Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: oral
The No Observed Effect Level (NOEL) for 4-(phenylazo)benzene-1,3-diamine in rats is estimated to be 158.86 mg/Kg bw/day after repeated exposure via oral route, by OECD QSAR toolbox.

Repeated dose toxicity: inhalation
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 substance 4-(phenylazo)benzene-1,3-diamine, which is reported as 0.00020265 Pa. Thus, exposure to inhalable dust, mist and vapour of the chemical 4-(phenylazo)benzene-1,3-diamine is highly unlikely. Therefore this study is considered for waiver.

Repeated dose toxicity: dermal
The acute toxicity value for 4-(phenylazo)benzene-1,3-diamine (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 4-(phenylazo)benzene-1,3-diamine shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 4-(phenylazo)benzene-1,3-diamine shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

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
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 by OECD QSAR Toolbox version 3.4. The supporting QMRF report has been attached
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
Data is predicted by OECD QSAR Toolbox version 3.4 with logPow as the primary descriptor
GLP compliance:
not specified
Species:
rat
Strain:
other: SD
Sex:
not specified
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Frequency of treatment:
not specified
No. of animals per sex per dose:
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
Key result
Dose descriptor:
NOEL
Effect level:
158.865 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no significant changes were noted at mentioned dose level
Critical effects observed:
not specified

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

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anilines (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> Substituted Anilines by Protein binding by OASIS v1.4

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Anilines (amino-meta) AND Anilines (Unhindered) by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found OR SN1 >> Nitrenium Ion formation >> Aromatic nitro by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.69

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.77

Conclusions:
The No Observed Effect Level (NOEL) for 4-(phenylazo)benzene-1,3-diamine in rats is estimated to be 158.86 mg/Kg bw/day after repeated exposure via oral route, by OECD QSAR toolbox.
Executive summary:

Repeated dose oral toxicity was evaluated for 4-(phenylazo)benzene-1,3-diamine using SSS QSAR prediction database V3.4. The study assumed the use of rats in a subacute study. Since no significant changes were noted, the No Observed Effect Level (NOEL) for 4-(phenylazo)benzene-1,3-diamine is estimated to be 158.86 mg/Kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
158.86 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is of K2 rating and is obtained from OECD QSAR toolbox.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
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

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
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
Predicted data for the substance 4-(phenylazo)benzene-1,3-diamine and its structurally related substance were reviewed for Repeated dose oral toxicity endpoint and are represented here as weight of evidence approach:

Repeated dose oral toxicity was evaluated for 4-(phenylazo)benzene-1,3-diamine using SSS QSAR prediction database V3.4. The study assumed the use of rats in a subacute study. Since no significant changes were noted, the No Observed Effect Level (NOEL) for 4-(phenylazo)benzene-1,3-diamine is estimated to be 158.86 mg/Kg bw/day.

The subacute repeated dose toxicity study of structurally related substance 2-chloro-p-phenylenediamine (CAS No. 615-66-7) in female Sprague-Dawley rats was conducted to evaluate the adverse effects by oral route (obtained from Fd Chem. Toxic. Vol. 22, no. 2, pp. I47 149, 1984). The test chemical was administered by oral gavage in the concentration of 100, 200 and 400 mg/kg/day. The results showed reduction in mean body weight gain of 200 and 400 mg/kg/day treated rats. No mortality were observed. Clinical signs was not observed. In addition, statistically significant increase in the number of resorptions was observed in 400 mg/kg/day treated female rats as compared to control.  No changes were observed in gross pathology of treated rats as compared to control. Thus, the no-observed adverse effect level (NOAEL) of 2-chloro-p-phenylenedi amine (o-chloro-p-PD) (CAS No. 615-66-7) in rats was considered to be 200 mg/kg/day.

Considering above data and by applying weight of evidence approach it can be concluded that the substance 4-(phenylazo)benzene-1,3-diamine will not show any effects on the specific target organ and is not toxic on Repeated exposure and hence it is considered to be not classified on Repeated exposure via oral route as per CLP regulation.

Justification for classification or non-classification

Considering above data and by applying weight of evidence approach it can be concluded that the substance 4-(phenylazo)benzene-1,3-diamine will not show any effects on the specific target organ and is not toxic on Repeated exposure and hence it is considered to be not classified on Repeated exposure via oral route as per CLP regulation.