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Administrative data

Description of key information

In chronic studies (rat and dog, 6-mo and 1-yr) sedation was the primary drug-related clinical sign and was observed at all doses, with severity being dose related.

[FDA]

 

As stated in CLP Guidance, where the same target organ toxicity of similar severity is observed after single and repeated exposure to a similar dose, it may be concluded that the toxicity is essentially an acute (i.e. single exposure) effect with no accumulation or exacerbation of the toxicity with repeated exposure. In such a case classification with STOT-SE only would be appropriate.

 

Since sedation and other CNS effects (reversible effects) has been observed both in acute and chronic, at all dose levels tested and these types of effects has been considered for the classification as STOT RE is not relevant.

 

Other types of adverse effects reported are less relevant and are inconclusive for the classification of the substance.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
repeated dose toxicity: oral, 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:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Conclusions:
Sedation was the primary drug-related clinical sign and was observed at all doses, with severity being dose-related. Body weight was affected in both males and females; however, males were more markedly affected than females. Final body weights were reduced (compared to CM) by 17, 31, and 35% in LDM, MDM, and HDM. In females, final mean body weights (compared to CF) were slightly elevated in LDF, but reduced at the MD and HD (6 and 9%, respectively). No marked drug-related effects were observed on ophthalmology, hematology, clinical, chemistry, or urinalysis parameters. There were small changes in wbc ct and LFTs at the HD; however, the effects were small (LFT increased by <2-fold). A complete-battery of organ weights were not obtained; only kidney, liver, and testes were weighed. Changes in the weight of these organs were consistent with those in body weight.

Microscopic findings were detected in lung, adrenal gland, and prostate. Lung changes consisted of pleuritis in a few HD animals and multifocal granulomatous pneumonia. The latter finding was observed in all grps, including controls; however, the incidence and severity of the finding was dose-related. The granulomas were characterized as accumulations of foamy macrophages; the sponsor attributed this finding to "chronic, low level aspiration of the compound during dosing". However, there was no mention of detection of drug-related particles in lung samples. Foamy macrophages can result from drug-related phospholipidosis, as a reaction to inhalation of foreign bodies, or the cause may not be evident. The information provided was not sufficient to determine the possible cause. However, considering the dose-related incidence in males and females, a direct drug-related effect cannot be dismissed. Adrenal gland changes consisted of multifocal cystic degeneration and telangiectasia in MDF and HDF, and diffuse hypertrophy in MDF and HD animals. The diffuse hypertrophy was characterized as increased cytoplasmic mass in cells of the zona fasciculata. The sponsor attributed this finding to stress, and the blood vessel changes and cystic degeneration to age-related degeneration.
However, these explanations are not consistent with the dose-related incidences of these findings. The sponsor attributed the prostatitis to age and/or stress, as well as to
" ... hormones and immunologie factors ... " Again, the dose-related severity and incidence would suggest some drug involvement.

Drug-related clinical signs were noted in all drug-treated dogs, and consisted of reduced motor activity, recumbency, leaning/pressing against the cage, pawing, limb extension/unusual pasture, tremors, hypersalivation, ptosis, and panting. Signs noted at all doses, but not necessarily in all drug-treated animals included
vocalization,increased activity, pacing/ circling, aggressive behavior toward humans, cage biting, muscle fasciculation, emesis, and prolapse of nictitating membrane.

Body weight gain was reduced (compared to C) in males at all doses, in a dose-related manner; increases in body weight of CM, LDM, MDM, and HDM by the end of the study were 26, 16, 9, and -2%, respectively). In females; there were no dose-related changes in body wt; body weight gain was reduced only in MDF. Food consumption was not affected by drug-
treatment, i. e., changes in body weight were not reflected in changes in food consumption.

There were no drug-related changes in ECG parameters, systolic blood pressure, or rectal temperature. Miosis, blepharospasm, and prolapse of the nictitating membrane were noted upon ophthalmology examination. Miosis was noted at the MD and HD, and the latter findings were time- and dose-dependent; blepharospasm was noted at all doses, whereas, prolapse of the nictitating membrane was observed in MD and HD animals. There were no clear drug-related findings on hematology or urinalysis parameters. On clinical chemistry parameters, drug-related findings consisted primarily of increases in all phos and ALT at the HD. The effect on these parameters increased with duration of dosing, with high values being detected in all phos in 4/8 HD (243-404 U/L) and in ALT in 8/8 HD (58-183
U/L). There were no drug-related effects on kidney, liver, or testis wt not accounted for by changes in body weight.

