QUININE HYDROCHLORIDE
1. EXPLANATION
This substance had not been evaluated previously by the Joint
FAO/WHO Expert Committee on Food Additives.
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 of quinine hydrochloride per liter. Such
drinks are popular and have been widely consumed for almost 200 years.
Quinine rapidly breaks down when exposed to sunlight. Thus it is also
appropriate to consider the toxicity of these breakdown products,
particularly deoxyquinine.
Quinine and its derivatives are widely used therapeutically for
treatment of protozoal infections such as malaria and treatment of
nocturnal leg cramps. There is an extensive literature on the
pharmacokinetics and toxicity of quinine at high doses, well above
that ingested through the consumption of tonic waters (e.g. Bateman &
Dyson, 1986; Webster, 1985; Bacon et al., 1988; White, 1987; White
et al., 1982; Orme, 1987).
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
Quinine is readily and completely absorbed from the small
intestine when given orally. Quinine is a potent local irritant and
is not generally administered by either intramuscular or subcutaneous
injection. Peak plasma concentration is reached within one to three
hours following a single oral dose. Therapeutic doses of 1 g/day of
quinine for several days result in an average plasma quinine
concentration of approximately 7 µg/ml with a plasma half-life of
about 12 hours. Approximately 70% of plasma quinine is bound to
proteins. Quinine is extensively metabolized in the liver with less
than 5% excreted unaltered in the urine (Webster, 1985; White, 1987).
The pharmacokinetics of quinine are variable (clearance 0.9-1.8
ml/kg/min., half-life 8.4-18.2 hours). Quinine readily crosses the
placenta (Webster, 1985; White, 1987).
2.1.2 Biotransformation
Most metabolites, identified as hydroxy derivatives, are excreted
in the urine (Webster, 1985; White, 1987).
2.2 Toxicology studies
2.2.1 Acute studies
No data available.
2.2.2 Short term studies
2.2.2.1 Rats
Five groups of 5 male and 5 female rats (Sprague-Dawley, Charles
River, CD) were fed a diet containing the equivalent of 0.25, 100, 200
and 250 mg/kg bw/day of quinine hydrochloride for 4 weeks. There were
reductions in the food consumption and body weight gains of the two
high dose groups. There were no treatment-related clinical or
histopathological findings. On the basis of this study, the authors
concluded that dose levels of up to 200 mg/kg bw/day of quinine
hydrochloride would be appropriate for a 13-week toxicity study
(Colley et al., 1982a).
Diets containing the equivalent of 0, 1, 10, 40, 100 or 200 mg/kg
bw/day of quinine hydrochloride were fed to 6 groups of 40 Sprague-
Dawley (Charles River, CD) rats (20 male and 20 female per group) for
13 weeks. Following this exposure 5 male and 5 female rats from each
group were placed on the control diet for an additional 6 weeks. Rats
in the two highest dose groups consumed less food and gained less
weight than the controls. Results from hematology, blood
biochemistry, urinalysis and histopathology examinations were within
normal ranges except for a decrease in total serum protein and
globulin levels, increased urea nitrogen levels and depletion of
periportal glycogen in the livers of rats in the two highest dose
groups. No toxicity was observed on ophthalmoscopic observation and
hearing function (pinna reflex) tests. During the withdrawal period,
food intake increased in the group (males and females) that previously
received 200 mg/kg bw/day and in males that previously received 100
mg/kg bw/day. There was also increased weight gain in male and female
rats previously receiving 100 and 200 mg/kg bw/day. Blood chemistry
values measured during the final week of the withdrawal period were
not different from the controls. The authors concluded that 40 mg/kg
bw/day of quinine hydrochloride was a no-effect level (Colley
et al., 1982b). A subsequent histopathologic examination of the
optic nerve of the 200 mg/kg bw/day group revealed no treatment-
related effects (Warren et al., 1984).
In a 13 week diet study, 4 groups of 20 male and 20 female
Sprague-Dawley rats were exposed to the equivalent of 0, 60, 85 or 120
mg/kg bw/day of quinine hydrochloride. Following this exposure 5 male
and 5 female rats from each group were placed on the control diet for
a 6 week withdrawal period. Reduced food consumption, decreased body
weight gains, and decreased kidney weights were observed in the 85 and
120 mg/kg bw/day dose groups. A treatment-related loss of fur was
noted in the 120 mg/kg bw/day dose group. During the withdrawal
period, food consumption was slightly lower in the 85 and 120 mg/kg
bw/day group, but there were no differences in body weight gain,
compared to controls. The authors concluded that 60 mg/kg bw/day was
a no-effect level (Watson et al., 1983; Warren et al., 1984).
