Disodium 2-[[5-carbamoyl-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridyl]azo]-4-[[4-chloro-6-[[3-[[2-(sulphonatooxy)ethyl]sulphonyl]phenyl]amino]-1,3,5-triazin-2-yl]amino]benzenesulphonate

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 ofdisodium 2-[[5-carbamoyl-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridyl] azo]-4-[[4-chloro -6-[[3-[[2-(sulphonato oxy)ethyl]sulphonyl] phenyl]amino]-1,3,5-triazin-2-yl]amino]benzenesulphonate(CAS No. 84000 -63 -5) in rat by the oral route. No adverse effects was observed. Therefore, the no observed adverse effect level (NOAEL) ofdisodium 2-[[5-carbamoyl -1-ethyl-1,6-dihydro- 2-hydroxy -4-methyl-6-oxo-3- pyridyl] azo]-4-[[4-chloro-6-[[3- [[2-(sulphona tooxy)ethyl]sulphonyl] phenyl]amino]-1,3,5-triazin- 2-yl]amino]benzenesulphonatefor reproductive toxicity study was considered to be 904.44 mg/kg bw/day (actual dose received).

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

Specific details on test material used for the study:

- Name of test material: Disodium 2-[[5-carbamoyl-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl -6-oxo-3-pyridyl]azo]- 4-[[4-chloro-6-[[3-[[2- (sulphona tooxy)ethyl]sulphonyl]phenyl]amino]-1,3,5-triazin-2-yl]amino]benzenesulphonate.
- Molecular formula : C26H24ClN9Na2O12S3
- Molecular weight : 832.1576 g/mol
- Smiles notation: CCn1c(c(c(c(c1=O)C (=O)N)C)/N=N/c2cc(ccc2S(=O)(=O)[O-]) Nc3nc(nc(n3)Cl)Nc4cccc(c4)S(=O)(=O)CCOS(=O) (=O)[O-])O. [Na+].[Na+]
- Substance type: Organic

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Treatment of the parental (P) generation began 10 weeks prior to mating and continued until euthanasia.

Frequency of treatment:

Daily

Dose / conc.:

904.44 mg/kg bw/day (actual dose received)

Control animals:

not specified

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

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

ORGAN WEIGHT: Yes

Postmortem examinations (parental animals):

GROSS NECROPSY: Yes

HISTOPATHOLOGY / ORGAN WEIGHTS: Yes

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

904.44 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

reproductive performance

other: No effects observed.

Critical effects observed:

no

Remarks on result:

not measured/tested

Critical effects observed:

not specified

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

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 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Imides (Acute toxicity) AND Substituted Triazines (Acute toxicity) AND Vinyl Sulfones by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Imides (Acute toxicity) OR Substituted Triazines (Acute toxicity) OR Vinyl Sulfones by US-EPA New Chemical Categories ONLY

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Nucleophilic addition AND Nucleophilic addition >> Addition to carbon-hetero double bonds AND Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones AND SNAr AND SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds AND 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: "f"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates AND SNAr AND SNAr >> Nucleophilic aromatic substitution AND SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Acid moiety AND Acrylamides AND Hydrazines AND Imides AND Salt AND Triazines, Aromatic by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acid moiety OR Acrylamides OR Hydrazines OR Imides OR Salt OR Triazines, Aromatic by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones 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 ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure OR Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= -5.64

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.104

Conclusions:

The no observed adverse effect level (NOAEL) of disodium 2-[[5-carbamoyl -1-ethyl-1,6-dihydro- 2-hydroxy-4-methyl-6-oxo-3-pyridyl] azo]-4-[[4-chlo ro-6-[[3- [[2-(sulphona tooxy)ethyl]sulphonyl] phenyl]amino]-1,3,5-triazin- 2-yl]amino]benzenesulphonate for reproductive toxicity study was considered to be 904.44 mg/kg bw/day (actual dose received).

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 disodium 2-[[5-carbamoyl-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridyl] azo]-4-[[4-chloro -6-[[3-[[2-(sulphonatooxy)ethyl]sulphonyl] phenyl]amino]-1,3,5-triazin-2-yl]amino]benzenesulphonate (CAS No. 84000 -63 -5) in rat by the oral route. No adverse effects was observed. Therefore, the no observed adverse effect level (NOAEL) of disodium 2-[[5-carbamoyl -1-ethyl-1,6-dihydro- 2-hydroxy -4-methyl-6-oxo-3-pyridyl] azo]-4-[[4-chloro-6-[[3- [[2-(sulphona tooxy)ethyl]sulphonyl] phenyl]amino]-1,3,5-triazin- 2-yl]amino]benzenesulphonate for reproductive toxicity study was considered to be 904.44 mg/kg bw/day (actual dose received).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

