Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
Clioquinol Toxcity in Dogs
GLP compliance:
not specified
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Housing:housed singly
- Diet (e.g. ad libitum):dry diet (Spratt’s Dog Diet P62, Spillers Ltd., Barking, Essex)
- Water (e.g. ad libitum):Water was freely available
- Acclimation period:
Route of administration:
oral: unspecified
Vehicle:
other: gelatine capsules
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
25 Weeks
Frequency of treatment:
Intermittent
Remarks:
Doses / Concentrations:
0,250 ,400 mg of pure clioquinol/kg of body weight/day.
Basis:

No. of animals per sex per dose:
Control:6 dogs

250 mg/kg bw/day:6 dogs

400 mg/kg bw/day:6 dogs
Control animals:
yes, concurrent vehicle
Details on study design:
Nine male and 9 female Beagles were allotted to 3 groups: group 1 received empty gelatine capsules and acted as control; group 2 was given 250 mg; and
group 3 400 mg of pure clioquinol/kg of body weight/day. The test compound was administered undiluted in gelatine capsules, daily for 25 weeks.
The dogs were housed singly and were initially offered 400 g of a dry diet each morning; 200 ml cows’ milk was offered, on week-days only, throughout the experiment.Water was freely available.

Observations and examinations performed and frequency:
Ophthalmoscopic examination revealed paleness of the optic papilla in one female dog receiving the high dosage. The pupillary light reflex was
found to be sluggish.

Haematological monitoring showed that the red cell counts tended to be lower in the dosed groups than in the controls. This was noted after 4 weeks
of administration of the test compound and persisted till the end of the study. The only other abnormality detected as a result of laboratory investigations that could have been attributable to treatment was a higher mean urinary creatine: creatinine ratio in the dosed groups than in control animals,
indicative of a disturbed muscle function. This was found after 12, 18, 20 and 22 weeks’ administration of the test compound, but after 24 weeks the
means were similar in all groups.

Macroscopic post-mortem examination revealed atrophy of the limb musculature in 3 females in group 3 that had survived the entire 25-week
treatment period; this muscle wasting was associated with general debility and attributed to treatment with the test compound.The absolute organ weights were considered to be within normal limits. However, in the dogs of groups 2 and 3, the mean liver weight expressed as a percentage of the body weight was significantly greater than the control values (P < 0.05), a not infrequent finding in toxicity studies .

Urineanalysis:urine samples were obtained for complete urine analysis, including examination of sediment

Histological changes were identified in the dorsal columns of the spinal cord in one dog receiving 250 mg/kg daily and in 4 dogs receiving 400mg/kg daily. In one of the dogs given the high dose the changes were present at various levels of the cord, whereas in the dog receiving 250 mg/kg daily
they were restricted to the cervical and thoracic regions, and in the 3 remaining high dose-level animals (two of which were the dogs killed on day 11
the cervical region only was affected. In these last-mentioned animals, the changes were minimal and located close to the nucleus gracilis of the medulla.

The lesions were of a dystrophic nature, probably acute in onset and werenot considered to be due to any ageing process. The morphological features included axonal swelling and degeneration, myelin breakdown with myelinophagia and occasional astrocyte activation (Figs. l-4). Similar changes,
including sxonal swelling, were seen in the optic nerve of one dog . Although the peripheral nerves and the spinal and autonomic ganglia
were examined thoroughly, no pathological changes were detected. Nor were any pathological changes detected in sections taken from the flexor muscleof the 5th digit and stained with Sudan black B . The myelin sheaths were preserved and the muscular motor and anulospiral endings were demonstrated.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)
The animals were killed and the organs examined macroscopically. The major organs were weighed, and pieces of these and other tissues were removed and prepared for histological examination.


HISTOPATHOLOGY: Yes (see table) / No / No data
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
abnormal gait with partial or complete hind limb paralysis, yellowing of the hair and patchy hair loss.
Mortality:
mortality observed, treatment-related
Description (incidence):
abnormal gait with partial or complete hind limb paralysis, yellowing of the hair and patchy hair loss.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Individual animals on 250 mg/kg daily showed episodes of depressed body weight gain and/or weight loss, alternating with periods of normal development.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
loss of appetite from the first week of dosing.
Ophthalmological findings:
effects observed, treatment-related
Description (incidence and severity):
Ophthalmoscopic examination revealed paleness of the optic papilla in one female dog receiving the high dosage. The pupillary light reflex was found to be sluggish
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Haematological monitoring showed that the red cell counts tended to be lower in the dosed groups than in the controls
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Neurological examination revealed disturbance of the placing and postural reactions in all the animals in group 3 and some in group 2.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The absolute organ weights were considered to be within normal limits.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Macroscopic post-mortem examination revealed atrophy of the limb musculature in 3 females in group 3 that had survived the entire 25-week treatment period;
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histological changes were identified in the dorsal columns of the spinal cord in one dog receiving 250 mg/kg daily and in 4 dogs receiving 400 mg/kg daily.
Dose descriptor:
LOEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: depressed body weight gain and/or weight loss,disturbance of the placing and postural reactions
Critical effects observed:
not specified
Conclusions:
The repeated dose toxicity LOEL (Low observed effect level ) of clioquinol was observed at a dose concentration of 250 mg/kg bw (total dose) in a 25 weeks study period .