2.2.3 Long-term/carcinogenicity studies
No data available.
2.2.4 Reproduction studies
No data available.
2.2.5 Special studies on gentoxicity
The vast majority of tests indicate that quinine hydrochloride is
not mutagenic (Table 1).
Table 1: Results of genotoxicity assays of quinine hydrochloride
Concentration
of quinine
Test System Test Object hydrochloride Results Reference
Ames test1 S.typhimurium 0.1-2000 µg/ Negative BIBRA, 1979
TA1535, TA1537 plate
TA1538, TA98
TA100
Ames test1 S.typhimurium 1-1000 µg/ Negative BIBRA, 1979
TA98, TA100 plate
Ames test1 S.typhimurium 50-5000 µg/ Negative Münzer &
TA1535, TA1537 plate Renner, 1983
TA1538, TA100
TA98
Ames test2 S.typhimurium 1-50 µg/plate Negative BIBRA, 1979
TA98
Ames test2 S.typhimurium 5-20 µg/plate Positive King et al.,
TA98 (quinine 1979
dihydrochloride)
DNA-repair Human fibroblasts 0-400 µg/ml Negative BIBRA, 1979
Cell Syrian hamster 12.5-200 µg/ml Negative BIBRA, 1979
transformation kidney cells
(BHK 21 C13)
Table 1 (contd).
Concentration
of quinine
Test System Test Object hydrochloride Results Reference
Cell BHK 21 C13 6.5-100 µg/ml Negative Richold, et al.,
transformation cells 1981a
Cell BHK 21 C13 12.5-200 µg/ml Negative Richold, et al.,
transformation cells 1981a
Sister chromatid Chinese 55-110 mg/kg bw Negative Münzner &
exchange hamster Renner, 1983
Sister Mice (NMRI 110 mg/kg bw Positive Münzner &
chromatid C3H) Renner, 1983
exchange
Sister Mice (C57BL) 55-110 mg/kg bw Positive Münzner &
chromatid Renner, 1983
exchange
Micronucleus Chinese 110 mg/kg bw Negative Münzner &
test hamster Renner, 1983
Micronucleus Mice (NMRI 110 mg/kg bw Negative Münzner &
test C3H) Renner, 1983
Chromosome Chinese 110 mg/kg bw Negative Münzner &
aberration Hamster Renner, 1983
test
Table 1 (contd).
Concentration
of quinine
Test System Test Object hydrochloride Results Reference
Chromosome Mice (NMRI) 110 mg/kg bw Negative Münzner &
aberration Renner, 1983
test
Chromosome Mice (C3H) 110 mg/kg bw Negative Münzner &
aberration Renner, 1983
test
1 Both with and without rat liver S-9 fraction
2 With rat liver S-9 fraction.
2.2.6 Special studies on genotoxicity of derivatives
Studies on the genotoxicity of derivatives of quinine
hydrochloride were negative (Table 1).
2.2.7 Special studies on teratology
2.2.7.1 Rats
Four groups of 25 pregnant specific pathogen free rats (CRL: COBS
CD (SD) BR strain) from Charles River UK were dosed by gavage on day
6 to day 15 of gestation with either 0, 50, 100 or 200 mg/kg bw/day of
quinine hydrochloride. Rats in the two highest dose groups gained
less weight than controls, but only the highest dose group consumed
less food. These findings are consistent with those in the 13 week
feeding study which showed minimal toxic effects at 100 mg/kg bw/day
(section 2.2.2.1). Litter and mean fetal weights were significantly
reduced in the 200 mg/kg bw/day dose group. There was a significant
increase in total variant sternebrae in the 200 mg/kg bw/day dose
group and a slight increase in the 100 mg/kg bw/day dose group
compared to controls. There were no differences in pregnancy data,
total resorptions, litter size, sex ratio or major malformations
between dose groups. The authors concluded that the 100 mg/kg bw/day
group showed no adverse effects on embryo or fetal development
(Edwards et al., 1984).
