Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 779 mg/kg bw when Wistar male and female rats were orally exposed with 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid.    

Thus, as per criteria of CLP regulation, 7-[[2-[(aminocarbonyl) amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid can be not classified for reproductive toxicity.    

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
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 3.4 and the supporting QMRF report has been attached.
Reference:
Composition 0
Qualifier:
no guideline available
Principles of method if other than guideline:
Prediction is done using OECD QSAR Toolbox version 3.4 with respect to the descriptor log Kow.
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
Name of the test chemical: 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid
Molecular formula: C20H16ClN9O10S3
Molecular weight: 674.0504 g/mol
Smiles Notation: S(=O)(=O)(c1c(/N=N/c2c(NC(=O)N)cc(Nc3nc(nc(n3)Cl)N)cc2)cc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1)O
InChI: 1S/C20H16ClN9O10S3/c21-17-26-18(22)28-20(27-17)24-9-1-2-12(13(5-9)25-19(23)31)29-30-14-7-11-8(4-16(14)43(38,39)40) 3-10(41(32,33)34)6-15(11)42(35,36)37/h1-7H,(H3,23,25,31)(H,32,33,34)(H,35,36,37)(H,38,39,40)(H3,22,24,26,27,28)/b30-29+
Substance Type: Organic
Physical State: solid
Species:
rat
Strain:
Wistar
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:
Premating exposure period: 2 weeks for male rats
2 weeks for female rats
Exposure period: 22 days
Duration of the test: approx. 54 days
Frequency of treatment:
Daily
Details on study schedule:
not specified
Dose / conc.:
779 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
not specified
Control animals:
not specified
Details on study design:
not specified
Positive control:
not specified
Parental animals: Observations and examinations:
not specified
Estrous cyclicity (parental animals):
not specified
Sperm parameters (parental animals):
not specified
Litter observations:
not specified
Postmortem examinations (parental animals):
not specified
Postmortem examinations (offspring):
not specified
Statistics:
not specified
Reproductive indices:
not specified
Offspring viability indices:
not specified
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:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
Dose descriptor:
NOAEL
Effect level:
778.77 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
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: No effects observed.
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Remarks on result:
not measured/tested
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
Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

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" )  and ("c" and ( not "d") )  )  and "e" )  and "f" )  and ("g" and "h" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Acid moiety OR Anilines (Unhindered) OR Substituted Ureas OR Triazines, Aromatic by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Activated N-heterocycles by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 16 - Sulfur S AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Group 17 - Halogens F by Chemical elements

Domain logical expression index: "e"

Similarity boundary:Target: NC(=O)Nc1cc(Nc2nc(N)nc(Cl)n2)ccc1N=Nc1cc2c(cc1S(O)(=O)=O)cc(S(O)(=O)=O)cc2S(O)(=O)=O
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "f"

Similarity boundary:Target: NC(=O)Nc1cc(Nc2nc(N)nc(Cl)n2)ccc1N=Nc1cc2c(cc1S(O)(=O)=O)cc(S(O)(=O)=O)cc2S(O)(=O)=O
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.09

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.24

Conclusions:
The NOAEL was estimated to be 779 mg/kg bw when Wistar male and female rats were orally exposed with 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid.
Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid. The NOAEL was estimated to be 779 mg/kg bw when Wistar male and female rats were orally exposed with 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid.    

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
779 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

Reproductive toxicity:

In different studies, 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimation in rodents, i.e. most commonly in rats for 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid along with the study available on structurally similar read across substance FD & C RED NO. 40 (CAS no 25956-17-6), RED 2G (CAS no 3734-67-6) and FD &C Red 4 (CAS No.- 4548-53-2) The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 7-[[2-[(aminocarbonyl) amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid. The NOAEL was estimated to be 779 mg/kg bw when Wistar male and female rats were orally exposed with 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid.    

In another experimental study Collins et al (Food Chem. Toxic. Vol. 27, No. 11, pp. 707-713. 1989) on structurally similar read across substance FD & C RED NO. 40 (CAS no 25956-17-6), Osborne-Mendel female rat were treated with FD & C RED NO. 40 in the concentration of 0, 30, 75, 150, 300, 600 and 1000 mg/ kg bw orally by gavage from Gestation day 0 to day 19. Initial body weight at day 0 and maternal body-weight gain during gestation were similar in all groups. Mean food consumption on days 0-7, 7-14, 14-20 and 0-20 of treated animals was similar to that of the control animals. Similarly, No unusual behaviors were observed in the animals during the study. The pregnancy rate ranged from 85.71 to 95.35% with no evidence of dose correlation. The mean numbers of corpora lutea and implants per female were similar in all groups. No litters were totally resorbed were observed as compared to control. In addition, the mean number of viable foetuses per female was similar in all groups. The number of early deaths per litter and the number of early plus late deaths per litter were greatest in the 600 mg/kg group, but these appeared to be random occurrences. The percentage of females with at least one resorption was similar in all groups. The percentage of females given 600 mg/kg that had at least two resorptions was significantly greater than the percentage in the control females, but there was no dose related effect in the percentage of females with at least two resorptions. Mean foetal weights of males and females and crown rump lengths were similar in all groups. The number of litters with runts was similar in all groups. No dose-related changes were seen 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 14thrib bud are considered random occurrences and were not related to dosage. Therefore, NOAEL was considered to be 1000 mg/kg bw for P and F1 generation when Osborne-Mendel female rat were treated with FD & C RED NO. 40 orally by gavage from gestation day 0 to day 19.

Further supported by experimental study given by NTRL (NTRL, OTS0516606-2, 1989) on structurally similar read across substance RED 2G (CAS no 3734-67-6), male and female mice were treated with RED 2G in the concentration of 0, 30, 150,750 and 1500 mg/kg bw/day in feed. No effect on survival, body weight and food consumption of treated mice were observed as compared to control. Increased heinz bodiez and methaemoglobins and decreased packed cell volumes were observed at 750 and 1500 mg/kg bw/day as compared to control. Similarly, Increase in relative spleen weight and splenic size were observed at 750 and 1500 mg/kg bw/day treated mice as compared to control. In addition, increased erythropoiesisand increased haemosiderin content, increase in haemosiderin in tile pruximal convoluted tubules of the kidney and Erytbroid hyperplasia of bone marrow were observed at 750 and 1500 mg/kg bw/day, Lesions in the liver were observed at 1500 mg/kg bw/day and Haemosiderin in the spleens were observed at 150 mg/kg bw/day treated mice as compared to control. No effect on histopathology of testes, uterus and ovaries were observed in treated mice. Therefore, NOAEL was considered to be 1500 mg/kg bw/day for F0 generation when male and female mice were treated with RED 2G orally in diet for6 weeks.

Again supported by experimental study conducted by Carsonet al(J. Toxicol.-Cut. & Ocular Toxicol. 3(3), 309-331 (1984)) on structurally similar read across substance FD&C Red 4 (CAS No 4548-53-2), 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 effects 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 effects 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.

Thus, based on the above study and predictions on 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid and its read across substances, it can be concluded that NOAEL value is 779 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 7-[[2-[(aminocarbonyl) amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid can be not classified for reproductive toxicity.    

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 above study and predictions on 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid and its read across substances, it can be concluded that NOAEL value is 779 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 7-[[2-[(aminocarbonyl) amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid can be not classified for reproductive toxicity.