1,2-Benzenediol, 4-[(4-methylphenyl)sulfonyl]-

Endpoint summary

Description of key information

For acute oral and dermal toxicity, guideline studies were available for a structural analogue (CH03951).

Additionally, QSAR results are provided to further support the conclusions of the read-across.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

2019-2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
[Describe why the read-across can be performed (e.g. common functional group(s), common precursor(s)/breakdown product(s) or common mechanism(s) of action]

See attached documents.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
[Provide here, if relevant, additional information to that included in the Test material section of the source and target records]
See attached documents.


3. ANALOGUE APPROACH JUSTIFICATION
[Summarise here based on available experimental data how these results verify that the read-across is justified]
See attached documents.

4. DATA MATRIX
See attached documents.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

December 2001

Deviations:

yes

Remarks:

The study plan deviation is considered not to have affected the integrity of the study

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002

Deviations:

yes

Remarks:

The study plan deviation is considered not to have affected the integrity of the study

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

2008

Deviations:

yes

Remarks:

The study plan deviation is considered not to have affected the integrity of the study

Qualifier:

according to guideline

Guideline:

other: JMAFF Guidelines

Version / remarks:

2000, including the most recent revisions

Deviations:

yes

Remarks:

The study plan deviation is considered not to have affected the integrity of the study

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture and piloerection were noted for all animals between Days 1 and 3. Uncoordinated movements were noted for three out of six animals on Day 1.

Gross pathology:

Abnormalities of the kidneys (pelvic dilation) were found in two out of six animals at macroscopic post mortem examination. This finding is occasionally seen in rats of this age and strain and was therefore considered not related to treatment. Macroscopic post mortem examination of the other animals did not reveal any abnormalities.

Interpretation of results:

GHS criteria not met

Conclusions:

Using read-across from a structural analogue, the LD50 of CH04008 for acute oral toxicity to rats was determined at >2000 mg/kg.

Reference 2

Endpoint:

acute toxicity: oral

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 adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
T.E.S.T.

2. MODEL (incl. version number)
T.E.S.T. v4.0.1

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
c1(O)c(O)cc(S(=O)(=O)c2ccc(C)cc2)cc1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF or providing a link]
See QMRF attached.

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
See QPRF attached.

6. ADEQUACY OF THE RESULT
[Explain how the prediction fits the purpose of classification and labelling and/or risk assessment]
The predicted LD50 values (>= 4101 mg/kg bw) are clearly above the threshold for classification (2000 mg/kg bw).

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

T.E.S.T. QSAR is developed by US EPA. The Toxicity Estimation Software Tool (T.E.S.T.) has been developed to allow users to easily estimate toxicity using a variety of QSAR methodologies. T.E.S.T allows a user to estimate toxicity without requiring any external programs.

Specific details on test material used for the study:

c1(O)c(O)cc(S(=O)(=O)c2ccc(C)cc2)cc1

Species:

rat

Route of administration:

oral: unspecified

Dose descriptor:

LD50

Effect level:

>= 4 101 mg/kg bw

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information

Conclusions:

The T.E.S.T. QSAR estimated the oral rat LD50 to be between 4101 and 15297 mg/kg. The substance is therefore not classified as acute toxic through oral route.

Executive summary:

QPRF:T.E.S.T. v 4.0.1(20 May 2014)

 

