CLIOQUINOL - cdn.azierta.cloudR. M. de Madrid, Tomo 24.326, Folio 172, Sección 8, Hoja M-437435....

CLIOQUINOL (IODOCHLORHYDROXYQUINOLINE)

PDE

DETERMINATION STRATEGY

VER. 1.0

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This report is valid for five years since the date of the assessment review data. “Reproduction or unauthorized distribution is strictly prohibited. The present document is licensed to a “single client” or organization, and

may not be re-sold, copied, or redistributed to other companies or organizations. The use by any company other than the one indicated in the watermark is prohibited. The Parties agree that, in the event of violation of this clause, without limiting the Disclosing Party´s other rights and remedies, the Disclosing Party shall be entitled to an injunction and other equitable relief, including but not limited to specific performance, against the Receiving Party for breaching or threatening to breach this Agreement”.

AZIERTA Contract Scientific support Consulting, S.L. R. M. de Madrid, Tomo 24.326, Folio 172, Sección 8, Hoja M-437435. CIF: B-85125334

Vía de las Dos Castillas 33, Edificio 7. 28224. Pozuelo de Alarcón | Madrid www.azierta.com | [email protected] | +34 912 771 076

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TABLE OF CONTENT

1. BASIC INFORMATION .................................................................................................. 3

2. HAZARDS IDENTIFIED ................................................................................................ 5

3. SUMMARY OF ASSESSMENT PROCESS (CALCULATION OF PDE VALUE) ............ 6

4. IDENTITY OF THE ACTIVE SUBSTANCE .................................................................... 9

5. OBJECTIVE AND SEARCH STRATEGY .................................................................... 11

6. INTRODUCTION ......................................................................................................... 12

7. HAZARD IDENTIFICATION ........................................................................................ 13

a. Pharmacodynamic data .......................................................................................... 13 b. Acute toxicity ........................................................................................................... 14 c. Repeated dose toxicity ............................................................................................ 15 d. Carcinogenicity ....................................................................................................... 17 e. In vitro / in vivo genotoxicity studies ........................................................................ 17 f. Reproductive and developmental toxicity ................................................................. 17 g. Other studies .......................................................................................................... 19

8. IDENTIFICATION OF CRITICAL EFFECTS ................................................................ 19

a. Most sensitive indicator of an adverse effect seen in non-clinical toxicity data ..... 20 b. Clinical therapeutic and adverse effects ............................................................... 20

9. RATIONALE FOR NOAEL VALUES SELECTION ....................................................... 21

10. APPLICATION OF ADJUSTMENT FACTORS (rationale for the adjustment factors) . 22

a. F1: Interspecies differences ................................................................................. 22 b. F2: Inter-individual differences ................................................................................ 22 c. F3: Duration of exposure ......................................................................................... 22 d. F4: Nature of toxicity ............................................................................................... 23 e. F5: Quality of data................................................................................................... 23

11. PK CORRECTION..................................................................................................... 24

12. REFERENCES .......................................................................................................... 25

13. EXPIRATION DATE: RISK ASSESSMENT ............................................................... 27

ANNEX 1: PHARMACOKINETICS AND METABOLISM .................................................. 28

ANNEX 2: GLOSSARY ................................................................................................... 29

ANNEX 3. SUMMARY OF THE EXPERT CV .................................................................. 35

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1. BASIC INFORMATION

Company name: oooooooooooooooooo

Company Address:

Adress

Adress Adress Adress Adress

Adress Adress

Expert name: N00000000000000a

Signature:

Version: 1.0

Date: 24/03/2020

Assessment review data: March 2020

Expiration date: March 2025

Chemical name: 5-chloro-7-iodoquinolin-8-ol

Drug Product: Clioquinol (iodochlorhydroxyquinoline) (oral,

topical)






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REVISION

NUM.

(version)

TITLE APPROVAL

DATE REVISION DESCRIPTION

01 (1.0)

Clioquinol

(iodochlorhydroxyquinoline)

(oral, topical): PDE

determination strategy.

March 2020 First issue






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2. HAZARDS IDENTIFIED

Yes No Unknown

Genotoxicant X X X

Reproductive developmental

toxicant X X X

Carcinogen X X X

Highly sensitizing potential

X X X

*Negative an antibacterial agent, prescribed for dermatophytosis, mycosis barbae,

seborrhoeic dermatitis, infected eczema, furunculosis

**No an antibacterial agent, prescribed for dermatophytosis, mycosis barbae,

seborrhoeic dermatitis, infected eczema, furunculosis

*** an antibacterial agent,






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3. SUMMARY OF ASSESSMENT PROCESS (CALCULATION OF PDE VALUE)

PDE value (oral, topical) 0.000 mg/day

HAZARD IDENTIFICATION

Pharmacodynamic data

Clioquinol is a broad-spectrum antibacterial with antifungal properties. Application of clioquinol to extensive or eroded areas of the skin may lead to increased protein-bound iodine (PBI) levels within 1 week.