Executive summary:

The study was conducted to test Clioquinol toxcity in dogs at a dose level of 0, 250, 400 mg of pure clioquinol/kg of body weight/day for 25 weeks. Individual animals on 250 mg/kg daily showed episodes of depressed body weight gain and/or weight loss, alternating with periods of normal development. Ophthalmoscopic examination revealed paleness of the optic papilla in one female dog receiving the high dosage. The pupillary light reflex was found to be sluggish.Histological changes were identified in the dorsal columns of the spinal cord in one dog receiving 250 mg/kg daily and in 4 dogs receiving 400 mg/kg daily. thus we can conclude that the repeated dose toxicity LOEL (Low observed effect level ) of clioquinol was observed at a dose concentration of 250 mg/kg bw (total dose) in a 25 weeks study period .

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
250 mg/kg bw/day
Study duration:
chronic
Species:
dog
Quality of whole database:
The data is K2 level as the data has been obtained from an experimental study from the journal " Toxicology" .Based upon this available data it is expected that this chemical clioquinol does not exhibit repeated dose oral toxicity to dog.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6
Qualifier:
according to guideline
Guideline:
other: Estimated data
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 2.3.
GLP compliance:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Route of administration:
inhalation: vapour
Type of inhalation exposure:
not specified
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
weekly 5
Control animals:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
body weight decrease
Dose descriptor:
LOEL
Effect level:
159.486 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Critical effects observed:
not specified
Organ:
not specified

The prediction was based on dataset comprised from the following descriptors: "effect LOEL"
Estimation method: Taking average value from the 5 nearest neighbours
Domain logical expression:Result: In Domain

(("a" or "b" or "c" or "d" or "e" or "f" ) and ("g" and "h" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Phenols (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Arene AND Aryl halide AND Heterocyclic fragment AND Phenol AND Pyridine(substituted) by Organic functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl AND Aryl halide AND Fused heterocyclic aromatic AND Phenol AND Pyridine AND Quinoline/ Isoquinoline by Organic Functional groups (extended)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aryl halide AND Heterocyclic fragment AND Phenol AND Pyridine(substituted) by Organic functional groups (nested)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aryl halide AND Overlapping groups AND Phenol AND Quinoline/ Isoquinoline by Organic Functional groups (nested)(extended)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Aromatic compound AND Aryl chloride AND Aryl halide AND Aryl iodide AND Halogen derivative AND Hydroxy compound AND Phenol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.61

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.64

Conclusions:
The repeated dose toxicity LOEL (Lowest observed effect level) of clioquinol to rat by the inhalation route was estimated at a dose concentration of 159.4855 mg/kg bw/day.On the basis of this LOEL value it is concluded that the test substance is not toxic to rat by the inhalative route below the above mentioned dose.
Executive summary:

The repeated dose toxicity LOEL (Lowest observed effect level) of clioquinol to rat by the inhalation route was estimated at a dose concentration of 159.4855 mg/kg bw/day.On the basis of this LOEL value it is concluded that the test substance is not toxic to rat by the inhalative route below the above mentioned dose.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
159.486
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is K2 level as the data has been obtained from QSAR model considered by OECD.

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

Additional information

Repeated dose toxicity (Oral)

For Repeated dose toxicity

 

Based on the various studies available with Klimish rating 2 for the target substances for CAS: 130-26-7.This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results is summarized as follows

 

Sr. No

End point

Value

Species

Route

Effects

Remarks

1

LOEL

536 mg/ kgbw/day

Rat

Oral

Histopathological findings were observed

Predicted data for target chemical

2

LOEL

250 mg/kg bw/d

Dog

Oral

depressed body weight gain and/or weight loss,disturbance of the placing and postural reactions

Publication data for target chemical

2

LOEL

200 mg/kg bw/d

Dog

Oral

myocardial degeneration,gross pathology

Publication data for target chemical

 

Based on the studies summarized in the above table with oral routes it can be observed that LOEL values varies from 200 - 536 mg/Kg bw/ d. The effects observed on the these doses was listed as follows

·        Histopathological findings were observed

·        depressed body weight gain and/or weight loss,disturbance of the placing and postural reactions.

·        myocardial degeneration,gross pathology

Thus based on above discussion it can be concluded that substance CAS: 130-26-7 is expected to show the stoxicological effect based on above effects.Since low effect dose value (LOAEL) is 200 mg/Kg bw/d which was also supported by the predicted LOEL value of 536 mg/kg bw/d, thus based on this value it can be concluded that substance CAS: 130-26-7 is considered to be not toxic to repeated dose via oral route for the above mentioned dose. Also there are no known evidence of adverse effect to Human of CAS: 130-26-7.

Repeated dose toxicity: inhalation

The repeated dose toxicity LOEL (Lowest observed effect level) of clioquinol to rat by the inhalation route was estimated at a dose concentration of 159.4855 mg/kg bw/day.On the basis of this LOEL value it is concluded that the test substance is not toxic to rat by the inhalative route below the above mentioned dose.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

The repeated dose toxicity LOEL  (Low observed effect level ) of clioquinol was observed at a dose concentration of 250 mg/kg bw (total dose) in a 25 weeks study period

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

The repeated dose toxicity LOEL (Lowest observed effect level) of clioquinol to rat by the inhalation route was estimated at a dose concentration of 159.4855 mg/kg bw/day.On the basis of this LOEL value it is concluded that the test substance is not toxic to rat by the inhalative route below  the above mentioned dose.

Justification for classification or non-classification

The substance clioquinol do not show repeated dose toxicity effect for oral and inhalation route and thus will not be considered for further classification.