3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1)

Endpoint summary

Description of key information

Acute oral toxicity: 

Acute oral toxicity dose (LD50) for 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9) was predicted based on OECD QSAR toolbox 279 mg/kg bw and different study available on closely related read across substance Methyltriphenylphosphonium bromide (CAS no: 1779-49-3) by National Technical Reports Library (OTS0555371, 1992) 118 mg/kg bw. Both these studies concluded that the LD50 value is between 50-300 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) can be classified as category 3 of acute oral toxicity.

Acute Inhalation Toxicity:

3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9) has very low vapour pressure (2.27E-06 Pa at 25° C), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point was considered for waiver.

Acute Dermal toxicity: 

Acute oral toxicity dose (LD50) for 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9) was predicted based on OECD QSAR toolbox 8222 mg/kg bw and different studies available on closely related read across substance N,N-dimethyl-p-toluidine (99-97-8) > 2000 mg/kg bw and Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts (84605-29-8) > 2000 mg/kg bw. All these studies concluded that the LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1)can be classified as category 5 for acute dermal toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

Name: 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) SMILES:CCN(CC)c1ccc2c(c1)o{+}(.[Zn]{2-}(Cl)(Cl)(Cl)(Cl).o{+}1c3cc(N(CC)CC)ccc3nc3ccc(N(CC)CC)cc13)c1cc(N(CC)CC)ccc1n2
InChI:1S/2C20H26N3O.4ClH.Zn/c2*1-5-22(6-2)15-9-11-17-19(13-15)24-20-14-16(23(7-3)8-4)10-12-18(20)21-17;;;;;/h2*9-14H,5-8H2,1-4H3;4*1H;/q2*+1;;;;;+2/p-4
Molecular Weight:856.093 g/mole
Molecular Formula:C20H26N3O.1/2Cl4Zn

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

not specified

Doses:

279 mg/kg bw

No. of animals per sex per dose:

not specified

Control animals:

not specified

Details on study design:

not specified

Statistics:

not specified

Preliminary study:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

279 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality observed

Mortality:

not specified

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((((((("a" or "b" or "c" or "d" )  and ("e" and ( not "f") )  )  and "g" )  and "h" )  and "i" )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and "n" )  and "o" )  and "p" )  and ("q" and ( not "r") )  )  and ("s" and "t" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Amine OR Anion OR Aromatic compound OR Cation OR Tertiary amine OR Tertiary mixed amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aliphatic Nitrogen, one aromatic attach [-N] OR Amino, aliphatic attach [-N<] OR Aromatic Carbon [C] OR Aromatic Nitrogen OR Aromatic Oxygen, not {v+2} OR Olefinic carbon [=CH- or =C<] OR Zinc [Zn] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aromatic amine OR Fused carbocyclic aromatic OR Fused heterocyclic aromatic OR Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aromatic amine OR Aryl OR Fused carbocyclic aromatic OR Fused heterocyclic aromatic by Organic Functional groups ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> alpha,beta-Unsaturated carbonyl compounds OR Michael Addition >> alpha,beta-Unsaturated carbonyl compounds >> alpha,beta-Aldehydes  OR Schiff base formation OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes by Protein binding by OASIS v1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Reactive unspecified by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Halogens AND Non-Metals AND Transition Metals by Groups of elements

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Alkali Earth OR Alkaline Earth OR Metalloids OR Metals OR Rare Earth by Groups of elements

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Group 12 - Trans.Metals Zn,Cd,Hg AND Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Group 7 - Trans.Metals Mn,Tc,Re by Chemical elements

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Aromatic amine AND Aryl AND Fused carbocyclic aromatic AND Fused heterocyclic aromatic by Organic Functional groups ONLY

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aromatic amine AND Aryl AND Fused carbocyclic aromatic AND Fused heterocyclic aromatic by Organic Functional groups ONLY

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Amino, aliphatic attach [-N<] AND Aromatic Carbon [C] AND Aromatic Nitrogen AND Aromatic Oxygen, not {v+2} AND Olefinic carbon [=CH- or =C<] AND Zinc [Zn] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as (N/A) by Database Affiliation

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Bioconcentration NITE by Database Affiliation

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.67

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is <= 18.1

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

LD50 was estimated to be 279 mg/kg bw, when Sprague-Dawley male and female rats were treated with 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9) via oral gavage route.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9). The LD50 was estimated to be 279 mg/kg bw, when Sprague-Dawley male and female rats were treated with 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) via oral gavage route.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

279 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Quality of whole database:

Waiver

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

Name - 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1)
Molecular Weight - 324.445 g/mole
InChI - 1S/C20H26N3O/c1-5-22(6-2)15-9-11-17-19(13-15)24-20-14-16(23(7-3)8-4)10-12-18(20)21-17/h9-14H,5-8H2,1-4H3/q+1
Smiles - c1cc(cc2[o+]c3cc(ccc3nc12)N(CC)CC)N(CC)CC

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Type of coverage:

occlusive

Vehicle:

not specified

Details on dermal exposure:

not specified

Duration of exposure:

24 hours

Doses:

8222 mg/kg

No. of animals per sex per dose:

not specified

Control animals:

not specified

Details on study design:

not specified

Statistics:

not specified

Preliminary study:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

8 222 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

not specified

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and ("f" and ( not "g") )  )  and "h" )  and "i" )  and ("j" and "k" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Zinc metal and salts by OECD HPV Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Soluble complexes of Zinc by US-EPA New Chemical Categories

