Clioquinol

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

other: Predicted data

Title:

536 mg/kg/day; Estimation for effect LOEL for CAS 130-26-7

Author:

Sustainability Support Services (Europe) AB

Year:

2014

Bibliographic source:

SSS QSAR Prediction Team

Materials and methods

Test guideline

Guideline:

other: NTP long-term;OECD TG 422;OECD TG 407

Principles of method if other than guideline:

Prediction using category approach; QSAR Toolbox 3.1; Read Across; 5 nearest analogues; Log Kow as descriptor

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Clioquinol

EC Number:

204-984-4

EC Name:

Clioquinol

Cas Number:

130-26-7

Molecular formula:

C9H5ClINO

IUPAC Name:

5-chloro-7-iodoquinolin-8-ol

Details on test material:

SMILES:c1(I)c(O)c2c(c(Cl)c1)cccn2

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Administration / exposure

Route of administration:

oral: gavage

Duration of treatment / exposure:

42 days

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

changes were observed

Effect levels

Dose descriptor:

LOEL

Effect level:

536 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Histopathological findings were observed

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

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

((((((("a" or "b" or "c" or "d" or "e" or "f" or "g" )  and ("h" and ( not "i") )  )  and "j" )  and ("k" and ( not "l") )  )  and "m" )  and ("n" and ( not "o") )  )  and ("p" and "q" )  )

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 Aromatic heterocyclic halide AND Aryl AND Aryl halide AND Fused carbocyclic aromatic AND Fused heterocyclic aromatic AND Phenol AND Pyridine AND Quinoline/ Isoquinoline by Organic functional groups

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alcohol, olefinic attach [-OH] AND Aromatic Carbon [C] AND Aromatic Nitrogen AND Chlorine, aromatic attach [-Cl] AND Chlorine, olefinic attach [-Cl] AND Hydroxy, aromatic attach [-OH] AND Iodide, aromatic attach [-I] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "e"

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: "f"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At AND Group 17 - Halogens I by Chemical elements

Domain logical expression index: "g"

Similarity boundary:Target: c1(I)c(O)c2c(c(Cl)c1)cccn2
Threshold=50%,
Dice(Atom centered fragments)

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.1

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acyl transfer via nucleophilic addition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates and isothiocyanates OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Acyl azides OR Acylation >> Direct acylation involving a leaving group >> Acyl halide of carboxylic acids OR Acylation >> Direct acylation involving a leaving group >> Carbamates OR Acylation >> Direct acylation involving a leaving group >> N-acylamides OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl azides OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl halides OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ester aminolysis >> Dithioesters OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated alkyl or aryl esters OR Acylation >> Ester aminolysis or thiolysis >> Diarylesters OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents OR Ionic OR Ionic >> Electrostatic interaction of tetraalkylammonium ions with protein carboxylates OR Ionic >> Electrostatic interaction of tetraalkylammonium ions with protein carboxylates >> Tetraalkylammonium ions OR Michael addition OR Michael addition >> a,b-unsaturated carbonyl compounds OR Michael addition >> a,b-unsaturated carbonyl compounds >> a,b-unsatuarted aldehydes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-carbonyl compounds with polarized double bonds OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Nitroalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Vinyl sulfonyl compounds OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes >> Activated electrophilic ethenylarenes OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes >> Vinyl pyridines OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Naphtoquinone and naphtoquinone imines OR Michael addition >> Quinone type compounds >> Quinone (di)imines OR Michael addition >> Quinone type compounds >> Quinone methides OR Michael addition >> Quinone type compounds >> Quinones OR Nucleophilic addition OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond >> Ketones OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond >> Thiocyanates OR Nucleophilic addition >> Nucleophilic addition at polarized N-functional double bond OR Nucleophilic addition >> Nucleophilic addition at polarized N-functional double bond >> C-Nitroso compounds OR Radical OR Radical >> Free radical formation OR Radical >> Free radical formation >> Organic peroxy compounds OR Schiff base formation OR Schiff base formation >> Nucleophilic cycloaddition to diketones OR Schiff base formation >> Nucleophilic cycloaddition to diketones >> Diketones OR Schiff base formation >> Pyrazolones and pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and pyrazolidinones derivatives >> Pyrazolones and pyrazolidinones OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SN1 OR SN1 >> Nucleophilic substitution (SN1) on alkyl (aryl) mercury cations OR SN1 >> Nucleophilic substitution (SN1) on alkyl (aryl) mercury cations >> Mercury compounds OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Activated alkyl esters OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-activated haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Phosphonates OR SN2 >> Nucleophilic substitution on benzylic carbon atom OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> alpha-activated benzyls OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> Benzylic esters OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides >> Heterocyclic sulfenamides OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated halogens OR SNAr >> Nucleophilic aromatic substitution on activated halogens >> Activated haloarenes by Protein binding by OASIS v1.1

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Very fast by Bioaccumulation - metabolism half-lives

Domain logical expression index: "k"

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: "l"