Drug-related histopathology was detected in liver and kidney. Intrahepatic cholestasis, characterized by the sponsor as " ... bile plugs within canaliculi and phagocytized bile within Kupffer cells... ", was noted in all HD animals. No evidence of hepatic necrosis or inflammation was noted. Accumulation of lipofuscin was detected in the renal proximal tubules, with the incidence and severity being dose-related (1/4 CF, 3/4 MDM, 2/4 MDF, and all HD animals).

There were no unscheduled deaths during the study. Drug-related clinical signs were evident at all doses and were listed by the sponsor as " ... ptosis, tremors, recumbency, head pressing, pawing, unusual postures, increased and for decreased activity, aggressive behavior, cage biting/licking, muscle fasciculations, ataxia, rapid respiration, and vocalization". Aggressive behavior was so severe in 1 HDM (# 27) that the second daily dose was discontinued in this animal from Day 130 on. No drug-related effects were noted on mean body weight, food consumption, physical examination/vital signs, ECG /blood pressure, ophthalmology, hematology, clinical chemistry, or urinalysis parameters. Increases in ALT (2-3 fold), however, were noted in individual animals (1 CM, 2 LDM, 3 HDM, 2 HDF), but were not dose-related on the final measurement day (i.e., Day 357-360). There were also no drug-related findings on any of the terminal studies, including histopathology.
Endpoint:
repeated dose toxicity: oral, other
Remarks:
dog 1-yr study
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Reference:
Composition 0
Test material information:
Composition 1
Species:
dog
Strain:
Beagle
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
gavage
Duration of treatment / exposure:
1 year
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
5 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
20 mg/kg bw/day (nominal)
Control animals:
yes

There were no unscheduled deaths during the study. Drug-related clinical signs were evident at all doses and were listed by the sponsor as " ... ptosis, tremors, recumbency, head pressing, pawing, unusual postures, increased and for decreased activity, aggressive behavior, cage biting/licking, muscle fasciculations, ataxia, rapid respiration, and vocalization". Aggressive behavior was so severe in 1 HDM (# 27) that the second daily dose was discontinued in this animal from Day 130 on. No drug-related effects were noted on mean body weight, food consumption, physical examination/vital signs, ECG /blood pressure, ophthalmology, hematology, clinical chemistry, or urinalysis parameters. Increases in ALT (2-3 fold), however, were noted in individual animals (1 CM, 2 LDM, 3 HDM, 2 HDF), but were not dose-related on the final measurement day (i.e., Day 357-360). There were also no drug-related findings on any of the terminal studies, including histopathology.

Conclusions:
There were no unscheduled deaths during the study. Drug-related clinical signs were evident at all doses and were listed by the sponsor as " ... ptosis, tremors, recumbency, head pressing, pawing, unusual postures, increased and for decreased activity, aggressive behavior, cage biting/licking, muscle fasciculations, ataxia, rapid respiration, and vocalization". Aggressive behavior was so severe in 1 HDM (# 27) that the second daily dose was discontinued in this animal from Day 130 on. No drug-related effects were noted on mean body weight, food consumption, physical examination/vital signs, ECG /blood pressure, ophthalmology, hematology, clinical chemistry, or urinalysis parameters. Increases in ALT (2-3 fold), however, were noted in individual animals (1 CM, 2 LDM, 3 HDM, 2 HDF), but were not dose-related on the final measurement day (i.e., Day 357-360). There were also no drug-related findings on any of the terminal studies, including histopathology.
Endpoint:
repeated dose toxicity: oral, other
Remarks:
dog - 6-mo study
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Reference:
Composition 0
Test material information:
Composition 1
Species:
dog
Strain:
Beagle
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
not specified
Duration of treatment / exposure:
6 months.
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
5 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
40 mg/kg bw/day (nominal)
No. of animals per sex per dose:
4 dogs/sex/group
Control animals:
yes

