2-methoxy-5-nitroanilinium chloride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

The reproductive toxicity of 2-methoxy-5-nitroanilinium chloride (67827-72-9)was estimated by SSS (2017) using OECD QSAR toolbox v 3.3 with log kow as the primary descriptor and NOAEL was estimated to be 654.52mg/kg bw. When male and female Sprague-Dawley ratswere exposed with 2-methoxy-5-nitroanilinium chloride (67827-72-9)orally.Thus, based on the above predictions and experimental study of 2-methoxy-5-nitroanilinium chloride (67827-72-9)and its structurally similar read across substance, No Observed Adverse Effect Level (NOAEL) was considered to be 654.52mg/kg bw Thus, comparing this value with the criteria of CLP regulation 2-methoxy-5-nitroanilinium chloride (67827-72-9)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 v3.3 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, 2018

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: 2-methoxy-5-nitroanilinium chloride
- IUPAC name: 2-methoxy-5-nitroanilinium chloride
- Molecular formula: C7H9ClN2O3
- Molecular weight: 204.6121g/mol
- Smiles: Cl.COc1ccc(cc1N)[N+](=O)[O-]
- Inchl: 1S/C7H8N2O3.ClH/c1-12-7-3-2-5(9(10)11)4-6(7)8;/h2-4H,8H2,1H3;1H
- Substance type: Organic

Species:

rat

Strain:

Sprague-Dawley

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:

not specified

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:

Approximately 9 weeks

Frequency of treatment:

Daily

Details on study schedule:

No data available

Dose / conc.:

654.52 mg/kg bw/day (nominal)

No. of animals per sex per dose:

No data available

Control animals:

not specified

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:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

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:

no mortality observed

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:

NOAEL

Generation:

F1

Effect level:

654.52 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

mortality

other: overall no developmental toxic effects

Remarks on result:

other: overall no developmental toxic effects

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids AND SN1 AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids by DNA binding by OASIS v.1.3

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Aromatic nitro by DNA binding by OECD

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Cysteine peptide depletion

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Low reactive OR Low reactive >> N-substituted aromatic amides by DPRA Cysteine peptide depletion

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 Piperazine-, dioxane-, morpholine-, tetrahydrothiopyran-like derivatives and cyclohexanamine (17c) by DART scheme v.1.0

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary AND Ammonium salt AND Aryl AND Ether AND Nitrobenzene by Organic Functional groups

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of logP Multicase which is >= -4.79

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of logP Multicase which is <= 3.19

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 654.52mg/kg bw. When male and female Sprague-Dawley rats were exposed with 2-methoxy-5-nitroanilinium chloride (67827-72-9)orally.

Executive summary:

The reproductive toxicity of 2-methoxy-5-nitroanilinium chloride (67827-72-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor andNOAEL was estimated to be 654.52mg/kg bw. When male and female Sprague-Dawley ratswere exposed with 2-methoxy-5-nitroanilinium chloride (67827-72-9)orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

654.52 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2018)

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 2-methoxy-5-nitroanilinium chloride (67827-72-9)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 2-methoxy-5-nitroanilinium chloride (67827-72-9).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 of 2-methoxy-5-nitroanilinium chloride (67827-72-9)was estimated by SSS (2017) using OECD QSAR toolbox v 3.3 with log kow as the primary descriptor and NOAEL was estimated to be 654.52mg/kg bw. When male and female Sprague-Dawley ratswere exposed with 2-methoxy-5-nitroanilinium chloride (67827-72-9)orally.

Further supported by experimental study conducted byTheodore Wbrnick,Ben Marr Lanman and Jean Louis Fiuux(TOXICOLOGY AND APPLIED PHARMACOLOGY 32,450-460 (1975))on structurally similar read across substance 2-amino-4-nitrophenol (99-57-0).Reproductive and developmental toxicity study of 2-amino-4-nitrophenol (99-57-0) was performed on male and female CFE-S rats .20 male and 20 female rats /dose group were used. One male was mated with one female until copulation was confirmed by the presence of sperm during daily vaginal inspections (day 0 of pregnancy).The females then were weighed, transferred into individual cages. The test material mixed with feed were administers in dose concentration 0, 97.5,616 mg/kg bw/day (0, 1950,7800 ppm)from day from day 6 through day 15. Pregnancy was further confirmed by biweekly weighing of the females. All females were killed by chloroform inhalation on the 19th day of pregnancy and the fetuses delivered by Caesarian section. The number and distribution of fetuses, and the number of corpora lutea, live and stillboin fetuses, and early and late resorptions were recorded. Each fetus was weighed, measured, and examined for gross abnormalities. One-third of each litter was examined for visceral abnormalities by employing the slicing method of Wilson (1965). The remaining two-thirds were cleared and the bone structure stained with alizarin red S in order to define any skeletal abnormalities (Murphy, 1965)No dose-related significant differences were observed in the parameters examined. The 616mg/kg /day (7800 ppm) dose group excreted blue-brown colour urine. No grossly abnormal pups were noted in the 97.5 mg/kg /day dose group (244 pups); there was one in control group (244 pups). One grossly abnormal pup was noted out of the 262 examined in the 616 mg/kg /day dose group. However, the average numbers of implantation sites, live pups, and early or late resorptions were not significantly different among the groups. Hence No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 616 mg/kg/day (7800ppm.When male and female CFE-S rats were treated with2-amino-4-nitrophenol (99-57-0) orally.

Further supported by experimental study conducted byBurnett CL, Bergfeld WF, Belsito DV, Klaassen CD, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, Alan Andersen F.(International Journal of Toxicology 2009;Nov-Dec;28(6 Suppl 2):217S-51S.) on structurally similar read across substance 4-amino-3- nitrophenol (610-81-1). Reproductive and developmental toxicity study of 4-amino-3-nitrophenol(610-81-1) was performed on pregnant female Sprague-Dawley rats .24 female rats /dose group were used. The test material mixed with0.5%carboxymethylcellulosewere administers in dose concentration 0,5, 20, or 400 mg/kg/d from day 6 through day 19.Clinical signs were checked daily, and body weight gain and food consumption were recorded. On day 20, the females were killed and necropsied. Litter parameters were measured and the fetuses were examined for external, visceral, or skeletal abnormalities. No mortality was observed during the treatment period. Three rats in the 400-mg/kg/d group exhibited ptyalism. No significant effects were observed in the litter parameters or in the fetuses at any dose. Hence the NOAEL for maternal and prenatal exposure to 4-amino-3- nitrophenol was considered to be 400 mg/kg/d.

Thus, based on the above predictions and experimental study of 2-methoxy-5-nitroanilinium chloride (67827-72-9)and its structurally similar read across substance, No Observed Adverse Effect Level (NOAEL) was considered to be 654.52mg/kg bw Thus, comparing this value with the criteria of CLP regulation 2-methoxy-5-nitroanilinium chloride (67827-72-9)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 2-methoxy-5-nitroanilinium chloride (67827-72-9)cannot be classified as reproductive toxicant.