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Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity

The reproductive toxicity of 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2)was estimated by SSS (2017) using OECD QSAR toolbox v3.3with log kow as the primary descriptor and NOAEL was estimated to be 615.55mg/kg bw.When male and female  Sprague-Dawley rats were exposed with 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2) orally.Thus, based on the above predictions and experimental study on 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2) and its structurally similar read across substance No Observed Adverse Effect Level (NOAEL) was considered to be 615.55 mg/kg bw . Thus, comparing this value with the criteria of CLP regulation 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2) 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:
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:
IUPAC name: 2-chlorobenzene-1,4-diammonium sulphate
Molecular formula: C6H7ClN2.xH2O4S
Molecular weight:240.6661
substance type: organic
physical state: light grey colored solid powder.
InChI:1S/C6H7ClN2.H2O4S/c7-5-3-4(8)1-2-6(5)9;1-5(2,3)4/h1-3H,8-9H2;(H2,1,2,3,4)
Smiles:S(=O)(=O)(O)O.c1(c(ccc(c1)N)N)Cl
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals 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:
71 days prior to mating and throughout breeding, gestation and lactation until necropsy.
Frequency of treatment:
daily
Details on study schedule:
No data available
Dose / conc.:
615.55 mg/kg bw/day (nominal)
No. of animals per sex per dose:
30
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:
no effects observed
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:
615.55 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
reproductive performance
Remarks on result:
other: No toxic effects on reproductive performance was observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
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:
615.55 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: overall no developmental toxic effects observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
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" or "d" or "e" )  and ("f" and ( not "g") )  )  and "h" )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and "n" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anilines (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD ONLY

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Anilines (amino-para) OR Anilines (Unhindered) OR Inorganic Compound by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Inorganic chemical AND Not covered by current version of the decision tree AND 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 Known precedent reproductive and developmental toxic potential OR NO2-alkyl/NO2-benzene derivatives (8b) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) >> Other non-steroidal estrogen receptor (ER) binding compounds (2b-2) 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: "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 Anilines (Hemolytic anemia with methemoglobinemia) Rank A AND Anilines (Hepatotoxicity) Rank C AND Not categorized by Repeated dose (HESS)

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Amine AND Aromatic compound AND Aryl chloride AND Aryl halide AND Halogen derivative AND Primary amine AND Primary aromatic amine AND Sulfuric acid AND Sulfuric acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Anion by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.24

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.86

Conclusions:
In reproductive toxicity study, NOAEL was estimated to be 615.55mg/kg bw. When male and female Sprague-Dawley rats were exposed with 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2) orally.
Executive summary:

The reproductive toxicity of 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2)was estimated by SSS (2017) using OECD QSAR toolbox v3.3with log kow as the primary descriptor and NOAEL was estimated to be 615.55mg/kg bw.When male and female  Sprague-Dawley ratswere exposed with 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2) orally.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
615.55 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 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2)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 for 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2). 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-chlorobenzene-1,4-diammonium sulphate (6219-71-2)was estimated by SSS (2017) using OECD QSAR toolbox v3.3with log kow as the primary descriptor and NOAEL was estimated to be 615.55mg/kg bw. When male and female Sprague-Dawley rats were exposed with 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2) orally.

