1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity

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 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8).Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 745.0 mg/kg bw. When male and female wistar rats were exposed with 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8) orally. Thus, based on the studies and predictions on 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8) and its read across substances it was considered that no adverse effects on reproductive parameter were observed. Thus, comparing this value with the criteria of CLP regulation 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8).cannot be classified as reproductive toxicant.

 

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:

Data is from OECD QSAR toolbox v3.3 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 v3.3, 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 test material (IUPAC name): 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate
- Common name: 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate
- Molecular formula: C18H21N6.C2H3O2
- Molecular weight: 380.4496 g/mol
- Smiles notation: CC(=O)[O-].Cn1cn[n+](c1/N=N/c2ccc(cc2)N(C)Cc3ccccc3)C
- InChl: 1S/C18H21N6.C2H4O2/c1-22(13-15-7-5-4-6-8-15)17-11-9-16(10-12-17)20-21-18-23(2)14-19-24(18)3;1-2(3)4/h4-12,14H,13H2,1-3H3;1H3,(H,3,4)/q+1;/p-1
- Substance type: Organic

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:

Males were dosed 28 days
Females were dosed 54 days

Frequency of treatment:

once per day, 7 days per week

Details on study schedule:

No data available

Dose / conc.:

745 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

No data available

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:

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

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:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: overall 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:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Remarks on result:

not determinable

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 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((((((((("a" or "b" )  and ("c" and ( not "d") )  )  and "e" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and "j" )  and ("k" and ( not "l") )  )  and "m" )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and ("t" and ( not "u") )  )  and ("v" and ( not "w") )  )  and ("x" and "y" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD ONLY

Domain logical expression index: "b"

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

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Radical OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds by DNA binding by OASIS v.1.3

Domain logical expression index: "e"

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 AND SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Aromatic azo AND SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine AND SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD ONLY

Domain logical expression index: "f"

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: "g"

Referential boundary: The target chemical should be classified as Imidazole derivatives (13a) OR Known precedent reproductive and developmental toxic potential OR Polyhalogenated benzene derivatives (8c) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aliphatic N-nitro group (Genotox) OR alpha,beta-unsaturated carbonyls (Genotox) OR Aromatic diazo (Genotox) OR Aromatic mono-and dialkylamine (Genotox) OR Hydrazine (Genotox) OR Metals, oxidative stress (Nongenotox) OR Phtalate (or buthyl) diesters and monoesters (Nongenotox) OR Structural alert for genotoxic carcinogenicity OR Structural alert for nongenotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer (with extensions) ONLY

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Aliphatic amines (Mucous membrane irritation) Rank C OR Aliphatic nitriles (Hepatotoxicity) Rank B OR Amineptine (Hepatotoxicity) Alert OR Oxyphenistain (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "m"

Similarity boundary:Target: CC(=O)O{-}.N{+}1(C)C(N=Nc2ccc(N(C)Cc3ccccc3)cc2)N(C)C=N1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Acetoxy AND Ammonium salt AND Aromatic amine AND Aryl AND Azo AND Benzyl AND Overlapping groups AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups (nested)

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Acetoxy AND Ammonium salt AND Aromatic amine AND Aryl AND Azo AND Benzyl AND Overlapping groups AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups (nested)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Morpholine OR Nitrile by Organic Functional groups (nested)

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Acetoxy AND Ammonium salt AND Aromatic amine AND Aryl AND Azo AND Benzyl AND Overlapping groups AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups (nested)

Domain logical expression index: "s"

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

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Acetoxy AND Ammonium salt AND Aromatic amine AND Aryl AND Azo AND Benzyl AND Overlapping groups AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups (nested)

Domain logical expression index: "u"

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

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Acetoxy AND Ammonium salt AND Aromatic amine AND Aryl AND Azo AND Benzyl AND Overlapping groups AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups (nested)

Domain logical expression index: "w"

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

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.15

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.35

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be745.0 mg/kg bw. When male and female wistar rats were exposed with 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8) orally.

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 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8).Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be745.0 mg/kg bw. When male and femalewistarrats were exposed with 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8) orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

745 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, 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8) has been investigated for developmental 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 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8).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 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8).Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be745.0 mg/kg bw. When male and femalewistarrats were exposed with 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8) orally.

 It is further supported by experimental study conducted by European Commission (EC) - Scientific Committee on Consumer Safety (SCCS) (Basic Red 51 (COLIPA n° B116) SCCS/1332/10)on structurally similar read across substance Basic Red 51 (77061-58-6).The reproductive and developmental toxicity study of Basic Red 51 (77061-58-6)was performed on mated female  wistar (Hanlbm (SPF)rats according to OECD 414.22 mated female per dose group were administered with 10ml /kg aqueous solution of test material in dose concentration0, 20, 60 and 180 mg/kg bw/dayonce daily for 11 days (Days 6 to 17 post coitum).While The control group received only the vehicle (double distilled water).Food consumption was recorded for the following periods: days 0-6, 6-12, 12-18 and 18-21 post coitum; body weight was recorded daily from day 0 until day 21 post coitum. Clinical observations and mortality were recorded at least twice daily. At post mortem, on day 21, necropsy, all internal organs were examined with emphasis on the uterus, uterine contents, position of foetuses in the uterus and number of corpora lutea. The uteri of all females with live foetuses were weighed at necropsy on day 21 post coitum; the foetuses were removed from the uterus, weighed, sexed, and examined for gross external abnormalities.