There was one unscheduled death during the study. One HDM was sacrificed during Wk 12 after fracturing several teeth and the jaw during cage-biting; this behavior was considered drug-related by the sponsor. Drug-related clinical signs were noted in all drug-treated dogs, and consisted of reduced motor activity, recumbency, leaning/pressing against the cage, pawing, limb extension/unusual pasture, tremors, hypersalivation, ptosis, and panting. Signs noted at all doses, but not necessarily in all drug-treated animals included vocalization,increased activity, pacing/ circling, aggressive behavior toward humans, cage biting, muscle fasciculation, emesis, and prolapse of nictitating membrane. Body weight gain was reduced (compared to C) in males at all doses, in a dose-related manner; increases in body weight of CM, LDM, MDM, and HDM by the end of the study were 26, 16, 9, and -2%, respectively). In females; there were no dose-related changes in body wt; body weight gain was reduced only in MDF. Food consumption was not affected by drug-treatment, i. e., changes in body weight were not reflected in changes in food consumption. There were no drug-related changes in ECG parameters, systolic blood pressure, or rectal temperature. Miosis, blepharospasm, and prolapse of the nictitating membrane were noted upon ophthalmology examination. Miosis was noted at the MD and HD, and the latter findings were time- and dose-dependent; blepharospasm was noted at all doses, whereas, prolapse of the nictitating membrane was observed in MD and HD animals. There were no clear drug-related findings on hematology or urinalysis parameters. On clinical chemistry parameters, drug-related findings consisted primarily of increases in all phos and ALT at the HD. The effect on these parameters increased with duration of dosing, with high values being detected in all phos in 4/8 HD (243-404 U/L) and in ALT in 8/8 HD (58-183 U/L). There were no drug-related effects on kidney, liver, or testis wt not accounted for by changes in body weight. The only gross lesions noted at necropsy were self-inflicted injury in 1 HDM (i.e., fractured teeth, maxilla) resulting from aggressive, cage-biting behavior. Drug-related histopathology was detected in liver and kidney. Intrahepatic cholestasis, characterized by the sponsor as " ... bile plugs within canaliculi and phagocytized bile within Kupffer cells... ", was noted in all HD animals. No evidence of hepatic necrosis or inflammation was noted. Accumulation of lipofuscin was detected in the renal proximal tubules, with the incidence and severity being dose-related (1/4 CF, 3/4 MDM, 2/4 MDF, and all HD animals).

Conclusions:
Drug-related clinical signs were noted in all drug-treated dogs, and consisted of reduced motor activity, recumbency, leaning/pressing against the cage, pawing, limb extension/unusual pasture, tremors, hypersalivation, ptosis, and panting. Signs noted at all doses, but not necessarily in all drug-treated animals included
vocalization,increased activity, pacing/ circling, aggressive behavior toward humans, cage biting, muscle fasciculation, emesis, and prolapse of nictitating membrane.

Body weight gain was reduced (compared to C) in males at all doses, in a dose-related manner; increases in body weight of CM, LDM, MDM, and HDM by the end of the study were 26, 16, 9, and -2%, respectively). In females; there were no dose-related changes in body wt; body weight gain was reduced only in MDF. Food consumption was not affected by drug-
treatment, i. e., changes in body weight were not reflected in changes in food consumption.

There were no drug-related changes in ECG parameters, systolic blood pressure, or rectal temperature. Miosis, blepharospasm, and prolapse of the nictitating membrane were noted upon ophthalmology examination. Miosis was noted at the MD and HD, and the latter findings were time- and dose-dependent; blepharospasm was noted at all doses, whereas, prolapse of the nictitating membrane was observed in MD and HD animals. There were no clear drug-related findings on hematology or urinalysis parameters. On clinical chemistry parameters, drug-related findings consisted primarily of increases in all phos and ALT at the HD. The effect on these parameters increased with duration of dosing, with high values being detected in all phos in 4/8 HD (243-404 U/L) and in ALT in 8/8 HD (58-183
U/L). There were no drug-related effects on kidney, liver, or testis wt not accounted for by changes in body weight.

