2H-Indol-2-one, 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-

Endpoint summary

Description of key information

The acute toxicity of the substance was tested in albino mice and Sprague-Dawley rats. The substance was administered to mice (strain nor specified) at doses of 500 and 2000 mg/kg p.o. (3/sex/groups) and 300, 500, and 1000 mg/kg i.p. (3M only).

Rats received doses of 500 and 2000 mg/kg p.o. (3/sex) and 500 and 2000 mg/kg i.p. (3M only).

Drug-related deaths occurred only in male mice at 1000 mg/kg i. p. Sedation was the primary clinical sign with both routes. CNS signs tended to have a more rapid onset and prolonged duration with i. p. dosing. No target organ for toxicity was identified.

LD50's were calculated to be >2000 mg/kg p.o. in both mice and rats and >2000 mg/kg i.p. in rats, and 500-1000 mg/kg i.p. in mice.

This study was not definitive due to the lack of a complete battery of measurements, of control groups, and the small n/group.

 

The available date are conclusive but not sufficient for the classification of the substance for acute oral toxicity.

To assess dermal toxicity, ziprasidone was applied to intact skin at a single dose of 2000 mg for 24 hrs. Animals (n= 5) were examined 2 days after drug application. In the dermal study, no drug-related mortality or clinical signs or changes in body wt or food consumption were observed, nor were any signs if dermal irritation detected.

The available date are conclusive but not sufficient for the classification of the substance for acute dermal toxicity

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:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Species:

mouse

Strain:

not specified

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

not specified

Doses:

500 and 2000 mg/kg

No. of animals per sex per dose:

3

Control animals:

not specified

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Sedation was the primary clinical sign. CNS signs tended to have a more rapid onset and prolonged duration with  i. p. dosing (respect p.o. route) . No target organ for toxicity was identified.

Interpretation of results:

GHS criteria not met

Conclusions:

For ziprasidone hydrochloride monohydrate the mouse LD50 is > 2000 mg/kg/bw.

Executive summary:

The acute toxicity of the substance was tested in mice. As a results, the mouse LD50 is > 2000 mg/kg/bw, so the substance is not classified for acute oral toxicity.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

not specified

Doses:

500 and 2000 mg/kg p.o.

No. of animals per sex per dose:

3

Control animals:

not specified

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

LD50's were calculated to be >2000 mg/kg p.o.

This study was not definitive due to the lack of a complete battery of measurements, of control groups, and the small n/group.

Interpretation of results:

GHS criteria not met

Conclusions:

For ziprasidone hydrochloride monohydrate the rat LD50 is > 2000 mg/kg/bw.

Executive summary:

The acute toxicity of the substance was tested in Sprague-Dawley rats. As a results, the rat LD50 is > 2000 mg/kg/bw, so the substance is not classified for acute oral toxicity.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

other information

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Ziprasidone and ziprasidone hydrochloride monohydrate have the same common functional groups, breakdown products and common mechanism of action.
The only structural difference is that the source molecule is the salified monohydrate form of ziprasidone.
In dilute aqueous conditions of defined pH a salt will behave no differently to the parent acid, at identical concentration of the particular speciated form present and will be fully dissociated.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

The purity of the chemical source substance i.e. ziprasidone hydrochloride monohydrate is not well specified in the reference document (secondary literature). However, the source of the data is the FDA Pharmacology review with application number 20-825, so, since this is a review of a substance used as an active pharmaceutical ingredient we can be assumed that impurity relevant for the hazard profile of the substance are not present in the test material.
For the chemical target, there are no relevant (for the hazard assessment of the substance) impurities, as reported by the Company.

3. ANALOGUE APPROACH JUSTIFICATION

As a results of the bibliographic search performed for ziprasidone is well clear that toxicological information on the ziprasidone hydrochloride monohydrate may be used to assess adverse health effects arising from exposure to ziprasidone - with the application of a molecular weight correction, if relevant -, if for this latter no data are available.

While the structure and the molecular weight of the two substance (i.e. source and target) are very similar, and the mechanism of action is common, the salts form i.e. the source substance is more soluble in water, so it is foreseeable that its bioavailability is greater and the read-across represents, in this case, a conservative approach to assess the heath adverse effects of ziprasidone.

