Clioquinol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Remarks:

based on generations indicated in Effect levels (migrated information)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Qualifier:

according to guideline

Guideline:

other: Effects of chinoform on pre- and post-natal development of rats at a dose level of

Principles of method if other than guideline:

Effects of chinoform on pre- and post-natal development of rats at a dose level of

GLP compliance:

not specified

Justification for study design:

not specified

Species:

rat

Strain:

not specified

Sex:

female

Route of administration:

oral: unspecified

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

30 day(s) pre-mating

Remarks:

Doses / Concentrations:
0,120, 300,and 750 mg/kg
Basis:

Control animals:

yes

Parental animals: Observations and examinations:

Pregnant rats treated with 120, 300,and 750 mg chinoform /kg showed decreased body wt. gains, decreased food-intake, and decreased water-intake at the beginning of administration. The body wts. of the mother rats treated with I were lower than those of the control group after delivery

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Changes observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Changes observed

Dose descriptor:

LOEL

Effect level:

120 other: mg/kg

Based on:

test mat.

Sex:

female

Basis for effect level:

other: decreased body wt. gains

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Dose descriptor:

LOEL

Generation:

F1

Effect level:

120 other: mg/kg

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: decreased body wt. gains, retardation of ossification

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Reproductive effects observed:

not specified

Conclusions:

The LOEL (low observed effect level ) of clioquinol in rats was observed at a dose level of 120 mg/kg/d

Executive summary:

Pregnant rats treated with 120, 300 or 750 mg chinoform/kg showed decreased body weight gains, decreased food-intake, and decreased water-intake at the beginning of administration. Body weights of the mother rats treated with chinoform were lower than those of the control group after delivery. The body weights of the fetuses from treated rats were lower than those of the fetuses of the control group. The retardation of ossification was observed in the 5th sternebra, proximal phalanx, and caudal vertebrae when chinoform was given at 300 and 750 mg/kg. The body weights of the offspring at birth were lower than those of the control. Thus we can conclude, that the maternal and developmental toxicity LOEL (lowest observed effect level) of chinoform in Pregnant rats was observed at a dose level of 120 mg/kg.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

451.71 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The data is K2 level as the data has been obtained from QSAR model considered by OECD.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction

The two generation reproductive toxicity LOEL (Lowest observed effect level) of clioquinol in rat was observed at a dose concentration of 451.7103 mg/kg bw/day.On the basis of this LOEL value it indicates that clioquinol does not exhibit toxic effects to rat below the above mentioned dose.

Short description of key information:

Study indicates that clioquinol does not exhibit reprotoxic effects to rat .

Justification for selection of Effect on fertility via oral route:

The two generation reproductive toxicity LOEL (Lowest observed effect level) of clioquinol in rat was observed at a dose concentration of 451.7103 mg/kg bw/day.On the basis of this LOEL value it indicates that clioquinol does not exhibit toxic effects to rat below the above mention dose.

Effects on developmental toxicity

Description of key information

Study indicates that clioquinol does not exhibit toxic developmental effects to rat.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Principles of method if other than guideline:

Clioquinol toxcity by repeated administration to Neonatal Rats

GLP compliance:

not specified

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Housing:housed together
- Diet (e.g. ad libitum):(NMF, Oriental Yeast Co., Tokyo)
- Water (e.g. ad libitum):(NMF, Oriental Yeast Co.,Tokyo)
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):22-26 oC

Route of administration:

subcutaneous

Vehicle:

other: 40% polysorbate 80 aqueous solu- tion

Details on exposure:

The same uterine rats were divided into 2 groups. One was the clioquinol-treated group, to which the clioquinol suspension was administered subcutaneously fixed dose of 150 mg/kg/d or an increasing dose of clioquinol, which was 150 mg/kg/d from 1 to 5 d, 300 mg/kg/d from 6 to 10 d and 600 mg/kg/d from 11 to 14 d of clioquinol, was given once a day for 14 d after birth.