Drug-related histopathology was detected in liver and kidney. Intrahepatic cholestasis, characterized by the sponsor as " ... bile plugs within canaliculi and phagocytized bile within Kupffer cells... ", was noted in all HD animals. No evidence of hepatic necrosis or inflammation was noted. Accumulation of lipofuscin was detected in the renal proximal tubules, with the incidence and severity being dose-related (1/4 CF, 3/4 MDM, 2/4 MDF, and all HD animals).
Endpoint:
repeated dose toxicity: oral, other
Remarks:
6-mo study
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Reference:
Composition 0
GLP compliance:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
not specified
Duration of treatment / exposure:
6 month
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
40 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
No. of animals per sex per dose:
15/sex/grp
Control animals:
yes

There were 11 unscheduled deaths. Of these, 8 were attributed to trauma during dosing or upon recapture (i.e., handling error). The cause of death in 1 CM, 1 LDF, and 1 HDM could not be determined. The primary drug-related clinical sign was sedation (to the point of unconsciousness) which was noted at all doses. One sign noted only at the HD was described as a peculiar tail reflex consisting of arching of the tail over the back. Difficulty in handling and food wastage also were limited to the HD grps. Body weight was affected in both males and females. In males, body weight loss was noted during the first wk of dosing (-5.4 gm vs. +47.0 gm in CM). Final mean body weight was reduced (compared to CM) at all doses in males (approx. 17, 31, and 35% in LDM, MDM, and HDM, respectively). In females, final mean body weight (compared to CF) was slightly elevated at the LD (3.5%), but reduced at the MD and HD (6 and 9%, respectively). Food consumption could not be accurately assessed at the HD due to instances of food wastage. In the lower dose grps, food consumption was reduced in males, but not females. There were no drug-related findings on ophthalmology (3, 6-mo); however, repeated orbital sinus bleeding may have compromised the evaluation. On hematology parameters, decreases were noted in wbc ct at the HD (37-20%), with the differential analysis indicating an increase in neutrophils (approx. 70%) and a decrease in lymphocytes (10-12%). The only notable findings in clinical chemistry parameters were increases in ALT (55-60% at Day 194), AST (81 and 45% at Day 194), and 5'-nucleotidase (36% at Day 194 in males only) at the HD. No drug-related findings were noted on urinalysis parameters. A complete battery of organ/tissue weights were not performed; only kidneys, liver, and testes were weighed. Changes in kidney and liver wt reflected decreases in body weight. Absolute testis wt, however, was similar among grps, reflecting either sparing of testis from body weight-induced changes or an increase in wt masked by reduced body weight gain.

According to the sponsor, there were no gross findings at necropsy (no summary or line listings were provided for survivors). The primary histopathology findings were as follows: (1) lung changes consisting of pleuritis (a few HD animals) and multifocal granulomatous pneumonia (all grps, but an increase in incidence and severity in 1 MDF and HD animals). This finding was characterized as aggregates of foamy macrophages and was attributed to aspiration of drug during dosing, (2) adrenal gland changes consisting of multifocal cystic degeneration and multifocal telangiectasia (i.e., dilation of small or terminal vessels) in MD and HD females (telangiectasia was also detected in 1 LDF), focal fibrosis in 1 HDF, and diffuse hypertrophy (characterized by increased cytoplasmic mass in cells of the zona fasciculata in MDF, and HD animals, (3) multifocal, suppurative prostatitis in MD and HD males. In terms of the adrenal changes, the sponsor suggested that adrenal cortical telangiectasia and cystic degeneration may "...represent different stages of the same degenerative process ... Cystic degeneration is .... believed to occur secondary to lesions in the cortical capillaries." Both findings were detected together in 1 MDF and 3 HDF; however, in 1 MDM, 3 MDF, 1 HDM, and 3 HDF only one or the other was found.

Conclusions:
Sedation was the primary drug-related clinical sign and was observed at all doses, with severity being dose-related. Body weight was affected in both males and females; however, males were more markedly affected than females. Final body weights were reduced (compared to CM) by 17, 31, and 35% in LDM, MDM, and HDM. In females, final mean body weights (compared to CF) were slightly elevated in LDF, but reduced at the MD and HD (6 and 9%, respectively). No marked drug-related effects were observed on ophthalmology, hematology, clinical, chemistry, or urinalysis parameters. There were small changes in wbc ct and LFTs at the HD; however, the effects were small (LFT increased by <2-fold). A complete-battery of organ weights were not obtained; only kidney, liver, and testes were weighed. Changes in the weight of these organs were consistent with those in body weight.