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> N,N-Dialkyldithiocarbamate Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Dithiocarbamates OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Amine AND Anion AND Aromatic compound AND Cation AND Tertiary amine AND Tertiary mixed amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "i"

Similarity boundary:Target: CCN(CC)c1ccc2c(c1)o{+}(.[Zn]{2-}(Cl)(Cl)(Cl)(Cl).o{+}1c3cc(N(CC)CC)ccc3nc3ccc(N(CC)CC)cc13)c1cc(N(CC)CC)ccc1n2
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.16

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= 12.3

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The LD50 was estimated to be 8222 mg/kg bw, when New Zealand White male and female rabbits were treated with 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) by dermal application occlusively for 24 hours.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for  3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) ( 63589-47-9). The LD50 was estimated to be 8222 mg/kg bw, when New Zealand White male and female rabbits were treated with 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) by dermal application occlusively for 24 hours.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

8 222 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3

Additional information

Acute oral toxicity:

In different studies, 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9) has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rats for 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) along with the study available on closely related read across substance Methyltriphenylphosphonium bromide (CAS no: 1779-49-3). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 3,7-bis(diethylamino) phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9). The LD50 was estimated to be 279 mg/kg bw, when Sprague-Dawley male and female rats were treated with 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) via oral gavage route.

The above study is supported by National Technical Reports Library (OTS0555371, 1992), for the closely related read across substance Methyltriphenylphosphonium bromide (CAS no: 1779-49-3). The acute oral toxicity was tested in 20 rats at the dose concentration range of 50-800 mg/kg bw. The test substance was dissolved as 10% in water (Vehicle). Animals were observed for mortality, clinical signs and body weight change for 14 days. 50% mortality was observed within 2.5-24 hr at 118 mg/kg bw. Clinical signs were observed in treated rats. At 50 mg/kg symptoms like diarrhea was observed in 2-4 hr. which was normal within 24 hr, considered to be slightly to moderate; At 100 mg/kg symptoms like diarrhea was observed in 2-4 hr which was considered as moderate to severe; and At the range of 200-800 mg/kg: Tremors, convulsions, diarrhea and death within 24 hr was observed which was considered to be highly toxic. Weight change was observed in more than 7 rats. Therefore, LD50 was considered to be approximately 118 mg/kg with confidential limit of 84-167mg/kg bw, when rats were treated with Methyltriphenylphosphonium bromide via oral route.

Thus, based on the above studies on 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9) and it’s read across substances, it can be concluded that LD50 value is between 50-300 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) can be classified as category 3 of acute oral toxicity.

Acute Inhalation Toxicity:

3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9) has very low vapour pressure (2.27E-06 Pa at 25° C), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point was considered for waiver.

Acute Dermal toxicity:

In different studies, 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9) has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rabbits for 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) along with the study available on closely related read across substance N,N-dimethyl-p-toluidine (99-97-8) and Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts (84605-29-8). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 3,7-bis(diethylamino) phenoxazin-5-ium tetrachlorozincate (2:1) ( 63589-47-9). The LD50 was estimated to be 8222 mg/kg bw, when New Zealand White male and female rabbits were treated with 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) by dermal application occlusively for 24 hours.

This is further supported by HSDB (Hazardous Substances Data Bank), US national Library of Medicine (2017), for the closely related read across substance N,N-dimethyl-p-toluidine (99-97-8). In acute dermal toxicity, 10 male and female New Zealand White rabbits was tested at the concentration of 2000 mg/kg bw. No mortality was observed at 2000 mg/kg bw. Therefore, LD50 was considered to be > 2000 mg/kg bw, when male and female New Zealand White rabbits were treated with N,N-dimethyl-p-toluidine by dermal application.

The above study supported by U. S. Environmental Protection Agency (2005), for the closely related read across substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts (84605-29-8). TheAcute Dermal toxicity study was conducted in rabbits at the concentration of 2000 and 8000 mg/kg bw. No treatment-related mortality was observed at doses ranging from 2000-8000 mg/kg. Dermal application of the test materials to abraded skin for 24 hours typically produced moderate-to-severe erythema and edema, which in some cases persisted through the 14-day observation period. Clinical signs included varying degrees of reduced food consumption, diarrhea, lethargy, ataxia, ptosis, motor incoordination and/or loss of righting reflex was observed. Body weight loss was observed. There were no remarkable gross necropsy observations. Therefore, LD50 was considered to be >2000 mg/kg bw, when rabbits were treated with Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts by dermal application to abraded skin for 24 hours.

Thus, based on the above studies on 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) can be classified as category 5 of acute dermal toxicity.

Justification for classification or non-classification

Based on the above studies and prediction on 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) (CAS no: 63589-47-9) and it’s read across substances, it can be concluded that LD50 value is between 50-300 mg/kg bw for acute oral and greater than 2000 mg/kg bw for acute dermal toxocity. Thus, comparing this value with the criteria of CLP regulation, 3,7-bis(diethylamino)phenoxazin-5-ium tetrachlorozincate (2:1) can be classified as category 3 for acute oral and category 5 for acute dermal toxicity.For Acute Inhalation toxicity wavier were added so, not possible to classify.