Registration Dossier
Registration Dossier
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EC number: 928-541-6 | CAS number: 146939-27-7
Endpoint summary
Administrative data
Description of key information
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.
To assess the potential for ziprasidone to produce eye irritation in rabbits (New Zealand White), ziprasidone was applied as a powder (44.9 mg) to the conjunctival sac of the left eye; the right eye served as a control.
Animals (n= 3/grp) were evaluated ("... with minimal manipulation and without the use of fluorescein) for 4 days postdosing. Apparently, at 24 hr postdosing, eyes were examined following application of 2% fluorescein.
No signs of ocular irritation were detected in cornea, iris, or conjunctivae. However, according to the text, the following were noted: (1) redness of the conjunctiva in the treated eye of each rabbit, (2) iritis and "slight circumcorneal reddening" in the eye of one rabbit; in this rabbit. By 48 hrs, all treated eyes appeared normal. Again, as in the dermal study, no positive controls were included in the study; also, no inert substance was tested to control for mechanical irritation effects.
Key value for chemical safety assessment
Skin irritation / corrosion
Link to relevant study records
- Endpoint:
- skin irritation: in vivo
- 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
- Amount / concentration applied:
- 2000 mg
- Duration of treatment / exposure:
- 24 h.
- Number of animals:
- 5
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- No signs of dermal irritation are detected.
- Endpoint:
- skin irritation / corrosion, other
- 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
- 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.
Referenceopen allclose all
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 of dermal irritation detected.
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.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not irritating)
Eye irritation
Link to relevant study records
- Endpoint:
- eye irritation: in vivo
- 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
- Vehicle:
- unchanged (no vehicle)
- Amount / concentration applied:
- 44.9 mg
- Observation period (in vivo):
- 4 days
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- No signs of ocular irritation were detected in cornea, iris, or conjunctivae.
- Endpoint:
- eye irritation, other
- 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
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- No signs of ocular irritation were detected in cornea, iris, or conjunctivae. However, according to the text, the following were noted: (1) redness of the conjunctiva in the treated eye of each rabbit, (2) iritis and "slight circumcorneal reddening" in the eye of one rabbit; in this rabbit. By 48 hrs, all treated eyes appeared normal. Again, as in the dermal study, no positive controls were included in the study; also, no inert substance was tested to control for mechanical irritation effects.
Referenceopen allclose all
No signs of ocular irritation were detected in cornea, iris, or conjunctivae. However, according to the text, the following were noted: (1) redness of the conjunctiva in the treated eye of each rabbit, (2) iritis and "slight circumcorneal reddening" in the eye of one rabbit; in this rabbit. By 48 hrs, all treated eyes appeared normal. Again, as in the dermal study, no positive controls were included in the study; also, no inert substance was tested to control for mechanical irritation effects.
To assess the potential for ziprasidone to produce eye irritation in rabbits (New Zealand White), ziprasidone was applied as a powder (44.9 mg) to the conjunctival sac of the left eye; the right eye served as a control.
Animals (n= 3/grp) were evaluated ("... with minimal manipulation and without the use of fluorescein) for 4 days postdosing. Apparently, at 24 hr postdosing, eyes were examined following application of 2% fluorescein.
No signs of ocular irritation were detected in cornea, iris, or conjunctivae. However, according to the text, the following were noted: (1) redness of the conjunctiva in the treated eye of each rabbit, (2) iritis and "slight circumcorneal reddening" in the eye of one rabbit; in this rabbit. By 48 hrs, all treated eyes appeared normal. Again, as in the dermal study, no positive controls were included in the study; also, no inert substance was tested to control for mechanical irritation effects.Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not irritating)
Respiratory irritation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for classification or non-classification
No sign of dermal and eye irritation were detected.
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