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Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

The  reproductive toxicity study of Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5)was estimated by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor and  NOAEL was estimated to be 386.11mg/kg bw. When male and female wistar rats were exposed with Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5) orally.

Thus, based on the above predictions and experimental study of Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro-4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5)and its structurally similar read across substance No Observed Adverse Effect Level (NOAEL) was considered to be 386.11 mg/kg bw Thus, comparing this value with the criteria of CLP regulation Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5)cannot be classified as reproductive toxicant.

 

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:
Data is from OECD QSAR toolbox v3.4 and the QMRF report has been attached.
Qualifier:
according to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Prediction was done using OECD QSAR toolbox v3.4, 2017
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Specific details on test material used for the study:
- Name of the test material: Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra
- IUPAC name: Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra
- Molecular weight: No data
- Molecular formula: C24H11Cl3CuN7O9S2.3Na
- Smiles:OS(=O)(=O)c1ccc2c(c1)C(=O)O{-}.[Cu]{2+}13N2=NC(c2ccccc2)N=N1c1cc(S(O)(=O)=O)cc(Nc2c(Cl)c(Cl)nc(Cl)n2)c1O{-}.3
Species:
rat
Strain:
Wistar
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data available
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
54 days
Frequency of treatment:
7 days /week
Details on study schedule:
No data available
Dose / conc.:
386.11 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
not specified
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations:

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: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

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

OTHER:
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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:
not specified
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:
386.11 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
reproductive performance
Remarks on result:
other: No effects on reproductive performance
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
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:
no effects observed
Histopathological findings:
no effects observed
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
386.11 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
gross pathology
histopathology: non-neoplastic
other: overall developmental effects
Remarks on result:
other: No effects on overall developmental parameters
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
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" or "c" )  and ("d" and ( not "e") )  )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and "m" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals AND Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes by DNA binding by OECD

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as 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 v1.4

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SNAr AND SNAr >> Nucleophilic aromatic substitution AND SNAr >> Nucleophilic aromatic substitution >> Halo-pyrimidines by Protein binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aromatic amine AND Aromatic heterocyclic halide AND Aryl AND Aryl halide AND Carboxylic acid AND Fused carbocyclic aromatic AND Fused saturated heterocycles AND Fused unsaturated heterocycles AND N-Alkyldiazene AND Phenol AND Pyrimidine AND Sulfonic acid AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Carboxylic acid ester OR Cycloalkane by Organic Functional groups

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Aromatic amine AND Aromatic heterocyclic halide AND Aryl AND Aryl halide AND Carboxylic acid AND Fused carbocyclic aromatic AND Fused saturated heterocycles AND Fused unsaturated heterocycles AND N-Alkyldiazene AND Phenol AND Pyrimidine AND Sulfonic acid AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Isocyanate by Organic Functional groups

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Aromatic amine AND Aromatic heterocyclic halide AND Aryl AND Aryl halide AND Carboxylic acid AND Fused carbocyclic aromatic AND Fused saturated heterocycles AND Fused unsaturated heterocycles AND N-Alkyldiazene AND Phenol AND Pyrimidine AND Sulfonic acid AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Nitrile by Organic Functional groups

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Aromatic amine AND Aromatic heterocyclic halide AND Aryl AND Aryl halide AND Carboxylic acid AND Fused carbocyclic aromatic AND Fused saturated heterocycles AND Fused unsaturated heterocycles AND Overlapping groups AND Phenol AND Sulfonic acid AND Unsaturated heterocyclic fragment by Organic Functional groups (nested)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Alkyl arenes by Organic Functional groups (nested)

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of Molecular weight which is >= 107 Da

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of Molecular weight which is <= 820 Da

Conclusions:
In reproductive toxicity study, NOAEL was estimated to be 386.11mg/kg bw. When male and female wistar rats were exposed with Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5) orally.
Executive summary:

The  reproductive toxicity study of Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5)was estimated by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor and  NOAEL was estimated to be 386.11mg/kg bw. When male and female wistar rats were exposed with Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5) orally.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
386.11 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from QSAR Toolbox 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 Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5) has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

The  reproductive toxicity study of Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5)was estimated by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor and  NOAEL was estimated to be 386.11mg/kg bw. When male and female wistar rats were exposed with Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5) orally.