Further supported by   experimental study conducted byJ-check (Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation, J-check- 2010)on structurally similar read across substance 2-Amino-5-methylbenzenesulfonic acid(88-44-8).In a Preliminary Reproduction Toxicity Screening Test, Crj:CD(SD) male and female rat were treated with 2-Amino-5-methylbenzenesulfonic acid in the concentration of 0 (vehicle), 100, 300, 1000 mg/kg/day orally by gavage in sesame oil for male consecutive 48 days of 14 days before mating and 14 days of mating period and 20 days after the end of the mating period. The female administration period was 14 days before the mating and during the mating period (maximum 14 days) and through 3 days of postpartum feeding (41 to 46 days) throughout the gestation period of the female. The females who did not deliver after copulation establishment were for 41 and 43 days up to the day before dissection on 25th gestation. Females that failed to mate were consecutive 48 days of 20 days after the mating period. No mortality was observed in treated male and female rats as compared to control. In male rats, 1 ocular secretion in the 100 mg / kg group of male, 1 hair loss in the 300 mg / kg group, 1 in the 1000 mg / kg group Crust and hair loss were observed in one case and in females, hair removal was observed in the 100 mg / kg group through pregnancy and nursing periods. In male, no effect on body weight and in female at 100 and 1000 mg / kg, statistically significant decrease in body weight were observed only on the 4th day of nursing compared to the control group. However, since there was no obvious difference on the other measurement day and it was a change only for 1 day, and since there was no obvious change in body weight gain during the nursing period, the influence of administration of the test substance It was not thought to be an accidental change. In male rats at 1000 mg/kg bw, statistically significant increase in daily food intake for the 8 to 15 days and the cumulative food consumption from 1 to 15 days and in female rats, no effect on food consumption was observed as compared to control. Similarly, No reproductive effect on copulation, implantation and sexual cycle, gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index, purturition or maternal behaviour, numbers of offspring or live offspring, sex ratio and live birth index were observed in treated rats as compared to control. At 300 and 1000 mg/kg bw, statistically significant decrease in absolute epididymis weight were observed but no relative weight change and no effect on testicular weight were observed in treated male rats as compared to control. No gross pathological changes were attributed to the administration of the test substance. At 1000 mg/kg bw, cell infiltration of the epididymis, case in skin erosion and squamous cell epithelial hyperplasia , 1 atrophy of the thymus, 1 lung inflammation, 1 stomach ulcer and 1 part of the adrenal cortex one hypertrophy were observed in male rats. At 300 mg/kg bw, seminiferous tubular atrophy of the testes, pulmonary inflammation, 1 case in the liver necrosis and 1 atrophy of the thymus were observed in male rats. At 100 mg/kg bw, 1 Young yolk sac cysts in females who spontaneously delivered, so it was considered that there was no effect on the ovaries of the test substances. 1 Skin inflammatory infiltration and squamous epithelial hyperplasia were observed. In males and females who did not mate, seminiferous tubular atrophy of the testes was observed in males. No abnormal findings were observed in females. No abnormal findings were observed in males who did not establish pregnancy and infertile females. Atrophy of the thymus and purulent inflammation of the uterus were observed in one case in all the dead animals. No abnormal finding was observed in the other case. In addition, No effect on Viability and body weight of neonates were observed on day 0 and 4 and nonclinical sign were observed in neonates as compared to control. No abnormal findings were observed in females. At autopsy on 4th day of nursing, in the male, thymus neck remnant was 1 in the control group, 1 in the renal pelvic enlargement in the 300 mg / kg group, in the female in the control group and in the 300 mg / kg group in the renal pelvic enlargement in the kidney It was recognized in 1 and 3 cases respectively. In both cases, expression was expressed in a few cases, which was not related to administration of the test substance. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when male and female rats treated with 2-Amino-5-methylbenzenesulfonic acid(88-44-8) orally by gavage for approx. 68 days.

Also in another experimental study conducted byU. S. Environmental Protection Agency (EPA)(U. S. Environmental Protection Agency, Hazard Characterization Document, March, 2015) on structurally similar read across substance with Sulfanilic acid (121-57-3). In a Reproduction Toxicity Screening Test, wistar male and female rat were treated with Sulfanilic acid (121-57-3)in the dose concentration of0 (water), 62.5 (50), 250 and 1000 mg/kg-bw orally by gavage in water .12 males and 12 females were placed in each dose group. Males were dosed daily for a minimum of four weeks, including a minimum of two weeks prior to mating and continued throughout the mating period until the study was terminated. Females were dosed two weeks prior to mating, until conception, throughout pregnancy and at least four days after delivery. Females showing no evidence of copulation were re-grouped with proven sires for a second mating phase. All the animals were observed for Survival, general condition, body weights, food and water consumption. At the end of the in-life phase, gross necropsy was performed, with organ mass recorded, tissues and organs preserved and processed histologically. A histopathological examination was conducted on samples from the 1000mg/kg-bw/day dose groups and the vehicle groups.

No mortality was observed in treated male and female rats as compared to control. Rats at the1000mg/kg-bw/day dose showed oronasal bleeding during the first week and occasionally throughout the study. No effects were seen on body mass as well as food and water consumption was noted. at gross necropsy, No changes in organ weights of reproductive organs were noted. Noteworthy were the statistically insignificant, mild effects on litter mass of the high dose group and on pre-implantation loss of the 250mg/kg-bw/day and 1000 mg/kg-bw/day dose group. Similarly there was a mild tendency of relatively low total numbers of pups born with increasing test item dosage and a low mean number of live pups per dam at day 4 post-partum. Hence NOAEL was considered to be 1000 mg/kg/day for P generation and LOAEL was considered to be 250 mg/kg bw /day for F1 generation, when male and female wistar rats treated with Sulfanilic acid (121-57-3) orally by gavage.

   Thus, based on the above predictions and experimental study on 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2) and its structurally similar read across substance No Observed Adverse Effect Level (NOAEL) was considered to be 615.55 mg/kg bw . Thus, comparing this value with the criteria of CLP regulation 2-chlorobenzene-1,4-diammonium sulphate (6219-71-2) 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-chlorobenzene-1,4-diammonium sulphate (6219-71-2) cannot be classified as reproductive toxicant.