Microscopic findings were detected in lung, adrenal gland, and prostate. Lung changes consisted of pleuritis in a few HD animals and multifocal granulomatous pneumonia. The latter finding was observed in all grps, including controls; however, the incidence and severity of the finding was dose-related. The granulomas were characterized as accumulations of foamy macrophages; the sponsor attributed this finding to "chronic, low level aspiration of the compound during dosing". However, there was no mention of detection of drug-related particles in lung samples. Foamy macrophages can result from drug-related phospholipidosis, as a reaction to inhalation of foreign bodies, or the cause may not be evident. The information provided was not sufficient to determine the possible cause. However, considering the dose-related incidence in males and females, a direct drug-related effect cannot be dismissed. Adrenal gland changes consisted of multifocal cystic degeneration and telangiectasia in MDF and HDF, and diffuse hypertrophy in MDF and HD animals. The diffuse hypertrophy was characterized as increased cytoplasmic mass in cells of the zona fasciculata. The sponsor attributed this finding to stress, and the blood vessel changes and cystic degeneration to age-related degeneration.
However, these explanations are not consistent with the dose-related incidences of these findings. The sponsor attributed the prostatitis to age and/or stress, as well as to
" ... hormones and immunologie factors ... " Again, the dose-related severity and incidence would suggest some drug involvement.
Executive summary:

In rat ziprasidone was administered by gavage at doses of 0, 10, 40, and 200 mg/kg. There were 11 unscheduled deaths, 8 of which were attributed to trauma during dosing or during recapture. (The nature of the injuries attributed to trauma sustained during re-capture suggested the possibility at the personnel responsible for care and for testing of the animals were not sufficiently trained. This issue was referred to DSI, but was not adequately resolved.) The other three deaths were not dose-related. Sedation was the primary drug-related clinical sign and was observed at all doses, with severity being dose-related. Body weight was affected in both males and females; however, males were more markedly affected than females. Final body weights were reduced (compared to CM) by 17, 31, and 35% in LDM, MDM, and HDM. In females, final mean body weights (compared to CF) were slightly elevated in LDF, but reduced at the MD and HD (6 and 9%, respectively). No marked drug-related effects were observed on ophthalmology, hematology, clinical, chemistry, or urinalysis parameters. There were small changes in wbc ct and LFTs at the HD; however, the effects were small (LFT increased by <2-fold). A complete-battery of organ weights were not obtained; only kidney, liver, and testes were weighed. Changes in the weight of these organs were consistent with those in body weight. According to the sponsor, there were no gross findings; however, no summary table(s) or line listings were provided. Microscopic findings were detected in lung, adrenal gland, and prostate. Lung changes consisted of pleuritis in a few HD animals and multifocal granulomatous pneumonia. The latter finding was observed in all grps, including controls; however, the incidence and severity of the finding was dose-related. The granulomas were characterized as accumulations of foamy macrophages; the sponsor attributed this finding to "chronic, low level aspiration of the compound during dosing". However, there was no mention of detection of drug-related particles in lung samples. Foamy macrophages can result from drug-related phospholipidosis, as a reaction to inhalation of foreign bodies, or the cause may not be evident. The information provided was not sufficient to determine the possible cause. However, considering the dose-related incidence in males and females, a direct drug-related effect cannot be dismissed. Adrenal gland changes consisted of multifocal cystic degeneration and telangiectasia in MDF and HDF, and diffuse hypertrophy in MDF and HD animals. The diffuse hypertrophy was characterized as increased cytoplasmic mass in cells of the zona fasciculata. The sponsor attributed this finding to stress, and the blood vessel changes and cystic degeneration to age-related degeneration.

However, these explanations are not consistent with the dose-related incidences of these findings. The sponsor attributed the prostatitis to age and/or stress, as well as to " ... hormones and immunologie factors ... " Again, the dose-related severity and incidence would suggest some drug involvement.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

Justification for classification or non-classification

As stated in CLP Guidance, where the same target organ toxicity of similar severity is observed after single and repeated exposure to a similar dose, it may be concluded that the toxicity is essentially an acute (i.e. single exposure) effect with no accumulation or exacerbation of the toxicity with repeated exposure. In such a case classification with STOT-SE only would be appropriate.

 

Since sedation and other CNS effects (reversible effects) has been observed both in acute and chronic, at all dose levels tested and these types of effects has been considered for the classification as STOT RE is not relevant.