5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride

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 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2).Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 183.33 mg/kg bw. When male and femalewistarrats were exposed with 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)orally.

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 v3.3 and the QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

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 the test material: 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride
- IUPAC name: 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride
- Molecular formula: C18H21N6Cl
- Moleclar weight: 356.8589 g/mol
- Substance type: Organic
- Smiles: Cc1cn[n+](n1/N=N/c2ccc(cc2)N(C)Cc3ccccc3)C.[Cl-]
- Inchi: 1S/C18H21N6.ClH/c1-15-13-19-23(3)24(15)21-20-17-9-11-18(12-10-17)22(2)14-16-7-5-4-6-8-16;/h4-13H,14H2,1-3H3;1H/q+1;/p-1/b21-20+;

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

Type of inhalation exposure (if applicable):

other: NOT_SPECIFIED

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:

The duration of treatment covered a 2-week premating and a mating period in both sexes, approximately 2 days post-mating in males, and the entire gestation period as well as approximately 2 weeks of the lactation period.

Frequency of treatment:

Once daily at approximately the same time in the morning. Females in labor were not treated.

Details on study schedule:

No data available

Dose / conc.:

183.33 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:

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:

no effects observed

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:

183.33 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

gross pathology

reproductive performance

Remarks on result:

other: No effects on reproductive 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

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:

not measured/tested

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

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 Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Halogens AND Non-Metals by Groups of elements

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Alkali Earth OR Metalloids OR Transition Metals by Groups of elements

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Group 16 - Oxygen O OR Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "h"

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: "i"

Referential boundary: The target chemical should be classified as Known precedent reproductive and developmental toxic potential OR Piperazine-, dioxane-, morpholine-, tetrahydrothiopyran-like derivatives and cyclohexanamine (17c) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls  by Protein binding by OASIS v1.3

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.59

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.7

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 183.33 mg/kg bw. When male and female wistar rats were exposed with 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)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 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2).Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 183.33 mg/kg bw. When male and femalewistarrats were exposed with 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

183.33 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,5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)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 for5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2).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 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2).Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 183.33 mg/kg bw. When male and femalewistarrats were exposed with 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)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 on5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)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 regulation5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)cannot be classified as reproductive toxicant.

Effects on developmental toxicity

Description of key information

Developmental toxicity

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the developmental toxicity was estimated for 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2).No teratogenic effects was observed. Hence, NOAEL was estimated to be 867 mg/kg bw. When male and femaleSprague-Dawley rats were exposed with 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)orally.

Link to relevant study records

Reference

Endpoint:

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:

equivalent or similar 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

Specific details on test material used for the study:

- Name of the test material: 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride
- IUPAC name: 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride
- Molecular formula: C18H21N6Cl
- Moleclar weight: 356.8589 g/mol
- Substance type: Organic
- Smiles: Cc1cn[n+](n1/N=N/c2ccc(cc2)N(C)Cc3ccccc3)C.[Cl-]
- Inchi: 1S/C18H21N6.ClH/c1-15-13-19-23(3)24(15)21-20-17-9-11-18(12-10-17)22(2)14-16-7-5-4-6-8-16;/h4-13H,14H2,1-3H3;1H/q+1;/p-1/b21-20+;

Species:

rat

Strain:

Sprague-Dawley

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

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

No data available

Duration of treatment / exposure:

Treatment period, Parental males: 49 days (14 days before mating and 35 days including 14 days for mating) Treatment period, Parental females: 40-46 days (from 14 days prior to mating to day 3 of lactation.)- Frequency of treatment: Daily- Post treatment observation period: 1 day- Duration of test, Parental males: 50 days Duration of test, Parental females: From 14 days prior to mating to day 4 of lactation. Duration of test, Pups: Until day 4 of lactation

Frequency of treatment:

Daily

Duration of test:

No data available

Dose / conc.:

867 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Maternal examinations:

No data available

Ovaries and uterine content:

No data available

Fetal examinations:

No data available

Statistics:

No data available

Indices:

No data available

Historical control data:

No data available

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:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

867 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

gross pathology

pre and post implantation loss

Remarks on result:

other: No effects on reproductive parameters was observed

Abnormalities:

not specified

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

867 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

fetal/pup body weight changes

external malformations

skeletal malformations

visceral malformations

Remarks on result:

other: overall no developmental effects was observed

Abnormalities:

not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Relation to maternal toxicity:

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 7 nearest neighbours
Domain  logical expression:Result: In Domain

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

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 ONLY

Domain logical expression index: "d"

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: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides by Protein binding by OASIS v1.3

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "m"

Similarity boundary:Target: CN{+}1(.Cl{-})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"

Similarity boundary:Target: CN{+}1(.Cl{-})C(N=Nc2ccc(N(C)Cc3ccccc3)cc2)N(C)C=N1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Multi Cyclic Hydrocarbons by rtER Expert System ver.1 - USEPA

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.066

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.07

Conclusions:

In developmental toxicity study, NOAEL was estimated to be 867 mg/kg bw. When male and female Sprague-Dawley rats were exposed with 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)orally.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the developmental toxicity was estimated for 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2).No teratogenic effects was observed. Hence, NOAEL was estimated to be 867 mg/kg bw. When male and femaleSprague-Dawley rats were exposed with 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)orally.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

867 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 developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity

In different studies,5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)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 for5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2).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 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2).Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 183.33 mg/kg bw. When male and femalewistarrats were exposed with 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)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 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 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 on5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)and its read across substances it was considered that no adverse effects on development of fetus . Thus, comparing this value with the criteria of CLP regulation5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)can be "Not classified" for developmental toxicity.

 

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (29508-47-2)can be "Not classified" for reproductive and developmental toxicity.