Registration Dossier

Administrative data

Description of key information

- Acute toxicity: oral:

In an acute oral toxicity study in female Wistar rats, following the acute toxic class method in accordance with OECD Guideline 423, the LD50 was established to be greater than 2000 mg/kg (van Sas, 2018).

- Acute toxicity: inhalation: the study is waived based on the following justification:

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance, a study was considered however not deemed scientifically justified for the dermal route of exposure due to its low potential for a significant rate of absorption through the skin. Based on the fact that the inhalation route of exposure is not considered relevant in the risk assessment for human exposure and the addition of a waiver for the acute dermal toxicity testing, an acute inhalation toxicity study will not be performed.

- Acute toxicity: dermal: the study is waived based on the following justification:

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance, an acute dermal toxicity study was performed. Hoewver, the substance was observed to be unstable in the selected vehicle. In addition, this study can be waived based on the fact that the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route, and no systemic toxicity is observed in in vivo studies with dermal exposure.    

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2017-12-14 to 2018-01-03
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: (JMAFF) No 8147
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Janssen Pharmaceutica N.V.; M16LB4523
- Expiration date of the lot/batch: 2018 February 09 (retest date)
- Purity/composition correction factor: 1

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
- Stability of the test substance in the solvent/vehicle: Stable in arachis oil for 3 hours (test facility study no. 520060)

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The preparations (w/w) were kept at room temperature and were dosed within 2 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficiently for these kinds of studies. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item as the correction factor is 1.

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Wistar strain Crl:WI (Han) (outbred, SPF-Quality), Charles River Deutschland, Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approx. 9-10 weeks
- Weight at study initiation: 160-181 grams
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): Free access to pelleted rodent diet
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: At least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C: actual daily mean temperature during the study period: 20 to 21°C
- Humidity (%): 40 to 70%: actual deaily mean relative humidity during the study period: 43 to 50%
- Air changes (per hr): 10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/12- hour dark cycle.

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at Charles River Den Bosch and on test item data supplied by the Sponsor. Based on stability analysis (CRL study no. 520060) it was considered that the used vehicle polyethylene glycol was not suitable for use in this test. Formulation in arachis oil has proven to be stable for 3 hours.
A report of Stability testing in different vehicles for this test item is attached to this entry.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

Doses:
2000 mg/kg bw (2 subsequent groups)
No. of animals per sex per dose:
3 females per group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/viability: twice daily.
Body weights: Days 1 (pre-administration), 8 and 15
Clinical signs: at periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The signs were graded according to fixed scales and the time of onset, degree and duration were recorded: maximum grade 4: grading slight (1) to very severe (4); maximum grade 3: grading slight (1) to severe (3); maximum grade 1: presence is scored (1).
- Necropsy of survivors performed: yes, at the end of the observation period all animals were sacrificed by oxygen/carbon dioxide procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.
Statistics:
No statistical analysis was performed
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture, pilerection and/or uncoordinated movements were noted for the animals on Days 1 and/or 2.
Body weight:
The mean body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of all animals.
Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of 4-Nitrobenzene-1-sulfonyl chloride in Wistar rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Based on these results, 4-Nitrobenzene-1-sulfonyl chloride does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
From 2017-09-05 to 2017-09-19
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
The test item was observed to be unstable in the vehicle used for this study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF Guidesline No 8147
Version / remarks:
November 2000, including the most recent revisions
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Janssen Pharmaceutica N.V., M16LB4523
- Expiration date of the lot/batch: 01-DEC-2017 (retest date)
-Purity/composition correction factor: 1

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
- Solubility and stability of the test substance in the solvent/vehicle: Based on stability analysis (CRL study no. 520060) it was considered that the used vehicle Polyethylene glycol 400 was not suitable for use in this test. A report of Stability testing in different vehicles for this test item is attached to this entry.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Preparation was kept at room temperature and dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulation was stirred during dosing, which ensures homogeneity sufficiently for these kinds of studies. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item as the correction factor is 1.

