Quinine

Endpoint summary

Description of key information

For quinine hydrochloride a no effect level of 60 mg/kg per day was defined.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study is not done according to OECD guideline. But it is a well documented study.

Qualifier:

no guideline followed

Principles of method if other than guideline:

First 13-week rat study:Quinine hydrochloride admixed with the diet was fed to 6 groups of 20 male and 20 female Sprague-Dawley rats at dosage levels of 0, 1, 10, 40, 100 or 200 mg/kg per day. The diet used was Spratt's Laboratory Animal Diet No. 2. Treatment was for 13 weeks with 5 males and 5 females from each group maintained on untreated diet for a further 6-week withdrawal period. The rats were housed in suspended metal cages in groups of 5. The room temperature was maintained at 20 +- 2°C and the relative humidity was 50% (+- 5%). A 12-h light/dark schedule was maintained. Clinical signs and food and water consumption were monitored throughout the study. Body weight was determined weekly. Ophthalmoscopic examinations were carried out after 4 and 12 weeks of compound administration, with haematological and biochemical examinations at the same time intervals. The examinations comprised estimations of packed cell volume, haemoglobin, erythrocyte count, total and differential leukocyte count, platelet count and thrombotest, plasma urea, glucose, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, sodium, potassium, chloride, calcium, inorganic phosphorus, creatinine and cholesterol. Post-mortem examinations included weighing of adrenals, brain, heart, kidney, liver, thyroid, pituitary, spleen, testes or ovaries and uterus and a wide range of tissues was prepared for routine histological examination.Second 13-week rat study:A second 13-week study was conducted in Sprague-Dawley rats in order to define more accurately the no-effect level. In this study 4 groups of 20 male and 20 female rats received quinine hydrochloride by dietary admixture at dose levels of 0, 60, 85 or 120 mg/kg per day. Treatment was for 13 weeks with 5 males and 5 females of each group maintained on untreated diet for a further 6 week withdrawal period. The animal management was as for the first studyOtotoxicity study:An assessment of possible ototoxic effects was also made in Sprague-Dawley rats following a 13-week treatment period at dietary intakes of 0, 85 and 200 mg/kg per day. Investigations of hearing thresholds were made using the pre-stimulus startle test method and electrocochleography.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Housing: metal cages in groups of 5- Diet (e.g. ad libitum): The diet used was Spratt's Laboratory Animal Diet No. 2.ENVIRONMENTAL CONDITIONS- Temperature (°C): 20 +- 2°C- Humidity (%): 50% (+- 5%)- Photoperiod (hrs dark / hrs light): 12-h light/dark schedule

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

First 13-week rat study: dosage levels of 0, 1, 10, 40, 100 or 200 mg/kg per daySecond 13-week rat study: dose levels of 0, 60, 85 or 120 mg/kg per dayOtotoxicity study: 0, 85 and 200 mg/kg per day

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:0, 1, 10, 40, 100 or 200 mg/kg per dayBasis:nominal in diet

Remarks:

Doses / Concentrations:0, 60, 85 or 120 mg/kg per dayBasis:nominal in diet

Remarks:

Doses / Concentrations:0, 85 and 200 mg/kg per dayBasis:nominal in diet

No. of animals per sex per dose:

5 males and 5 females of each concentration

Control animals:

yes

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: throughout the studyBODY WEIGHT: Yes - Time schedule for examinations: weeklyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes - Time schedule for examinations: throughout the studyWATER CONSUMPTION AND COMPOUND INTAKE: Yes - Time schedule for examinations: throughout the studyOPHTHALMOSCOPIC EXAMINATION: Yes - Time schedule for examinations: after 4 and 12 weeks of compound administrationHAEMATOLOGY: Yes - Time schedule for collection of blood: 4 and 12 weeks of compound administrationBIOCHEMIACL EXAMINATIONS: Yes - Time schedule for collection of blood: 4 and 12 weeks of compound administrationURINALYSIS: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table)

Clinical signs:

no effects observed

Description (incidence and severity):

no deaths

Mortality:

no mortality observed

Description (incidence):

no deaths

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

less weight than the controls

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

significantly lower than the control intakes.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

impairment

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

no effect on water intake

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No treatment-related findings were observed in the eyes

Haematological findings:

no effects observed

Description (incidence and severity):

no effect on the haematological parameters

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Higher phosphorus levels were recorded