1.	Substance	See “Test material identity”
2.	General information
2.1	Date of QPRF	See “Data Source (Reference)”
2.2	QPRF author and contact details	See “Data Source (Reference)”
3.	Prediction
3.1	Endpoint (OECD Principle 1)	Endpoint	Oral rat LD50 (amount of chemical in mg/kg body weight that causes 50% of rats to die after oral ingestion)
3.2	Algorithm (OECD Principle 2)	Model or submodel name	T.E.S.T.
		Model version	v. 4.0.1
		Predicted value (model result)	See “Results and discussion”
		Input for prediction	- Chemical structure via SMILES code
		Descriptor values	Different methods are used to derive the toxicity value (see result)
3.3	Applicability domain (OECD principle 3)	Domains:
		- Compounds can only contain the following element symbols: C, H, O, N, F, Cl, Br, I, S, P, Si, or As - Compounds must represent a single pure component		- Substance contains only allowed elements     -Substance represents a single pure component
3.4	The uncertainty of the prediction (OECD principle 4)	Statistical accuracy for training dataset: n = 7420 Method R2   K RMSE MAE Coverage Hierarchical 0.568 0.955 0.652 0.460 0.826 FDA 0.542 0.950 0.668 0.492 0.980 Nearest neighbor 0.519 0.954 0.677 0.491 0.994 Consensus 0.604 0.952 0.604 0.441 1   The consensus method achieved the best results in terms of both prediction accuracy and prediction coverage. The hierarchical method achieved slightly better prediction accuracy than the nearest neighbor and FDA methods but the prediction coverage was lower (83%).
3.5	The chemical mechanisms according to the model underpinning the predicted result (OECD principle 5)	Hierarchical method:The toxicity for a given query compound is estimated using the weighted average of the predictions from several different models. The different models are obtained by using Ward’s method to divide the training set into a series of structurally similar clusters. A genetic algorithm based technique is used to generate models for each cluster. The models are generated prior to runtime. FDA method: The prediction for each test chemical is made using a new model that is fit to the chemicals that are most similar to the test compound. Each model is generated at runtime. Nearest neighbor method: The predicted toxicity is estimated by taking an average of the 3 chemicals in the training set that are most similar to the test chemical. Consensus method: The predicted toxicity is estimated by taking an average of the predicted toxicities from the above QSAR methods (provided the predictions are within the respective applicability domains)

 

References

- User’s Guide for T.E.S.T. (version 4.0) (Toxicity Estimation Software Tool) – A program to estimate toxicity from molecular structure. US EPA

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2019-2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

December 2001

Deviations:

yes

Remarks:

The study plan deviation is considered not to have affected the integrity of the study

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002

Deviations:

yes

Remarks:

The study plan deviation is considered not to have affected the integrity of the study

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

2008

Deviations:

yes

Remarks:

The study plan deviation is considered not to have affected the integrity of the study

Qualifier:

according to guideline

Guideline:

other: JMAFF Guidelines

Version / remarks:

2000, including the most recent revisions

Deviations:

yes

Remarks:

The study plan deviation is considered not to have affected the integrity of the study

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Han, Outbred, SPF-Quality

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approx. 8-9 weeks
- Weight at study initiation: 139-167 g
- Fasting period before study:
Animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and until 3-4 hours after administration of the test item. Water was available.
- Housing:
On arrival and following assignment to the study, animals were group housed (up to 3 animals of the same sex and same dosing group together) in polycarbonate cages (Makrolon MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles. The room(s) in which the animals were kept were documented in the study records.
Animals were separated during designated procedures/activities. Each cage was clearly labeled.
- Diet (e.g. ad libitum):
Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum throughout the study, except during designated procedures.
The feed was analyzed by the supplier for nutritional components and environmental contaminants. Results of the analysis were provided by the supplier and are on file at the Test Facility.
It is considered that there were no known contaminants in the feed that would interfere with the objectives of the study.
- Water (e.g. ad libitum):
Municipal tap-water was freely available to each animal via water bottles.
Periodic analysis of the water was performed, and results of these analyses are on file at the Test Facility.
It is considered that there were no known contaminants in the water that would interfere with the objectives of the study.
- Acclimation period:
The animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing.

ENVIRONMENTAL CONDITIONS
Target temperatures of 18 to 24°C with a relative target humidity of 40 to 70% were maintained. The actual daily mean temperature during the study period was 20 to 21°C with an actual daily mean relative humidity of 50 to 53%. A 12 hour light/12 hour dark cycle was maintained. Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1% Aqueous carboxymethyl cellulose (CMC: Genfarma, Zaandam, The Netherlands)

Details on oral exposure:

VEHICLE
- Concentration in vehicle / Amount of vehicle (if gavage):
The dose volume for each animal was based on the body weight measurement prior to dosing. A dose volume of 10 mL/kg body weight was used for each dose.
- Justification for choice of vehicle:
Trial preparations were performed to select the suitable vehicle and to establish a suitable formulation procedure. These trials were not performed as part of this study and these preparations were not used for dosing. Raw Data of these trials will be retained by the Test Facility.