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: 5 male and 5 female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 10 weeks old)
- Weight at study initiation: 266, 267, 270, 287, 280 grams (males) and 171, 179, 175, 173, 179 grams (females)
- Housing: Individually housed in labeled Makrolon cages (MIII type, height 18 cm) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): ad libitum, free access to pelleted rodent diet.
- Water (e.g. ad libitum): ad libitum, free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions. During the acclimatization period the animals were group housed in Makrolon cages (MIV type, height 18 cm).

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 °C: actual daily mean temperature during the study period: 21 to 22°C
- Humidity (%): 40-70%: actual daily mean relative humidity of 46 to 67%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
not specified
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Details on dermal exposure:
TEST SITE
- Area of exposure: on the back of the animal
- % coverage: approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females
- Type of wrap if used: surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.

REMOVAL OF TEST SUBSTANCE
- Washing: after removal of dressing, the skin was cleaned of residual test item using tap water
- Time after start of exposure: 24 h

Dose volumne: 10 mL/kg bw
Duration of exposure:
24 h
Doses:
2000 mg/kg bw(single dosage) on Day 1
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Observation period: until day 15 after treatment
- Mortality/Viability: Twice daily.
- Body weights: Days 1 (pre-administration), 8 and 15.
- Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The time of onset, degree and duration were recorded and the symptoms graded according to fixed scales:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
- Necropsy: At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
Statistics:
No statistical analysis was performed.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Flat posture, piloerection and ptosis were noted for all animals on Day 1. General erythema, erythema maculate, scales, scabs and/or thickened area were seen in the treated skin-area of all animals during the observation period, these local effects were considered not to have affected the conclusion of the study. Additionally, scabs (Days 4 and 5) and scales (Days 14 and 15) were noted for one female and scabs on the right flank were noted for one female from Day 7 onwards.
Body weight:
The body weight gain during the observation period was within the range expected for rats used in this type of study.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
study cannot be used for classification
Conclusions:
The dermal LD50 value of 4-nitrobenzene-1-sulfonyl chloride in Wistar rats was established to exceed 2000 mg/kg body weight.
However, as it was observed that the test item was unstable in the vehicle used for this study, Polyethylene glycol 400, the results of this study cannot be used to derive the classification according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

-Acute toxicity: oral:

An acute oral toxicity study with 4 -nitrobenzene-1 -sulfonyl chloride according to the acute toxic class method in female Wistar rats (OECD guideline 423) was performed (van Sas 2018). The test item was administered by oral gavage to two subsequent groups of three female rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred. Hunched posture, uncoordinated movements and piloerection were noted for all animals on Day 1 and/or 2. The mean body weight gain shown by the animals over the study period was considered to be normal. No abnormalities were found at macroscopic post mortem examination of all animals.

The oral LD50 value of 4 -nitrobenzene-1 -sulfonyl chloride in Wistar rats was established to exceed 2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/ kg body weight.

-Acute toxicity: inhalation: the study is waived based on the following justification:

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance, a study was considered however not deemed scientifically justified for the dermal route of exposure due to its low potential for a significant rate of absorption through the skin. Based on the fact that the inhalation route of exposure is not considered relevant in the risk assessment for human exposure and the addition of a waiver for the acute dermal toxicity testing, an acute inhalation toxicity study will not be performed.

-Acute toxicity: dermal: the study is waived based on the following justification:

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance, an acute dermal toxicity study was performed. Hoewver, the substance was observed to be unstable in the selected vehicle. In addition, this study can be waived based on the fact that the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route, and no systemic toxicity is observed in in vivo studies with dermal exposure.    

Justification for classification or non-classification

Acute Oral classification:

Based on the available data, 4 -nitrobenzene-1 -sulfonyl chloride does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).

Acute Inhalation classification:

No data were available to decide on the classification for the inhalation route.

Acute Dermal classification:

No data were available to decide on the classification for the dermal route.