904.44 mg/kg bw/day

Study duration:

subchronic

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 disodium 2-[[5-carbamoyl-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridyl] azo]-4-[[4-chloro -6-[[3 -[[2-(sulphonatooxy)ethyl] sulphonyl] phenyl]amino]-1,3,5-triazin-2-yl]amino]benzenesulphonate (CAS No. 84000-63-5) along with its structurally similar read across substances FD & C RED NO. 40 (CAS No.- 25956-17-6) and FD &C Red 4 (CAS No.- 4548-53-2). The predicted data for target chemical disodium 2-[[5-carbamoyl-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridyl] azo]-4-[[4-chloro -6-[[3-[[2-(sulphonatoo xy)ethyl] sulp honyl] phenyl]amino]-1,3,5-triazin-2-yl]amino]benzenesulphonate (CAS No. 84000-63-5) 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 disodium 2-[[5-carbamoyl-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridyl] azo]-4-[[4-chloro -6-[[3-[[2- (sulph onatooxy)ethyl] sulphonyl] phenyl]amino]-1,3,5-triazin-2-yl]amino]benzenesulphonate (CAS No. 84000-63-5) in rat by the oral route. No adverse effects was observed. Therefore, the no observed adverse effect level (NOAEL) of disodium 2-[[5-carbamoyl -1-ethyl-1,6-dihydro- 2-hydroxy -4-methyl-6-oxo-3-pyridyl] azo]-4-[[4-chloro-6-[[3- [[2-(sulphona tooxy)ethyl]sulphonyl] phenyl]amino]-1,3,5-triazin- 2-yl]amino]benzenesulphonate for reproductive toxicity study was considered to be 904.44 mg/kg bw/day (actual dose received). 

 

In addition, the present study was conducted by T. F. X. COLLINS et al. (Fd Chem. Toxic. Vol. 27, No. 11, pp. 707-713. 1989) to determine the reproductive toxicity potential of FD & C RED NO. 40 (CAS No.- 25956-17-6) when given by gavage to rats. Osborne-Mendel rats were intubated with FD & C Red No. 40 at dose levels of 0, 30, 75, 150, 300, 600 or 1000 mg/kg body weight/day on days 0-19 of gestat ion. No developmental toxicity was observed when the animals were killed on day 20 of gestation. No dose-related changes were seen in maternal daily obser vations, food consumption, body-weight gain or implantations, or in foetal viability, body weight, body length, sex distribution or external variations. Skeletal and soft-tissue development appeared similar in foetuses of all groups. The isolated increases that occurred in the number of male foetuses, number of females with two or more resorptions, number of litters with three or more sternebral variations and incidence of 14th rib bud are considered random occurrences and were not related to dosage. Thus, under the condition of this study, the no-observed-adverse-effect level (NOAEL)for maternal and developmental toxicity study was found to be 1000.0 mg/kg bw/day. 

 

Moreover, in a reproductive toxicity study for another read across substance FD &C Red 4 (CAS No.- 4548-53-2) conducted by Steven Carson (J. Toxicol.-Cut. & Ocular Toxicol. 3(3), 309-331 (1984)) , Swiss-Webster male and female mice were treated with FD &C Red 4 (CAS No.- 4548-53-2) in the concentration of 1500 mg/kg bw/day in distilled water applied twice weekly on 6 cm2 dorsal area of skin. No effect were observed on survival, clinical sign and body weight of treated male and female mice as compared to control. Similarly, lesion in Mammary Gland and Subcutaneous papillary were obseved gross pathologically in treated mice, but the observed effect were similar to control. In addition, All grades malignant lymphoma and variation in nuclear morphology in liver, infarction, malignant and myeloid metaplasia, leukocytic aggregations in spleen, all grades malignant lymphoma , leukemic and round cell infiltration and leukocytic aggregation in kidneys , malignant lymphoma in lymph nodes, malignant lymphoma, Inflammation, pneumonitis, bronchitis and necrotic changes in lungs and all grades malignant lymphoma in thymus were observed in male and female treated mice. No significant difference in the incidence of this lesion were observed as compared to control and considered to be not treatment related. Therefore, NOAEL was considered to be 1500 mg/kg bw/day when Swiss-Webster male and female mice were treated with FD&C Red 4.

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 disodiu m 2-[[5-carbamoyl-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridyl] azo]-4-[[4-chloro-6-[[3-[[2-(sulphonatooxy)eth yl]sulphon yl]phenyl]amino]- 1,3,5-triazin-2-yl]amino]benzenesulphonate (CAS No.- 84000-63-5) cannot be classified as reproductive toxicant.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

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 disodium 2-[[5- carbamoyl-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridyl] azo]-4-[[4-chloro-6-[[3-[[2-(sulphonato oxy)ethyl]sulphonyl]phe nyl]amino]-1,3,5-triazin -2-yl]am ino]benzenesulphonate (CAS No. 84000-63-5) as reproductive toxicant is warranted.