Maternal deaths did not occur during the study and clinical signs of toxicity or reactions to treatment did not occur in any group. A dose-dependent reduction of the food consumption was observed during the treatment period in the mid- and high-dose groups (-7.6% and - 23.5% respectively); an increase of + 5.5 % was observed in the high dose group after the treatment period. The mean body weight gain was reduced only in the high dose group, these data being correlated with the decreased food consumption. Mean post-implantation loss and mean number of foetuses per dam were similar between treated and control dams in the low- and mid-dose groups. The increased post-implantation loss observed only in the mid dose group was considered to be incidental. No abnormal findings were noted in any female of any treated group. The mean foetal body weights were similar in all groups except for a slight increase observed in the mid-dose group, which was attributed to the slightly reduced mean number of foetuses per dam. The sex ratio for foetuses was similar in all groups. Some abnormal findings were noted during foetal examination: externally, one cleft palate was observed in the low dose group. Skeletal changes included a small number of foetuses in each group with abnormally shaped sternebrae. These were not considered related to the test substance, as they were within the range for historical controls. Hence the NOEL was considered to before the maternal effects is 20 mg/kg bw/day and for foetal effects the NOEL is 180 mg/kg bw/day ,The test material did not affects reproductive parameter and not toxic to embryo or foetus. When mated female wistar rats treated with Basic Red 51 (77061-58-6)via oral gavage for days 6 to 17 post coitum.

 It is further supported by experimental study conducted by European Commission (EC) - Scientific Committee on Consumer Safety (SCCS) (Basic Red 51 (COLIPA n° B116) SCCS/1332/10)on structurally similar read across substance Basic Orange 31(97404-02-9).The reproductive and developmental toxicity study of Basic Orange 31(97404-02-9) was performed on mated female  wistar (Hanlbm (SPF)rats according to CEC, N° 111/3387/93, according to ICH guidelines. 22 mated female per dose group were administered with 10ml /kg aqueous solution of test material in dose concentration 0, 15, 60 and 240 mg/kg bw/day once daily for 11 days (Days 6 to 17 post coitum).While The control group received only the vehicle (double distilled water).Food consumption was recorded for the following periods: days 0-6, 6-12, 12-18 and 18-21 post coitum; body weight was recorded daily from day 0 until day 21 post coitum. Clinical observations and deaths were recorded at least twice daily. After sacrifice on day 21 post coitum, all internal organs were examined, with emphasis on the uterus, uterine contents, position of foetuses in the uterus and number of corpora lutea. The uteri of all females with live foetuses were weighed at necropsy; the foetuses were removed from the uterus, weighed, and examined for sex and gross external abnormalities.

 No mortality was observed during treatment period. Reduced food consumption (-8.6% and - 20.9% in 60 and 240 mg/kg bw/day dose groups) was observed and reflected in diminished body weight gain. The bedding was stained orange, assumed to be due to excretion in the urine and faeces of parent compound or metabolites. Mean post-implantation loss and mean number of foetuses per dam were similar between treated and control dams. There was a slight decrease in mean foetal body weights in the 240 mg/kg bw/day dose groups .Statistically significant differences were observed in the sex ratio of foetuses (fewer male to female foetuses) in the 60 and 240 mg/kg bw/day dose groups. The study authors considered the difference not treatment related since implantation occurred prior to dosing, litter size and post-implantation losses were unaffected. Some abnormal findings were noted on external features (one abdominal hernia in the 15 mg/kg bw/day dose groups; low weight, cleft palate and tail defects in the 240 mg/kg bw/day dose groups) and skeletal parameters (small number of shaped sternebrae or wavy ribs in all groups, delayed ossification in the 240 mg/kg bw/day dose groups)). Delayed ossification commonly occurs secondary to maternal toxicity. Thus the skeletal findings were considered unrelated to the tested product. Hence the NOAEL was considered to be 60mg/kg bw for maternal and foetal effects. The test material did not reveal any teratogenic effects. When mated female wistar rats treated with Basic Orange 31(97404-02-9) via oral gavage.

Thus, based on the above studies and predictions on 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8) and its read across substances it was considered that no adverse effects on reproductive parameter were observed. Thus, comparing this value with the criteria of CLP regulation 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8).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 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (84000-82-8).cannot be classified as reproductive toxicant.