:
Based on the low level of toxicity and no mortality observed at 2002 mg/kg, material is not classified for acute dermal toxicity.
Conclusions:
The rat dermal LD50 is greater than 2002 mg/kg in male rabbits.
Executive summary:

This substance does not show adverse toxicity effects via the dermal route of exposure in animals when tested in accordance with OECD Guideline 402 and GLP. The rat dermal LD50 is greater than 2002 mg/kg in male rabbits. Prostration in one animal, and desquamation of the skin noted on test day 11 were observed. No specific organ toxicity is evident.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 002 mg/kg bw
Quality of whole database:
High due to high quality guideline studies

Additional information

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

oral route:

Male Wistar rats were exposed to test substance at doses of 2.0, 3.5, 5.0 and 8.75 g/kg. The oral LD50 is 3.6 g/kg. Sublethal effects of lethargy, diarrhea, piloerection, chromodacryorrhea, chromorhinorrhea and ptosis were observed. Necropsy observations included lung and gastrointestinal abnormalities (Moreno 1979).

dermal route:

In an acute dermal toxicity study similar to OECD Guideline 402, New Zealand White rabbits were exposed to 20 g/kg of the test substance. The LD50 on Day 14 post-exposure was greater than 20 g/kg. Toxic signs observed included lethargy, diarrhea, ataxia, ptosis, alopecia, emaciation, and yellow nasal discharge. Based on the results of this study, the test substance would not be classified in accordance with CLP. This toxicity study is classified as acceptable and satisfies the guideline requirement for acute dermal toxicity in rabbits.

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

oral route:

Sublethal effects of depression, diarrhea, and reduced food intake were observed. Necropsy observations included reduction of body fat, no specific organ toxicity is evident (Bullock 1975).

dermal route:

This substance does not show any evidence of toxicity via the dermal route of exposure in animals when tested in accordance with OECD Guideline 402. The dermal LD50 is greater than 5000 mg/kg in male rabbits. Severe erythema and edema noted at 24 hours. Necrotic-appearing areas of lung tissue observed in five rabbits. Further histology of the lungs revealed confluent bronchopneumonia or chronic interstitial pneumonia.

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

oral route:

The substance does not show any evidence of toxicity via the oral route of exposure in animals when tested similar to OECD Guideline 401. The rat oral LD50 is 3,200 mg/kg in male and 3,100 mg/kg in female rats. Sublethal effects included hypokinesia and diarrhea; necropsy observations were unremarkable; no specific organ toxicity is evident; all animals showed expected bodyweight gain during the course of study.

inhalative route:

In an acute inhalation toxicity study similar to OECD guideline 403 (no GLP conditions), male and female rats were exposed to test substance at a nominal concentration of 2.3 mg/l under continuous air flow conditions for 4 h. The LC50 is >2.3 mg/l. Diarrhea was noted in one animal, all other animals appeared normal. Based on the results of this study, the test substance would be unclassifiable in accordance with the classification system of GHS. The LC50 only eliminates Category 1 or 2 classification.This toxicity study is classified as acceptable and satisfies the guideline requirement for acute inhalation toxicity in rats.

dermal route:

This substance does not show adverse toxicity effects via the dermal route of exposure in animals when tested in accordance with OECD Guideline 402. The rat dermal LD50 is greater than 2002 mg/kg in male rabbits. Prostration in one animal, and desquamation of the skin noted on test day 11 were observed. No specific organ toxicity is evident.

 

Justification for classification or non-classification

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

oral: LD50 > 3100 mg/kg bw

inhalative: LC50 > 2300 mg/m3 (no higher concentration reachable, because no adverse effects at this concentration observed, therefore no classifcation was done)

dermal: LD50 > 2002 mg/kg bw


Route: .live2