Value of solubility :
Ziprasidone about 0.5 μg/mL
Ziprasidone hydrochloride about 210 μg/mL


4. DATA MATRIX

Analogue approach has been applied for the hazard assessment of the following endpoint of ziprasidone:
- Acute oral toxicity
- Acute dermal toxicity
- Skin corrosion/irritation
- Eye Irritation/corrosion
- Repeated dose toxicity
- Carcinogenicity
- Mutagenicity
- Toxicity to reproduction

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

The acute toxicity of the substance was tested in albino mice and Sprague-Dawley rats. The substance was administered to mice (strain nor specified) at doses of 500 and 2000 mg/kg p.o. (3/sex/groups) and 300, 500, and 1000 mg/kg i.p. (3M only).

Rats received doses of 500 and 2000 mg/kg p.o. (3/sex) and 500 and 2000 mg/kg i.p. (3M only).

Drug-related deaths occurred only in male mice at 1000 mg/kg i. p. Sedation was the primary clinical sign with both routes. CNS signs tended to have a more rapid onset and prolonged duration with i. p. dosing. No target organ for toxicity was identified.

LD50's were calculated to be >2000 mg/kg p.o. in both mice and rats and >2000 mg/kg i.p. in rats, and 500-1000 mg/kg i.p. in mice.

This study was not definitive due to the lack of a complete battery of measurements, of control groups, and the small n/group.

 

Acute toxicity data of ziprasidone hydrochloride monohydrate has not been corrected by molecular weight since the value of LD50s obtained are >2000 mg/kg.

The available date are conclusive but not sufficient for the classification of the substance for acute oral toxicity.

Interpretation of results:

GHS criteria not met

Conclusions:

LD50's were calculated to be >2000 mg/kg p.o. in both mice and rats and >2000 mg/kg i.p. in rats, and 500-1000 mg/kg i.p. in mice.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

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:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Species:

rabbit

Strain:

New Zealand White

Sex:

not specified

Interpretation of results:

GHS criteria not met

Conclusions:

In the dermal study, no drug-related mortality or clinical signs or changes in body wt or food consumption were observed, nor were any signs if dermal irritation detected.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

other information

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

Ziprasidone and ziprasidone hydrochloride monohydrate have the same common functional groups, breakdown products and common mechanism of action.
The only structural difference is that the source molecule is the salified monohydrate form of ziprasidone.
In dilute aqueous conditions of defined pH a salt will behave no differently to the parent acid, at identical concentration of the particular speciated form present and will be
fully dissociated.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

The purity of the chemical source substance i.e. ziprasidone hydrochloride monohydrate is not well specified in the reference document (secondary literature). However, the
source of the data is the FDA Pharmacology review with application number 20-825, so, since this is a review of a substance used as an active pharmaceutical ingredient we can be
assumed that impurity relevant for the hazard profile of the substance are not present in the test material.

For the chemical target, there are no relevant (for the hazard assessment of the substance) impurities, as reported by the Company.


3. ANALOGUE APPROACH JUSTIFICATION

As a results of the bibliographic search performed for ziprasidone is well clear that toxicological information on the ziprasidone hydrochloride monohydrate may be used to
assess adverse health effects arising from exposure to ziprasidone - with the application of a molecular weight correction, if relevant -, if for this latter no data are
available.

While the structure and the molecular weight of the two substance (i.e. source and target) are very similar, and the mechanism of action is common, the salts form i.e. the
source substance is more soluble in water, so it is foreseeable that its bioavailability is greater and the read-across represents, in this case, a conservative approach to
assess the heath adverse effects of ziprasidone.

Value of solubility :
Ziprasidone about 0.5 μg/mL
Ziprasidone hydrochloride about 210 μg/mL


4. DATA MATRIX

Analogue approach has been applied for the hazard assessment of the following endpoint of ziprasidone:
- Acute oral toxicity
- Acute dermal toxicity
- Skin corrosion/irritation
- Eye Irritation/corrosion
- Repeated dose toxicity
- Carcinogenicity
- Mutagenicity
- Toxicity to reproduction

Reason / purpose for cross-reference:

read-across source

To assess dermal toxicity, ziprasidone was applied to intact skin at a single dose of 2000 mg for 24 hrs. Animals (n= 5) were examined 2 days after drug application. In the dermal study, no drug-related mortality or clinical signs or changes in body wt or food consumption were observed, nor were any signs if dermal irritation detected.

Acute toxicity data of ziprasidone hydrochloride monohydrate has not been corrected by molecular weight since the value of LD50 obtained is >2000 mg/kg.

Interpretation of results:

GHS criteria not met

Conclusions:

In the dermal study, no drug-related mortality or clinical signs or changes in body wt or food consumption were observed, nor were any signs if dermal irritation detected.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Justification for classification or non-classification

Oral and dermal LD50's were calculated to be >2000 mg/kg.