3,7-bis(diethylamino)phenoxazin-5-ium acetate

Endpoint summary

Description of key information

Prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose oral toxicity was predicted for the test compound 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7). The study assumed the use of male and female Sprague-Dawley rats in subchronic study of 4 weeks on daily basis. No significant alterations were noted at the dose level of 186.1714mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7)is considered to be 186.1714mg/Kg bw/day. Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

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:

Prediction is done using OECD QSAR Toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: AS mention below

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3, 2017

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material (IUPAC name): 3,7-bis(diethylamino)phenoxazin-5-ium acetate
- Molecular formula: C22H29N3O3
- Molecular weight: 383.489 g/mol
- Smiles notation: c1c2nc3ccc(cc3[o+]c2cc(N(CC)CC)c1)N(CC)CC.C(C)(=O)[O-]
-InChl:1S/C20H26N3O.C2H4O2/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;1-2(3)4/h9-14H,5-8H2,1-4H3;1H3,(H,3,4)/q+1;/p-1
- Substance type: Organic

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

Details on route of administration:

Not specified

Vehicle:

not specified

Details on oral exposure:

Not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

Not specified

Remarks:

No data

No. of animals per sex per dose:

Not specified

Control animals:

not specified

Details on study design:

Not specified

Positive control:

Not specified

Observations and examinations performed and frequency:

Not specified

Sacrifice and pathology:

Not specified

Other examinations:

Not specified

Statistics:

Not specified

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

Not specified

Dose descriptor:

NOAEL

Effect level:

186.171 other: mg/kg/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No toxic effect were observed at this dose.

Remarks on result:

other: No toxic effect were observed

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

no

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

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: "b"

Referential boundary: The target chemical should be classified as Peroxy Acids by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as 4,4'-Diethylaminoethoxyhexestrol (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Metalloids by Groups of elements

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> Epoxides and Related Chemicals OR SN2 >> Epoxides and Related Chemicals >> Epoxides by Protein binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.746

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.66

Conclusions:

The predicted No Observed Adverse Effect Level (NOAEL) for 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7) is considered to be 186.1714mg/Kg bw/day.

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose oral toxicity was predicted for the test compound 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7). The study assumed the use of male and female Sprague-Dawley rats in subchronic study of 4 weeks on daily basis. No significant alterations were noted at the dose level of 186.1714mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7)is considered to be 186.1714mg/Kg bw/day. Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

186.171 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

K2 data from QSAR

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity Oral:

Prediction model based estimation and data available for the target chemical was reviewed to determine the toxic nature of 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7) upon repeated exposure by oral, dermal and inhalation route of exposure. The studies are as mentioned below:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose oral toxicity was predicted for the test compound 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7). The study assumed the use of male and female Sprague-Dawley rats in subchronic study of 4 weeks on daily basis. No significant alterations were noted at the dose level of 186.1714mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7)is considered to be 186.1714mg/Kg bw/day. Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

In another short-term repeated dose toxicity: oral study was performed for read across substance which share similar structure by SIDS INITIAL ASSESSMENT PROFILE (OECD SIDS COCAM 3,2012) forDi-tert-butyl Peroxide(110-05-4). Repeated dose toxicity study was assessed for Di-tert-butyl Peroxide for its possible repeated dose toxicity effect. For this purpose Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test was performed according to OECD Guideline 422.The test material was exposed to the male and female rats by oral gavage for subchronic period. The test material was used at the concentration of 0, 100, 300 or 1000 mg/kg/day. Increased relative weights; minimal centrilobular and diffuse hepatocellular hypertrophy in liver; moderate diffuse tubular degeneration/regeneration with slight multifocal single cell necrosis and hyaline casts as well as hyaline droplets in kidneys of males was observed at 1000 mg/kg bw/day in treated animal compare to control. At 300 mg/kg bw/day increased relative liver and kidney weights were observed in treated males and females rats compare to control.

Therefore NOAEL was considered to be 100 mg/kg/day in male and female rats for Di-tert-butyl Peroxide by Oral gavage for sub chronic study.

Based on the data available for the target chemical and its prediction, 3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7) does not exhibit toxic nature upon repeated exposure by oral route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7), which is reported as 5.15E-18 Pa at 25°C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micrometer which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical 3,7-bis(diethylamino)phenoxazin-5-ium acetate is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study

The acute toxicity value for3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7),(as provided in section 7.2.3) is 5135.0mg/kg bwmg/kg body weight. The substance was also found to be not irritating to skin. Also, given the use of the chemical as dye compound; repeated exposure by the dermal route is unlikely. Thus, it is expected that3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7)shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no dermal absorption data as well as no data available that suggests that3,7-bis(diethylamino)phenoxazin-5-ium acetate (79916-07-7)shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

 

Justification

Based on the data available for the target chemical and its prediction, 3,7-bis(diethylamino) phenoxazin-5-ium acetate (79916-07-7), does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the above annotation for the target chemical .3,7-bis(diethylamino) phenoxazin-5-ium acetate (79916-07-7), does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.