Further supported by   experimental study conducted byJ. F. BORZELLECA, E. I. GOLDENTHAL and F. X. WAZETER(Fd Chem. Toxk'. Vol. 24, No. 2, pp. 159-163, 1986) on structurally similar read across substance FD&C Blue No 2  (860-22-0). In a three generation reproduction study, groups of ten males and twenty female Charles River CD rats were fed FD&C Blue No 2 at dietary levels providing intakes of 0, 2.5, 25, 75 and 250 mg/kg bw/day. Two females were placed in a male's cage for the entire mating period (15 days). Vaginal smears were performed daily until sperm or a copulatory plug was found; this was designated as day 0 of pregnancy. At the end of the mating period, each female was placed on corn-cob bedding in an individual plastic shoe-box cage and remained there until it was remated. Each female was rested for a minimum of 10 days after lactation before being mated again. Each mating was with a different male from the same dosage group.

 The control and treated F0 rats were maintained on their respective diets for 2 wk prior to the first mating period. They were then mated, when approximately 100 days old. The rats (F0) were mated twice. The pups (F1a) from the first mating were examined for external abnormalities and killed at the end of the 21-day lactation period. After the second mating, random selections were made of ten male and 20 female pups from the control and treated groups of the F1b litters to serve as the second generation (F1) parental rats. The remaining F1b pups were examined for external abnormalities, killed and discarded. The F0 parent rats were also killed at this time.

After weaning, the F1b pups selected for the second generation continued to be fed on their control or appropriately treated diet for 80 days and were then mated. The pups from the first mating (F2a) were examined for external abnormalities and killed at the end of the 21-day lactation period. From the second mating (F2b), selections were made of ten male and 20 female pups from the control and treated groups to serve as the third generation (F2) parental rats. The remaining pups (F2b) were examined for external abnormalities, killed and discarded. Following the third mating, one-half of the mated females were killed on day 19 of gestation and the uteri and ovaries were examined. The remaining females were allowed to deliver. After weaning, the F2c pups were examined for external abnormalities, killed and discarded. The F1 parent rats were then killed. Five male and five female rats from the control and each of the treated groups were necropsied and their tissues were collected for histopathology.

After weaning, the F2b pups selected for the third generation continued to be fed on their control or appropriately treated diet for 80 days and were then mated. Five male and five female pups (F3a) from the control and each of the treated groups were killed when 21 days old and necropsied, and tissues were collected for histopathology. The parent rats (F2) were then re-mated and the pups from the second mating (F3b) were examined for external abnormalities and killed at the end of the 21-day lactation period. The F 2 parent rats were then re-mated for the third mating (F3c). On day 19 of gestation, half of the dams from the control and treated groups were killed by chloroform anesthesia. Uteri were examined for any abnormal conditions and the presence of live and dead foetuses and of resorptions were recorded. All ovaries were inspected and the corpora lutea were counted. Remaining F2 parent rats were then killed and discarded.

The rats were observed twice daily for changes in behaviour or appearance and for morbidity and mortality. Individual body weights and food consumption were recorded weekly. Specific parameters for the reproductive phase of this study included observations of fertility, litter size, numbers of male and female pups, viability of the new born, survival of pups to weaning and growth of the pups. All stillborn offspring and any progeny that died during the study were examined either by skeletal clearing or by necropsy. Body weights of pups aged 4 days (before and after reduction of litters to ten pups) and aged 14 days were obtained by weighing as litters. The pups were weighed individually at 21 days of age. The thyroid, adrenals, lung, heart, spleen, stomach, jejunum, ileum, colon, liver, kidneys, urinary bladder, testes or ovaries and uterus from five male and five female rats from the F1 and F3, generations of the control and 250-mg/kg/day groups were embedded in paraffin, sectioned, stained with haematoxylin and eosin and examined microscopically.