DOSAGE PREPARATION (if unusual):
Test item dosing formulations (w/w) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements.
The dosing formulations were kept at room temperature until dosing. The dosing formulations were stirred until and during dosing.
No adjustment was made for specific gravity of the vehicle. No correction was made for the purity/composition of the test item.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
The oral route was selected as it is a possible route of human exposure during manufacture, handling or use of the test item.
The dose levels were based on the OECD test guidelines and were selected from the series 5 (lowest dose level), 50, 300 and 2000 (highest dose level) mg/kg body weight. The starting dose level should be the one that is likely to produce mortality in at least some of the animals and was selected based on available toxicity data of the test item.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6 (2 groups of 3)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Postdose observations were performed at periodic intervals on the day of dosing (at least three times) and once daily thereafter. The observation period was 14 days.
Animals were weighed individually on Day 1 (predose), 8 and 15. A fasted weight was recorded on the day of dosing.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology

Statistics:

The oral LD50 value of the test item was ranked within the following ranges: 0-5, 5-50, 50-300 or 300-2000 mg/kg b.w. or as exceeding 2000 mg/kg b.w. The LD50 cut-off value was established based on OECD guideline 423. No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture and piloerection were noted for all animals between Days 1 and 3. Uncoordinated movements were noted for three out of six animals on Day 1.

Gross pathology:

Abnormalities of the kidneys (pelvic dilation) were found in two out of six animals at macroscopic post mortem examination. This finding is occasionally seen in rats of this age and strain and was therefore considered not related to treatment. Macroscopic post mortem examination of the other animals did not reveal any abnormalities.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of CH03951 in Wistar Han 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, CH03951 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 (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Executive summary:

The objective of this study was to assess the toxicity of the test item when administered in a single dose to female rats at one defined dosage. Furthermore, the results of the study allowed the test item to be ranked according to most classification systems, currently in use. This study should provide a rational basis for risk assessment in man.

The study was carried out in compliance with the guidelines described in:

·     OECD No.423 (2001) "Acute Oral Toxicity, Acute Toxic Class Method".

·     EC No 440/2008, part B: "Acute Oral Toxicity, Acute Toxic Class Method".

·     EPA, OPPTS 870.1100 (2002), "Acute Oral Toxicity".

·     JMAFF Guidelines (2000), including the most recent revisions.

CH03951 was administered by oral gavage to two consecutive groups of three female Wistar Han 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 and piloerection were noted for all animals between Days 1 and 3. Uncoordinated movements were noted for three out of six animals on Day 1.

The 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.

The oral LD50 value of CH03951 in Wistar Han 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, CH03951 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 (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items 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:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Justification for type of information:

Testing by the inhalation route is only appropriate if exposure of humans via inhalation is likely. A dustiness test was conducted and only 2.81 mg dust/ g substance can become airborne under moderate agitation as comparable to conditions a the workplace (see IUCLID section 4.5). This results in a low emission potential. In a particle size distribution test (IUCLID section 4.5) the D50 of the substance is 62.4 μm. Moreover, the vapour pressure of the substance is very low and respiratory protection is always worn during production and use. It can be stated that the substance is not likely to be exposed to humans. Therefore, no inhalation test has been conducted.

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
[Please provide information for all of the points below addressing endpoint-specific elements that were not already covered by the overall category approach justification made available at the category level. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
Log Kow gives an indication of the lipid and water solubility. The lower Log Kow, the more water/less lipid soluble. Acute toxicity is therefore linked to Log Kow.

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL
The category is defined by similarities in substance type, chemical category, absence of metals, high toxic hazard, biodegradability and logKow. See the attached documents for more information.

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Interpretation of results:

GHS criteria not met

Conclusions:

Based on a read-across from 5 similar structures, LD50 for dermal toxicity is >2000 mg/kg bw.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

2019-2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
[Describe why the read-across can be performed (e.g. common functional group(s), common precursor(s)/breakdown product(s) or common mechanism(s) of action]

See attached documents.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
[Provide here, if relevant, additional information to that included in the Test material section of the source and target records]
See attached documents.


3. ANALOGUE APPROACH JUSTIFICATION
[Summarise here based on available experimental data how these results verify that the read-across is justified]
See attached documents.

4. DATA MATRIX
See attached documents.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

2017

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

No mortality occurred

Clinical signs:

other: Ptosis was noted for one animal on Day 1 and hunched posture was noted for two animals on Day 2.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on read-across from a structural analogue, the LD50 for acute dermal toxicity was determined at >2000 mg/kg bw.

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2019-2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

2017

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Crl: WI(Han); Outbred, SPF-Quality

Sex:

female

Details on test animals or test system and environmental conditions:

Test animals
Source:
Charles River Deutschland, Sulzfeld, Germany
Number of Animals:
3 females (nulliparous and non-pregnant)
Age at the Initiation of Dosing:
Young adult animals (approximately 10-11 weeks old) were selected.
Weight at the Initiation of Dosing:
194 to 199 g.

