1-phenylazo-2-naphthol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The reproductive toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with respect to the descriptor log Kow; to evaluate the toxic effects of administration of1-phenylazo-2-naphthol(CAS No.842 -07 -9) in rat by the oral route. No adverse effects was observed. Therefore, the no observed adverse effect level (NOAEL) of1-phenylazo-2-naphtholfor reproductive toxicity study was estimated to be 1000.0 mg/kg bw/day.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

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:

no guideline available

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3 with respect to the descriptor log Kow.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

F0-males: - for 2 weeks prior to mating, throughout mating and after mating at least until the minimum total dosing period of 28 days had been completed
F0-females:2 weeks prior to mating, throughout mating, and pregnancy and at least up to, and including the day before sacrifice.

Frequency of treatment:

Daily
Doses /

Dose / conc.:

1 000 mg/kg bw/day

Control animals:

not specified

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations:No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OTHER
MORTALITY: Mortality was observed.

Postmortem examinations (parental animals):

GROSS NECROPSY: Yes

HISTOPATHOLOGY / ORGAN WEIGHTS: Yes

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

gross pathology

histopathology: non-neoplastic

other: Did not revealed any treatment-related findings on parental animals.

Critical effects observed:

no

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Remarks on result:

not measured/tested

Critical effects observed:

not specified

Reproductive effects observed:

no

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

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

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 >> Aromatic azo by DNA binding by OECD

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Inorganic chemical OR Known precedent reproductive and developmental toxic potential OR NO2-alkyl/NO2-benzene derivatives (8b) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) >> 4-alkylphenol-like derivatives (2b-3) OR Not covered by current version of the decision tree OR Organophosphorus compounds (1b) OR Polyhalogenated benzene derivatives (8c) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "g"

Similarity boundary:Target: Oc1ccc2ccccc2c1N=Nc1ccccc1
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by rtER Expert System ver.1 - USEPA

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Alkylphenols OR Salicylates by rtER Expert System ver.1 - USEPA

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Schiff base formation OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aromatic diazo AND H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as alpha,beta-unsaturated carbonyls by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.34

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 8.2

Conclusions:

The no observed adverse effect level (NOAEL) of 1-phenylazo-2-naphthol for reproductive toxicity study was estimated to be 1000.0 mg/kg bw/day.

Executive summary:

The reproductive toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with respect to the descriptor log Kow; to evaluate the toxic effects of administration of 1-phenylazo-2-naphthol (CAS No.842 -07 -9) in rat by the oral route. No adverse effects was observed. Therefore, the no observed adverse effect level (NOAEL) of 1-phenylazo-2-naphthol for reproductive toxicity study was estimated to be 1000.0 mg/kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The data is Klimicsh 2 and from OECD QSAR toolbox version 3.3 (2017).

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Various studies including predicted results from the validated model and experimental study has been investigated for reproductive toxicity to a greater or lesser extent for the test chemical 1-phenylazo-2-naphthol (CAS No. 842-07-9) along with its structurally similar read across substance 1-(2,4-dimethylphenylazo)-2-naphthol (CAS No.- 3118-97-6) . The predicted data for target chemical 1-phenylazo-2-naphthol (CAS No. 842-07-9) has been compared with experimental study for a read across substance. The studies are summarized as below:  

 

The reproductive toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with respect to the descriptor log Kow; to evaluate the toxic effects of administration of 1-phenylazo-2-naphthol (CAS No.842 -07 -9) in rat by the oral route. No adverse effects was observed. Therefore, the no observed adverse effect level (NOAEL) of 1-phenylazo-2-naphthol for reproductive toxicity study was estimated to be 1000.0 mg/kg bw/day. 