 Fur and faeces were bluish-coloured in 75 mg/kg bw/day and 250 mg/kg bw/day groups. Gestation, viability and lactation indices of all litters from exposed animals did not differ from controls. Fertility indices were statistically significantly lower for F2female rats in the 2.5 and 25 mg/kg bw/day groups only and consequently considered as not being dose-related. Fertility indices were also reduced in F2b and F2cgroup of male rats. No statistically significant changes in the fertility index were observed in the F3generation. As effects on fertility indices in the F2generation were not dose-related and effects were not identified in the F1and F3generation this effect was not considered to be compound-related. Examination of the ovaries and uteri of F1dams killed on gestation day (GD) 19 revealed no gross anatomical abnormalities. No unusual changes were observed in the stillborn pups or in pups that died during the study. No compound-related gross or microscopic pathological lesions were noted in any of the F1or F3arats that were sacrificed and necropsied. Finally, no compound-related organ-weight variations were recorded in the F1rats. Therefore NOAEL was considered to be250 mg /kg bw/day for FD & C BLUE NO. 2 (860-22-0) in Charles River CD male and female rats by oral administration (feed) in 3 generation study. (F0,F1 andF2 generation)

 

Also in another experimental study conducted byJ. F. BORZELLECA, E. I. GOLDENTHAL, F. X. WAZETER and J. L. SCHARDEIN(Fd Chem. Toxic. Vol. 25, No. 7, pp. 495-497, 1987)on structurally similar read across substance FD & C BLUE NO. 2 (860-22-0). In a reproductive and developmental toxicity study, pregnant female rats were treated with FD & C Blue NO. 2 in concentration of 0, 25, 75 and 250 mg/kg/day orally by gavage in 0.5% Methocel from days 6-15 of gestation. Dosages were selected from previously conducted pilot studies and represent adequate multiples of the anticipated human intake (0.005mg/kg/day).Male and female Charles River CD rats were approximately 90 days old at the start of the study. After a 2-wk acclimatization period, two female rats were housed with one male rat until evidence of copulation was found; the day of this finding was considered to be day 0 of pregnancy. Twenty pregnant rats were used in each control and treated group. They were observed twice daily during the gestation period for signs of overt toxicity. Body weights were recorded on days 0, 6, 12, 15 and 20 of gestation. The rats were killed with chloroform and Caesarean sections were performed on day 20 of gestation.

No effect was observed on survival, clinical sign and body weight gain of treated female rats were observed as compared to control. Similarly, no effect on number of corpora lutea, number of implantation sites, Early and Late resorptions, number of resorptions and number of dams with resorptions of treated female rats were observed as compared to control. In addition, No effect on viability, number of offspring (normal or abnormal), sex ratio and body weight of fetous of treated female rats were observed as compared to control. No effect on gross pathology skeletal and visceral abnormalities of fetous of treated female rats was observed as compared to control. Therefore, NOAEL was considered to be 250 mg/kg/day for F0 and F1 generation when pregnant female rats were treated with FD & C Blue NO. 2orally by gavage for 10 days. 

  Thus, based on the above predictions and experimental study of Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5)and its structurally similar read across substance No Observed Adverse Effect Level (NOAEL) was considered to be 386.11 mg/kg bw Thus, comparing this value with the criteria of CLP regulation Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5)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

Thus, comparing this value with the criteria of CLP regulation Trisodium [2-[[alpha-[[2-hydroxy-5-sulpho-3-[(2,5,6-trichloro- 4-pyrimidinyl)amino]phenyl]azo]benzyl]azo]-5-sulphobenzoato(5-)]cupra (70161-20-5)cannot be classified as reproductive toxicant.

 

Additional information