Acute toxicity Acute toxicity values for clioquinol were summarized in table 1.

Repeat-dose toxicity

Repeated dose (oral) toxicity studies were conducted in rats (12, 28,42, 91 days) and mice (91 days) for clioquinol. The effects observed in rats were hyperplasia/ thickening epithelium, Increased severities of extramedullary hemopoiesis, characterized as essentially erythropoiesis, decrease in hematocrit in females. Renal effects were seen in both species.

Carcinogenicity

Clioquinol (iodochlorhydroxyquinoline) is not listed as carcinogen by the IARC.

No carcinogenicity studies were reported for clioquinol (iodochlorhydroxyquinoline) in the available literature.

“In vitro”/”in vivo” genotoxicity studies

Negative results were obtained form in vitro genotoxicity study (Ames test). However, there were no in vivo






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genotoxicity studies conducted for clioquinol (iodochlorhydroxyquinoline) reported in the available literature.

Reproductive/developmental toxicity

Several reproductive and developmental studies conducted in rats revealed no teratogenic, embryotoxic or impairment of fertility for clioquinol.

IDENTIFICATION OF CRITICAL EFFECTS

Most sensitive indicator of an adverse effect seen in non-clinical toxicity

data

In conclusion, based on the information available, renal effects could be considered the main critical effects as they were observed in both species (mice and rats) in the longest duration studies.

Clinical therapeutic and adverse effects

Iodochlorhydroxyquinoline is an antibacterial agent, prescribed for dermatophytosis, mycosis barbae, seborrhoeic dermatitis, infected eczema, furunculosis and pityriasis versicolor (athlete’s foot). Blistering, itching, redness, peeling, dryness, allergic skin rashes and presence of other signs of hypersensitivity were seen as adverse effects.

Point of departure 000mg/kg/day






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APPLICATION OF ADJUSTMENT FACTORS

F1: Extrapolation between species (2-12)

A factor (values between 2 and 12) to account for extrapolation between

species to human.

This factor takes into account the comparative surface area: body

weight ratios for the species concerned and for man

F2: Inter-individual variability (10) A value of F2= 10 is conventionally used to allow for differences between individuals in the human population.

F3: Toxicological study chronic or acute (1-10). Not included

genotoxicity, carcinogenicity, neurotoxicity and teratogenicity

This factor varies depending on the length of the study from which the point of departure has been selected

F4: For severe toxicity (1-10)

A variable factor is applied considering the potential intrinsic toxicity of the molecule within the studies.

It may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity

F5: NOAEL vs LOAEL

(10 if LOAEL)

A variable factor, up to 10, applied to results in which a NOAEL/NOAEL has not been established, the PDE being

derived from a LOAEL

PK CORRECTION xxxxxxxxxx






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4. IDENTITY OF THE ACTIVE SUBSTANCE

Clioquinol (iodochlorhydroxyquinoline)

Synonyms: 5-21-03-00294 (Beilstein Handbook Reference), 5-Chlor-7-jod-8-hydroxy-

chinolin, 5-Chlor-7-jod-8-hydroxy-chinolin [German], 5-Chloro-7-iodo-8-

hydroxyquinoline, 5-Chloro-7-iodo-8-quinolinol, 5-Chloro-8-hydroxy-7-iodoquinoline, 7-

Iodo-5-chloro-8-hydroxyquinoline, 7-Iodo-5-chloroxine, AI3-16451, Ala-Quin, Alchloquin,

Alioform, Amebil, Amoenol, Bactol, Barquinol, BRN 0153637, Budoform, Caswell No.

193, CCRIS 6050, Chinoform, Chinoformum, Chloro-8-hydroxyiodoquinoline,

Chloroiodoquin, Chloroiodoquine, Chlorojodochin, Cifoform, Cliochinolo, Cliochinolo

[DCIT], Cliochinolum, Clioquinol, Clioquinolum, Clioquinolum [INN-Latin], Cliquinol,

Corque, Cort-Quin, Cortin, Cremo-quin, Dermaform, Dioquinol, Domeform, Domeform-

HC, EC 204-984-4, Eczecidin, EINECS 204-984-4, Emaform, Enteritan, Entero-bio form,

