QUININE
First draft prepared by
Professor R. Walker
University of Surrey
Guildford, Surrey,
United Kingdom
1. EXPLANATION
Quinine, as quinine salts or extracts from cinchona bark, is
used as a bittering agent in tonic type drinks, usually at a
concentration of approximately 80 mg quinine hydrochloride per
litre. Quinine is also used in some bitter alcoholic beverages and
to a small extent in flour confectionery. Quinine and its
derivatives have also been widely used therapeutically in the
treatment of protozoal infections, such as malaria, and of nocturnal
leg cramps.
The major dietary source of quinine is from soft drinks of the
tonic or bitter lemon type and the Committee received details of a
consumption study conducted in the United Kingdom, France and Spain,
among users of quinine-containing soft drinks. These data indicated
that while the 90th percentile intake averaged over 14 days was
between 6.1 and 9.3 mg/person/day, the maximum intake on a single
day varied from 75 mg/person in France to 104.4 mg/person in the
United Kingdom (Cadbury Beverages, Inc., 1991).
Quinine hydrochloride was evaluated at the thirty-fifth meeting
of the Committee (Annex 1, reference 88) when a toxicological
monograph was prepared (Annex 1, reference 89). A temporary ADI of
0-0.9 mg quinine/kg bw was allocated on the basis of human data but
the Committee considered that data from more extensive human studies
should be submitted by 1992.
Since the previous evaluation further data have become
available and are summarized in the following monograph addendum.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
No new information available.
2.2 Toxicological studies
No new information available.
2.3 Observations in humans
A double-blind four-way crossover study was carried out in
which 32 healthy volunteers (20 males, 12 females) aged between 18
and 50 years were given daily doses of 0 (lactose placebo), 80, 120
or 160 mg quinine hydrochloride for periods of 21 days. The test
substance was administered in gelatin capsules as four equal doses
at intervals of 5 h starting at 0800 h with a 9 h overnight
interval. The different dose regimes were separated by at least two
weeks.
Prior to commencement and at intervals throughout the period of
administration, haematology, serum and urine chemistry profiles were
examined together with other physiological, ophthalmic and
audiometric examinations as indicated in Table 1. Quinine
concentrations were determined on all serum and urine samples.
The serum quinine concentration plateaued by day 3 of dosing
and the mean concentrations (expressed as quinine hydrochloride)
were approximately 0.45, 0.65 and 0.9 µg/ml in the groups receiving
80, 120 and 160 mg/d, respectively. The corresponding mean urine
concentrations were 8.0-9.2, 10.6-14.0 and 15.8-21.0 µg/ml,
respectively.
No treatment-related effects were observed in urine output,
ECG, heart rate, blood pressure, peripheral fields, funduscopy,
colour vision, visual acuity, opticokinetic nystagmus response nor
audiometric parameters when compared with the period when placebo
was administered; serum chemistry and haematological parameters were
within normal ranges pre- and post-dosing.
Table 1. Measurement intervals
Examination Time of exposure (days)
Pre-dose 3 7 10 14 17 21
Physiological
24h urine*, serum + + + + + + +
chemistry+,
haematology°
ECG, heart rate, + + + +
blood pressure
Ophthalmic
ENG + + + + + + +
OKN, peripheral + + + + +
fields
Funduscopy + + + +
Colour vision + +
Visual acuity
Audiometric
Pure tone + +
threshold
0.25-8 kHz
ENG = electronystagmography; OKN = Opticokinetic nystagmus
* pH, S.G., protein, blood, bilirubin, glucose, ketones, nitrite
+ bilirubin, cholesterol, creatinine, glucose, total protein,
albumin, triglycerides, urea, Cl, PO43-, Na, K, Ca, Mg, alk-P-ase,
alanine aminotransferase, aspartate aminotransferase, GGT.
° WBC, RBC, Hb, PCV, MCV, MCHC, platelets, prothrombin time, activated
partial thromboplastin time.
During ENG examination, ocular flutter was noted on at least
one occasion in six volunteers but was unrelated to treatment,
occurring more frequently when volunteers were receiving placebo.
Nystagmus was displayed sporadically, on at least one occasion by
4/32 (12.5%) volunteers when receiving placebo or 80 mg quinine
hydrochloride/day and by 6/32 (18.8%) receiving 120 or 160 mg
quinine hydrochloride/day. The total number of observations of
nystagmus (out of 224 observations at each dose) was 10, 9, 18 and
18 at doses of 0, 80, 120 and 160 mg/d, respectively. The transitory
nystagmus was usually low-grade and no volunteer showed nystagmus on
every observation at any treatment level. Statistical analysis
indicated no significant difference in the occurrence of nystagmus
between the placebo and 80 mg/d treatment periods (group 1) nor
between the 120 and 160 mg/d (group 2); there was a significant
difference, p <0.05, between the two higher and lower treatments
(i.e., groups 1 and 2).
No subjective symptoms were attributable to treatment and there
were none of the other symptoms of intoxication reported at high
doses in other studies (BIBRA, 1991).
3. COMMENTS
The Committee concluded that the data demonstrated a clear NOEL
with respect to the ocular effects of 80 mg of anhydrous quinine
hydrochloride per day, equivalent to 72 mg of quinine free base. No
treatment-related effects on audition or clinical biochemical
abnormalities were observed at doses up to 160 mg of anhydrous
quinine hydrochloride per day.
4. EVALUATION
The previously established temporary ADI was withdrawn and, in
the light of data on levels of use in beverages, the results of the
consumption study and the additional data on humans, the Committee
concluded that current use levels in soft drinks of up to 75 mg/l
(as quinine base) were not of toxicological concern. However, the
Committee noted that a small group of consumers shows an
idiosyncratic hyper-reactivity to quinine, and recommended that the
consumer should be informed by appropriate means of the presence of
quinine in foods and beverages in which it is used. The contribution
of other uses of quinine in food and alcoholic beverages to daily
intakes was considered to be negligible.
5. REFERENCES
BIBRA (1991). Report on a study to investigate possible effects of
three dose levels of quinine hydrochloride on the vestibular,
auditory, and visual parameters of healthy volunteers - Main study.
BIBRA Project No. 3.0921/3. Unpublished report of BIBRA
International submitted to WHO.
CADBURY BEVERAGES INC. (1991). Quinine consumption study.
Unpublished report submitted to WHO by Cadbury Beverages Inc.