Two groups of 5 female Sprague-Dawley rats were exposed to either
0 or 0.25 mg/ml of quinine in their drinking water, starting two weeks
prior to pregnancy and continuing throughout pregnancy and lactation.
The treated dams were mated with untreated males. The quinine treated
group showed some decrease in fluid consumption but no change in food
intake or weight gain. Pups from the quinine treated dams weighed
significantly less at birth than those from the controls, had
significantly delayed eye opening and teeth eruption and one neonate
each was observed with syndactylia in the right forelimb or
anopthalmia of the right eye. Assuming that the female rat drinks
approximately 30 ml/day and weighs approximately 200 g, the treated
rats received a dose that is equivalent to approximately 40 mg/kg
bw/day. This report suffers from low numbers of animals and other
deficiencies that make the significance of the reported results
difficult to evaluate, e.g., it could not be determined if the terata
that were reported are from the same litter or if the culling of pups
from an average litter size of 13.6 to 8 was random (Lapointe & Nosal,
1979).
Table 2: Results of genotoxicity assays of derivatives of quinine hydrochloride
Concentration
Test System Test Object (compound) Results Reference
Ames test1 S.typhimurium 0-3000 µg/ Negative Richold &
TA1537,TA98, plate Jones, 1980
(deoxyquinine)
Ames test1 S.typhimurium 0-3000 µg/ Negative Richold et al.,
TA1535, TA1537 plate 1981b
TA1538, TA98 (QCA/644)2
TA100
Ames test1 S.typhimurium 0-3000 µg/ Negative Richold et al.,
TA1535, TA1537 plate 1981c
TA1538,TA908, (DQCA/678)3
TA100
Micronucleus Swiss Mice 70 mg/kg bw Negative Allen et al.,
test Specific (desoxyquinine) 1984
Pathogen
Free CD-1
1 Both with and without rat liver S-9 fraction
2 QCA/644 is 2-(1', 3'-Dicarboxy-2'-hydroyprop-2'-quinine)
3 DCQA/678 is 2-(1', 3'-Dicarboxy-2'-hydroxyprop-2'yl)desoxyquinine.
2.2.8 Special study on teratology of deoxyquinine
2.2.8.1 Rats
Four groups of 30 specific pathogen free rats (CRL: cobs cd (SD)
BR strain) from Charles River UK were dosed by oral gavage with either
0, 6.67, 20 or 60 mg/kg bw/day of deoxyquinine during days 6 to 15 of
gestation. Twenty rats of each group were killed and the fetuses
examined, with the remaining rats allowed to litter and undergo
developmental assessment. The mean litter sizes in the 6.67 and 60
mg/kg bw/day groups were decreased, which was attributed to
pre-implantation losses and not to treatment. There was an increased
percentage of fetuses with 14 ribs in the 60 mg/kg bw/day group.
There were no treatment-related developmental effects as assessed by
surface righting reflex, pinna unfolding, incisor eruption, startle
response, eye opening, air righting reflex, pupil reflex or startle
response. The authors concluded that there were no significant
adverse treatment-related effects at the levels of deoxyquinine used
in this study (Cozens et al., 1981).
2.2.8.2 Rabbits
Four groups of 15 female New Zealand white rabbits were bred with
untreated males and then dosed by gavage with either 0, 20, 40 or 80
mg/kg bw/day of deoxyquinine during days 6-18 inclusive of gestation.
Prior to this study a preliminary study indicated that 135 mg/kg
bw/day of deoxyquinine caused weight loss and death in rabbits. In
the teratology study, 3 animals of the 80 mg/kg bw/day group died
shortly after dosing and in the other animals in this group there was
reduced weight gain from days 10-23 of gestation compared to the
controls. There was no significant treatment-related developmental
toxicity (Edwards et al., 1982).
2.2.9 Special study of ototoxicity
2.2.9.1 Rats
Diets containing the equivalent of either 0, 85 or 200 mg/kg
bw/day of quinine hydrochloride were fed to 3 groups of 10
cesarian-derived Sprague-Dawley (Charles River, CD) rats (5 of each
sex) for 13 weeks. There was a dose-related reduction in food
consumption for females, some food reduction noted for the males and
a dose-related reduction in body weight gain for all treated groups.