Entero-Bioform, Entero-vioform, Entero-Vioformio, Enteroquinol, Enteroseptol,

Enterovalodon, Enterozol, Enterseptol, Enterum locorten, Entrokin, EPA Pesticide

Chemical Code 024001, HI-Enterol, HSDB 6843, Hydriodide-enterol, Hysone,

Iodenterol, Iodochlorhydroxyquin, Iodochlorhydroxyquin Cream,

Iodochlorhydroxyquinol, Iodochlorhydroxyquinoline, Iodochlorohydroxyquin,

Iodochlorohydroxyquinoline, Iodochloroquine, Iodochloroxine, Iodochloroxychinolinum,

Iodochloroxyquinoline, Iodoenterol, Iodoxyquinoline, Jodchloroxychinolinum, Lekosept,

Mycoquin, Nioform, NSC 3531, NSC 74938, Oralcer, Quin-O-Crème, Quinambicide,

Quinoform, Quinoform (antiseptic), Quinoform (VAN), Quinoline, chloro-8-hydroxyiodo-,

Rheaform, Rheaform Boluses, Rheaform Boluses (Veterinary), Rometin, UAD Lotion,

UNII-7BHQ856EJ5, Vioform, Vioform N.N.R., Vioform-Hydrocortisone, Vioform-

Hydrocortisone Mild.

Chemical Abstracts Service (CAS) Registry Number: 130-26-7.

Chemical Description and Physical Properties: log P (octanol-water): 3.470, Atmospheric

OH Rate Constant: 1.06E-11 cm3/molecule-sec.

Molecular formula: C9-H5-Cl-I-N-O.

Molecular weight: 305.4975 g/mol.

Melting point: 178.5 ºC.






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Figure 1. Structure of clioquinol (iodochlorhydroxyquinoline) (ChemIDPlus, 2020)






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5. OBJECTIVE AND SEARCH STRATEGY

In accordance with the “Guideline on setting health based exposure limits for use in risk

identification in the manufacture of different medicinal products in shared facilities”

(EMA/CHMP/CVMP/SWP/169430/2012) the determination of health based exposure

limits for a residual active substance is based on the calculation of the Permitted Daily

Exposure (PDE). Determination of a PDE involves (i) hazard identification by reviewing

all relevant data, (ii) identification of “critical effects”, (iii) determination of the no-

observed-adverse-effect level (NOAEL) of the findings that are considered to be critical

effects, and (iv) use of several adjustment factors to account for various uncertainties.

The NOAEL/NOEL/LOAEL/LOEL value has been used to calculate a PDE in this study.

It is the purpose of this document to provide a brief summary of the scientific information

relative to clioquinol (iodochlorhydroxyquinoline) compound.

With this aim, several pharmaceutical and medical databases were scanned to reduce

the risk of some reports missing. They include databases such as Pubmed, PubChem,

Toxline, Drugdex, RTECS (Registry of Toxic Effects of Chemical Substances), NTP

(National Toxicology Programm), CPDB (Carcinogenic Potency Database),

Classification by the monograph of IARC (monograph on the evaluation of carcinogenic

risk to human, International Agency for Research on Cancer monograph), DART

(Development and Reproductive Database), HSDB (Hazardous Substance Data Bank)

and data from medical agencies such as AEMPS (Agencia Española de Medicamentos

y Productos Sanitarios), CIMA (Centro de Información on-line de medicamentos), EMA

(European Medicinal Agency), FDA (Food and Drug Administration) and ECHA

(European Chemical Agency). In addition, the reference book Goodman and Gilman

(2006) was also consulted. The searched terms were “clioquinol” and

”iodochlorhydroxyquinoline”.






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13. EXPIRATION DATE: RISK ASSESSMENT

A risk assessment has been performed following the ICHQ9 “Quality Risk Management”

to establish the expiration periods for the PDE reports considering the associated risk.

The criteria for the assessment are described below:

Risk Factor Value Characteristics

EMA List of medicines under

additional monitoring

EMA/245297/2013 Rev.75

1 Not present

2 Present*

PDE value

1 Higher than 1µg/day

2 Equal/Lower than 1µg/day

2 PDE = TTC

*The substance appears in the EMA list (EMA/245297/2013 Rev.75) alone or in combination.

RPN = 1 (not listed in EMA/245297/2013 Rev.75) + 1 (PDE higher than 1 µg/day) = 2

Considering these criteria, the Risk Priority Number (RPN), which establishes the

expiration date for each document, is calculated as follows:

Risk Assessment

Low (2) Expired in 5 years

High (3-4) Expired in 3 years

As RPN = 2, expiration date 5 years.


CLIOQUINOL - cdn.azierta.cloudR. M. de Madrid, Tomo 24.326, Folio 172, Sección 8, Hoja M-437435....

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