Animal Identification
At study assignment, each animal was identified using a tail mark with indelible ink.

Environmental Acclimation
The animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing.

Housing
On arrival, animals were group housed (up to 5 animals of the same sex together) in polycarbonate cages (Makrolon MIV type; height 18 cm.) and following assignment to the study, animals were individually housed in polycarbonate cages (Makrolon MIII type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles. The room in which the animals were kept was documented in the study records.
Animals were separated during designated procedures/activities. Each cage was clearly labeled.

Environmental Conditions
Target temperatures of 18 to 24°C with a relative target humidity of 40 to 70% were maintained. The actual daily mean temperature during the study period was 20 to 21°C with an actual daily mean relative humidity of 48 to 53%. A 12 hour light/12 hour dark cycle was maintained. Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.

Food
Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum throughout the study, except during designated procedures.
The feed was analyzed by the supplier for nutritional components and environmental contaminants. Results of the analysis were provided by the supplier and are on file at the Test Facility.
It is considered that there were no known contaminants in the feed that would interfere with the objectives of the study.

Water
Municipal tap-water was freely available to each animal via water bottles.
Periodic analysis of the water was performed, and results of these analyses are on file at the Test Facility.
It is considered that there were no known contaminants in the water that would interfere with the objectives of the study.

Animal Enrichment
For psychological/environmental enrichment, animals were provided with paper (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom), except when interrupted by study procedures/activities.

Type of coverage:

occlusive

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1% Aqueous carboxymethyl cellulose

Details on dermal exposure:

Administration of Test item
A single dose of test item was administered to the appropriate animals by dermal application on Day 1. One day before dosing, an area of approximately 5x7 cm on the back of the animals was clipped. The test item was applied in an area of approximately 10% of the total body surface, i.e. approximately 18 cm² for females. The test item was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D), successively covered with Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only. The application period was 24 hours, after which the dressing was removed and the skin cleaned of residual test item using water.
The dose volume for each animal was based on the body weight measurement prior to dosing. A dose volume of 10 mL/kg body weight will be used for each dose.
The dosing formulations were stirred continuously during dose administration.

Justification of Route and Dose Levels
The dermal route was selected as it is a possible route of human exposure during manufacture, handling or use of the test item. The dose levels were based on the OECD test guidelines.

Duration of exposure:

24 hours

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

Mortality/Moribundity Checks
Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings.

Clinical Observations
Post-dose observations were performed at periodic intervals on the day of dosing (at least three times) and once daily thereafter. The observation period was 14 days.
All the animals were examined for reaction to dosing. The onset, intensity and duration of these signs was recorded (if appropriate), particular attention being paid to the animals during and for the first hour after dosing.
Animals were weighed individually on Day 1 (pre-dose), 8 and 15.
The skin reactions were assessed approximately 24, 48 and 72 hours after the removal of the dressing and test item. Adjacent areas of untreated skin of each animal served as controls.

Terminal Procedures
All animals were sacrificed by oxygen/carbon dioxide procedure at the end of the observation period. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities were recorded.

Statistics:

No statistics were applied

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

No mortality occurred

Clinical signs:

other: Ptosis was noted for one animal on Day 1 and hunched posture was noted for two animals on Day 2.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 value of CH03951 in Wistar Han rats was established to exceed 2000 mg/kg body weight.
Based on these results, CH03951 does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Executive summary:

The objective of this study was to determine the potential toxicity of CH03951, when given by a single dermal dose.

The study was carried out based on the guideline described in:

·     OECD No. 402 (2017) "Acute Dermal Toxicity".

CH03951 was administered to three female Wistar Han rat by a single dermal application at 2000 mg/kg body weight for 24 hours. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed or after terminal sacrifice (Day 15).

No mortality occurred.

Ptosis was noted for one animal on Day 1 and hunched posture was noted for two animals on Day 2. No signs of irritation was noted for any of the animals at any time point.

The body weights shown by the animals during the observation period was within the range expected for rats used in this type of study.

No abnormalities were found at macroscopic post mortem examination of the animals.

The dermal LD50 value of CH03951 in Wistar Han rats was established to exceed 2000 mg/kg body weight.

Based on these results, CH03951 does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Justification for classification or non-classification

No indications for acute toxic effects were found in guideline studies of a structural analogue nor did QSAR analyses indicate any acute toxicity issues.