Details on mating procedure:

spermatozoa were observed in the vaginal smear was designated as day 1 of pregnancy

Duration of treatment / exposure:

14days

Frequency of treatment:

once a day

Remarks:

Doses / Concentrations:
0, 120, 300 or 750 mg/kg
Basis:

No. of animals per sex per dose:

no data

Control animals:

other: Yes, untreated animals

Details on study design:

A clioquinol suspension prepared with 40/o polysorbate 80 aqueous solu- tion according to the method described previ- ously4) was administered subcutaneously in the backs of S- and R-rats once a day from 1 d after birth for 14 d. In all experiments, the dosing volume was 4.2 1/g body weight.d.The body weights of rats were measured every day before the administration.

Maternal examinations:

-The body weights of rats were measured every day before the administration.
-The body weight of the clioquinol-treated rats was severely sup- pressed and the body weight of surviving S-rats increased from 6.0 ::l::: 0.3 to I 1.2 ::::t::: 2.1 g in the same period
-Thus, increasing doses of clioquinol were ad-ministered in order to induce ataxia. Only one of ten R-rats developed ataxia at 11 d after administration, whereas out of eleven S-rats, one rat developed ataxia at 9 d, another at 10 d, and a third at 12 d after the administration.
-The lipid peroxide concentrations in the liver, kidney, brain, spinal cord and plasma of the clioquinol-treated rats were not significantly different from those of the untreated rats

Statistics:

Student's t- test;p > 0.05)

Historical control data:

These rats were sacrificed by drawing blood via cardiac puncture with a mi-crosyringe at 5, 10 and 15 d after the administra-tion

Details on maternal toxic effects:

Maternal toxic effects:yes

Dose descriptor:

LOEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

not specified

Description (incidence and severity):

not specified

Dose descriptor:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

other: not specified

Description (incidence and severity):

not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Conclusions:

The developmental toxicity LOEL (lowest observed effect level ) of chinoform (Clioquinol) in Pregnant rats was observed at a dose level of 120 mg/kg.

Executive summary:

Pregnant rats treated with 120, 300 or 750 mg chinoform/kg showed decreased body weight gains, decreased food-intake, and decreased water-intake at the beginning of administration. Body weights of the mother rats treated with chinoform were lower than those of the control group after delivery. The body weights of the fetuses from treated rats were lower than those of the fetuses of the control group. The retardation of ossification was observed in the 5th sternebra, proximal phalanx, and caudal vertebrae when chinoform was given at 300 and 750 mg/kg. The body weights of the offspring at birth were lower than those of the control.

Thus we can conclude, that the developmental toxicity LOEL (lowest observed effect level) of chinoform in Pregnant rats was observed at a dose level of 120 mg/kg.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The data is K2 level

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

WoE Summary of 130-26-7 for developmental toxicity

Based on the various studies available with Klimish rating 2 for the target substance 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
2	LOEL (Developmental toxcity)	237 mg/Kg bw/day	Mouse	oral	Reduced fetal body weights were identified at maternally toxic doses.	Predicted data for target chemical
	LOEL (Developmental toxcity)	300 mg/kg	Rat	subcutaneous	increasing level of lipid peroxide concentrations in plasma, liver, kidney, brain ,body weight	Publication data for target Cas
3	LOEL (Fetotoxcity )	120 mg/kg bw/d	Rat	Oral	Effects on Embryo or Fetus were observed Effects on Newborn - weaning or lactation index	Publication data for target Cas

Based on the studies summarized in the above table with oral route it can be observed that the LOAEL values varies from 120- 300 mg/Kg bw/d.The effects observed on the higher doses was listed as follows.

·        Reduced fetal body weights were identified at maternally toxic doses.

·        increasing level of lipid peroxide concentrations in plasma, liver, kidney, brain ,body weight

·        Effects on Embryo or Fetus were observed

·        Effects on Newborn - weaning or lactation index 

Thus based on above discussion it can be concluded that substance CAS: 130-26-7 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the low observed effect dose value (LOEL) is 120 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 Developmental toxicity as well as developmental effects at above mentioned dose. Also there are no known evidence of adverse effect on reproduction to Human of CAS: 130-26-7

Justification for selection of Effect on developmental toxicity: via oral route:

The LOEL (low observed effect level ) of clioquinol in rats was observed at a dose level of 300 mg/kg/d

Justification for classification or non-classification

The chemical clioquinol does not exhibit toxicity to the reproductive system within the doses mentioned in the study end points.