The above study is supported by the read across substance 1-(2,4-dimethylphenylazo)-2-naphthol (CAS No.- 3118-97-6) study. The reproductive toxicity study was performed byM. G. ALLMARKet al. (J. Pharma. Pharmacology; Vol. 8, Pg. no. 417-424, 1956) to evaluate the toxic effects of administration of 1-(2,4-dimethylphenylazo)-2-naphthol on rat. When the rats are exposed orally (gavage) to the test substance 1-(2,4-dimethylphenylazo)-2-naphthol (Sudan II) for 20 weeks at a dose conc. of 200 and 400 mg/kg bw/day, no adverse effects were observed at a dose level of 200 mg/kg bw/day. Testicular changes are observed in animals receiving the higher concentrations i.e; 400 mg/kg bw/day. A significant decline in blood haemoglobin values was found in all groups of both sexes at the dose level of both 200 and 400 mg/kg bw/day. Food consumption and food efficiency was affected by the test substance at the dose level of 400 mg/kg bw/day. In a number of cases the organ weights were about the same as the controls but the body weights of the test animals were less than the controls, suggesting the possible utilization of muscle protein. In other cases the body weights of test and control animals were about the same but the organ weights differed significantly. By the end of 20 weeks, 6 male rats receiving a dose of 200 mg/kg bw/day had died whereas all 10 female rats has survived for 20 weeks. However, 5 male and 3 female rats receiving a dose of 400 mg/kg bw/day had died by the end of the experiment. A detailed examination was made of the haematoxylin-eosin stained paraffin sections of a number of organs including lung, heart, liver, spleen, thyroid, pancreas, stomach, small intestine, kidney, urinary bladder, adrenal, testes, ovaries and thymus. Heart, liver, spleen, kidneys and testes were the organs chiefly affected. No consistent histopathological changes were observed in the tissues or organs of the test animal. Testicular changes are observed in animals receiving the higher concentrations. Therefore, no adverse effects level of 1-(2,4-dimethylphenylazo)-2-naphthol (Sudan II) in rats were observed at a dose level of 200 mg/kg bw/day. Hence, 1-(2,4-dimethylphenylazo)-2-naphthol (Sudan II) is not considered to be a reprotoxic for male and female rats at a dose level of 200 mg/kg bw/day.

 

Moreover, in the same study by M. G. ALLMARKet al. (J. Pharma. Pharmacology; Vol. 8, Pg. no. 417-424, 1956) for read across substance 1-(2,4-dimethylphenylazo)-2-naphthol (CAS No. 3118-97-6), the reproductive toxicity effects of 1-(2,4-dimethylphenylazo)-2-naphthol (FD&C Red No. 32) in young male and female rats by an oral route for 44 weeks was investigated. The rats were exposed by oral feed for 44 week to the concentrations of 0, 30,75 and 1500 mg/kgbw/day. No mortality was obserserved at the dose level of 30mg/kg bw/day in treated group compared to control. Mortality was observed ,by the end of 20 weeks in all the rats on the 1500 mg/kg bw/day level. Mortality was also observed ,by the end of 40 weeks in all the rats on the 75 mg/kg bw/day. No significant change were observed in clinical sign, body weight, food consumption , food efficiency, hematology, reproductive fuction , gross pathology and histopathology of male and female rats obserserved at the dose level of 30mg/kg bw/day in treated group compared to control. Therefore NOAEL was considered to be 30mg/kg bw/day for 1-(2,4-dimethylph enylazo)-2-naphthol (FD&C Red No. 32) in male and female rats by an oral route for 44 weeks.

 

Based on the above mentioned studies for target substance and to its read across substance by applying weight of evidence approach and also according to CLP criteria, it can be concluded that no adverse effects on sexual function and fertility was observed, therefore the substance 1-phenylazo-2-naphthol (CAS No. 842-07-9) cannot be classified as reproductive toxicant.

Justification for classification or non-classification

Based on the available data for the assessment of reproductive toxicity and following CLP Regulation EC No. 1272/2008 no classification of 1-phenylazo- 2-naphthol (CAS No.842-07-9) as reproductive toxicant is warranted.