Urinalysis findings:

no effects observed

Description (incidence and severity):

no treatment-related findings

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

not treatment-related effects on the weights of the organs

Gross pathological findings:

no effects observed

Description (incidence and severity):

no macroscopic abnormalities

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

In the first 13-week study there were no deaths that could be attributed to treatment or other signs of reaction. Rats receiving 200 or 100 mg/kg per day gained significantly less weight than the controls. Food intakes recorded for rats receiving 200 mg/kg per day were significantly lower than the control intakes. An impairment of efficiency of food utilization was recorded in the rats receiving 200 mg/kg per day. There was no effect on water intake. Laboratory investigations showed slightly elevated plasma urea levels in animals receiving 200 mg/kg per day and in males receiving 100 mg/kg per day. Higher phosphorus levels were recorded in females receiving 40 mg/kg per day and above. The albumin levels recorded for females receiving 200 mg/kg per day were slightly lower than those found in the control animals and lower total protein and globulin levels were recorded at week 12 for females receiving 200 or 100 mg/kg per day. No eye findings were made and hearing function was not impaired. Terminal studies showed no macroscopic abnormalities and organ weight analysis did not show any treatment-related effects on the weights of the organs examined. Morphological change was found in the livers of females receiving 200 or 100 mg/kg per day killed after 13 weeks. This showed as an increased incidence of moderate and/or marked periportal glycogen depletion. A no effect level of 40 mg/kg per day was defined.In the second 13-week study no deaths were recorded. There was suppression of body weight gain in males and females receiving 120 or 85 mg/kg per day and this was associated with lower food consumption. No treatment-related findings were observed in the eyes. There was no effect on the haematological parameters measured. Elevated phosphorus levels were found in female rats receiving 120 mg/kg per day, and these elevated levels tended to persist during the recovery phase Urinalysis did not reveal any treatment-related findings. The terminal studies showed the kidney weights of males receiving 85 or 120 mg/kg per day to be minimally greater than those of the controls. No morphological change was found in the kidneys that could account for this increase in size. No liver pathology was recorded. A no effect level of 60 mg/kg per day was defined. The kidney is identified as a potential target organ at high dose levels. In the ototoxicity study all animals showed good hearing sensitivity across the sound frequency range from 2.5 to 30 kHz and no treatment-related histopathological lesions were detected.

Dose descriptor:

NOEL

Effect level:

ca. 40 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: First 13-week rat study:based on decreased body weight and food consumption

Dose descriptor:

NOEL

Effect level:

ca. 60 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Second 13-week rat study:based on decreased body weight and food consumption

Critical effects observed:

not specified

Conclusions:

For quinine hydrochloride a no effect level of 60 mg/kg per day was defined.

Executive summary:

The subchronic study (13-week study) on rats, was published by Colley et al., 1989. In the toxicity studies, no deaths were recorded and there were no effects on water intake or urinary output and concentration. The subsequent morphological examinations showed no macroscopic abnormalities and organ weight analysis did not show any treatment-related effects on the weights of the organs examined. Furthermore, there were no effects on the eyes as assessed by indirect ophthalmoscopy and the results of the study let conclude that dietary quinine hydrochloride up to 200 mg/kg per day for 13 weeks did not cause permanent ototoxic effects in rats. There was a significant decrease in body weight after receiving 100 or 200 mg/kg quinine hydrochloride per day. This study allows to define the no effect level of quinine hydrochloride in the Sprague-Dawley rat to be 60 mg/kg per day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

60 mg/kg bw/day

Study duration:

subchronic

Species:

rat

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

Additional information

The subchronic study (13-week study) on rats, was published by Colley et al., 1989. In the toxicity studies, no deaths were recorded and there were no effects on water intake or urinary output and concentration. The subsequent morphological examinations showed no macroscopic abnormalities and organ weight analysis did not show any treatment-related effects on the weights of the organs examined. Furthermore, there were no effects on the eyes as assessed by indirect ophthalmoscopy and the results of the study let conclude that dietary quinine hydrochloride up to 200 mg/kg per day for 13 weeks did not cause permanent ototoxic effects in rats. There was a significantly decreased of body weight after receiving 200 or 100 mg/kg quinine hydrochloride per day. This study allows to define the no effect level of quinine hydrochloride in the Sprague-Dawley rat to be 60 mg/kg per day.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study is not done according to OECD guideline. But it is a well documented study.

Justification for classification or non-classification

Based on this subchronic oral study on rats, the NOEL of quinine hydrochloride is 60 mg/kg body weight/day. Thus, quinine does not need to be classified.