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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:
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 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.