Referential boundary: The target chemical should be classified as 1,2-aminoalcohol OR 1,2-diol OR 1,2-diphenol OR Acetal OR Alcohol OR Alkyl chloride OR Alkyl fluoride OR Alkyl halide OR Alkylarylether OR Alkyne OR Alpha-aminoacid OR Alpha-hydroxyacid OR Amine OR Anion OR Aryl bromide OR Aryl fluoride OR Azide OR Azo compound OR Boronic acid OR Boronic acid derivative OR Carbonic acid derivative OR Carbonyl compound OR Carboxylic acid OR Carboxylic acid amide OR Carboxylic acid amidine OR Carboxylic acid derivative OR Carboxylic acid ester OR Carboxylic acid hydrazine OR Carboxylic acid prim. amide OR Carboxylic acid salt OR Carboxylic acid sec. amide OR Carboxylic acid tert. amide OR Cation OR CO2 derivative (general) OR Dialkylether OR Diarylether OR Ether OR Hemiacetal OR Heterocyclic compound OR Hydrazine derivative OR Hydroxamic acid OR Hydroxylamine OR Imine OR Ketone OR Lactam OR Lactone OR Nitrile OR Nitro compound OR No functional group found OR N-oxide OR Organometallic compound OR Oxime OR Oxime ether OR Phosphonic acid OR Phosphonic acid derivative OR Phosphonic acid ester OR Phosphoric acid derivative OR Phosphoric acid ester OR Primary alcohol OR Primary aliphatic amine OR Primary amine OR Primary aromatic amine OR Quaternary ammonium salt OR Secondary alcohol OR Secondary aliphatic amine OR Secondary amine OR Secondary aromatic amine OR Secondary mixed amine (aryl, alkyl) OR Semicarbazone OR Sufoxide OR Sulfenic acid derivative OR Sulfinic acid derivative OR Sulfonamide OR Sulfone OR Sulfonic acid OR Sulfonic acid derivative OR Sulfonic acid ester OR Sulfuric acid OR Sulfuric acid derivative OR Sulfuric acid monoester OR Tertiary alcohol OR Tertiary aliphatic amine OR Tertiary amine OR Tertiary mixed amine OR Thiocarbonic acid derivative OR Thiocarboxylic acid amide OR Thiocarboxylic acid derivative OR Thioether OR Thiosemicarbazone by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "m"

Similarity boundary:Target: c1(I)c(O)c2c(c(Cl)c1)cccn2
Threshold=20%,
Dice(Atom centered fragments)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as No alert found by rtER Expert System ver.1 - USEPA

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Alkylphenols OR Mixed Phenols by rtER Expert System ver.1 - USEPA

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.04

Applicant's summary and conclusion

Conclusions:

The LOEL (low observed effect level ) value of Clioquinol in rats was observed at a dose level of 536 mg/kg body weight/day.

Executive summary:

WoE Summary for Cas: 130-26-7

 

The NOAEL value of clioquinolisestimated to be 536 mg/kg bw/day (nominal) for duration of 42 days on rat using the toolbox version 3.2.

The data is estimated to be based on the data summarized below

Sr no.	CAS no	End point	Value	Species	Doses	Duration	Effects	Remarks
1	527-60-6	LOEL	60 mg/kg bw/day	Rat	NA	42 days	Hyperplasia/Thickneing epithelium
2	2416-94-6	LOAEL	13500 mg/kg bw/day (actual dose received)	Rat	55, 273, 1346 mg/kg bw/d	28 days	Decrease in hematocrit in females
	2416-94-6	LOAEL	273 mg/kg bw/day (actual dose received)	Rat	55, 273, 1346 mg/kg bw/d	28 days	Decrease in hematocrit in females
3	136-77-6	NOEL	62.5 mg/kg/day	Mouse	0,62.5, 125,250,500, 1000 mg/kg/da	91 days	Renal effects
	136-77-6	LOEL	125 mg/kg/day	Mouse	0,62.5, 125,250,500, 1000 mg/kg/da	91 days	Renal effects
	136-77-6	LOEL	500 mg/kg/day	Rat	0,62.5, 125,250,500, 1000 mg/kg/da	91 days	Renal effects
4	700-13-0	LOAEL	400 mg/kg bw/day (nominal)	Rat	45, 125, 400 mg/kg bw/d	28 days	increased severities of extramedullary haemopoiesis, characterised as essentially erythropoiesis
5	576-26-1	Study LOEL	184 mg/kg/day	Rat	0.00, 67.00, 200.00, 670.00	14 days	-
	576-26-1	Study LOEL	100 mg/kg/day	Rat	0.00, 67.00, 200.00, 670.00	28 days	Mortality

 

The above table consist of various repeated dose (oral) toxicity studies available for the read across substances for CAS: 130-26-7.Based on the above results it can be observed that LOAEL or LOEL values are in the range of 60 – 1350 mg/kg bw./day for rat & mouse and NOEl value was found to be 62.5 mg/kg/day for mouse . The effects observed on the above doses are listed as follows.

·        Hyperplasia/Thickneing epithelium

·        increased severities of extramedullary haemopoiesis, characterised as essentially erythropoiesis

·        Renal effects.

·        Decrease in hematocrit in females

Thus based on above discussion it can be concluded that toxicity of the target chemical (536 mg/kg/day) is predicted from category members using read-across based on 5 values within the range 60 – 1350 mg/kg/day in sub-acute duration for rat from 5 nearest neighbors compared by prediction descriptors.