Auditory function was tested by pre-stimulus startle test at a
frequency of 10 KHz and sound pressure level of 50 db, which revealed
no group-related differences. Electrocochleography tests showed some
treatment and sex-related effects. Detailed cochlear
histopathological examinations were negative. The authors concluded
that exposure to quinine hydrochloride at the levels used in this
study did not result in any permanent ototoxic effects (Colley
et al., 1985).
2.3 Observations in man
Since quinine has a long history of drug use for the treatment of
malaria, there are numerous reports on its toxicity in humans. These
reports are usually associated with overdoses of quinine (Brintin
et al., 1980; Dyson et al., 1985; Webster, 1985; Bateman & Dyson,
1986; White, 1987, Orme, 1987; Bacon, et al., 1988). A fatal oral
dose for adults is approximately 8 g, or 140 mg/kg bw. At high (in
the range of 1 g/day) repeated therapeutic doses, quinine produces a
range of effects termed cinchonism which include auditory and visual
disturbances, headache and nausea. The auditory effects range from
tinnitus to deafness, but milder symptoms usually resolve when intake
of quinine is stopped. Visual disturbances range from blurred vision
to blindness and milder symptoms also generally resolve following
cessation of intake of quinine. However, an acute overdose of quinine
can result in permanent visual damage. The recommended therapeutic
administration of quinine is up to 650 mg three times per day
(Webster, 1985). There appear to be no reports of chronic toxicity
resulting from normal therapeutic usage (Bateman & Dyson, 1986).
Twenty normal adult volunteers (6 males and 14 females) consumed
1.25 liters of tonic water containing 80 mg quinine hydrochloride/l,
daily for 14 days (there were no controls). Seven subjects complained
of blurring of vision, five subjects complained of poor focussing and
14 reported headaches. There were significant changes in Goldman
perimeter fields of vision which returned to pre-test condition upon
re-examination 4 months after the end of the study. There were no
changes in visual acuity, audiometric records or blood chemistry
values. The mean plasma quinine levels on days 7 and 24 were 0.47 ±
0.14 and 0.51 ± 0.16 µg/ml, respectively. The authors concluded that
"there were no auditory, visual or other effects that could be
regarded as significant or irreversible" (Cantab Group and Medical
Science Research, 1985).
In a subsequent study, 2 groups of 5 subjects (adults of both
sexes) consumed either 120 mg of quinine hydrochloride in tonic water
or aerated drink free of quinine hydrochloride daily for 14 days. No
treatment-related complaints or adverse effects were reported. The
authors concluded that under the conditions of this study, 120 mg of
quinine hydrochloride/day produced no adverse effects (Cantab Group
and Medical Science Research, 1985).
In a study designed to assess the correlation of low-dose quinine
exposure to changes in electronystagmographic (ENG) recording,
seventeen human subjects (4 control, 9 low dose, 4 high dose) were
exposed to either 0, 52.5 or 105 mg of quinine per day from
commercially prepared tonic water for two weeks. The authors reported
that three of the four high dose subjects showed positional
abnormalities on at least one ENG tracing while there were no effects
in the low dose subjects (Zajtchuk et al., 1984).
3. COMMENTS
Biochemical studies, short-term studies in rats, teratology
studies in rats, and mutagenicity studies were reviewed. In these
studies, no-effect levels ranged from 40 mg per kg bw per day to 100
mg per kg bw per day. Mutagenicity studies were negative.
Varied complaints including headaches and transient visual
problems were reported in human volunteer studies using doses of 100
mg of quinine hydrochloride per person per day. These findings were
not confirmed in a second, controlled study using 120 mg per person
per day. A third study showed electronystagmographic changes in
stressed subjects for which a no effect level of 52.5 mg quinine per
person per day was determined.
The Committee concluded that a Temporary ADI could be established
on the basis of the human data. In view of the fact that the toxicity
of concern was acute and reversible in nature and that there is
extensive experience of human consumption without reports of acute
toxicity except very rarely in individuals with hypersensitivity, the
Committee saw no need to require a margin of safety.
4. EVALUATION
Level causing no toxicological effect
Rats: 4O mg quinine hydrochloride/kg bw/day
Humans: 0.9 quinine mg/kg bw/day.
Estimate of temporary acceptable daily intake
0-0.9 mg quinine/kg bw/day.
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See Also:
Toxicological Abbreviations
QUININE HYDROCHLORIDE (JECFA Evaluation)