QUINOLINE YELLOW*
Explanation
Quinoline Yellow was previously evaluated by the Joint FAO/WHO
Expert Committee on Food Additives in 1966, 1969, 1974, 1975, 1978,
and 1982 (Annex I, Refs. 13, 19, 35, 36, 38, 39, 46, 47, 48, 50, and
60). As the last evaluation, the temporary ADI of 0-0.5 mg/kg body
weight was extended to 1984 pending the results of metabolism studies
and a long-term toxicological study which were in progress. The
committee noted that there are two quinoline yellows, one of which is
about 30% methylated and the other non-methylated, and considered that
data from both compounds could be used for toxicological evaluation of
either of the quinoline yellows for food additive use.
Since the previous evaluation, additional data has become
available and is summarized and discussed in the following monograph
addendum.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
After administration of a single intra-gastric dose of 4 mg
14C- Quinoline Yellow to male Sprague-Dawley rats, only about 2%
of the radioactivity was eliminated in the urine and 94% was recovered
in the faeces within 120 hours. At termination, approximately 0.14% of
the activity remained in the carcass and negligible amounts were found
in expired air.
Groups of 4 (2 males, 2 females) Sprague-Dawley rats were given a
single intra-gastric dose of 1 mg/kg body weight 14C-Quinoline Yellow
and blood levels of radioactivity were measured at intervals of 1/4,
1/2, 1, 2, 4, 8, 24 and 48 hours after treatment. The peak of
radioactivity appeared in the total blood and the plasma between 0.5
and 1 hour after dosing. All the radioactivity was found in the plasma
and did not appear to enter the erythrocytes. The maximum plasma
concentration was less than 0.009% of the dose and most the activity
was bound to plasma proteins; the unbound, ultrafilterable activity
was 4% of the total plasma activity after 4 hours and 10% after 8
hours. The kinetics of the blood levels fitted a two-compartment model
with the following parameters: Tal/2 = 0.6 hour; Tll/2 = 11.8 hours
and T21/2 ; 70.0 hours.
* Monograph addendum
Biliary excretion studies were performed in rats dosed with
14C-Quinoline Yellow (2.85 mg/kg body weight) by gastric intubation.
The peak of biliary excretion occurred between 1.5 hour and 3 hours
after dosing and about 1% of the dose was excreted by this route in
31.5 hours.
Whole body autoradiography of male rats given a single oral dose
of 14C-Quinoline Yellow demonstrated that, after 1 hour, the activity
was primarily associated with the gastro-intestinal tract and
excretory organs; after 24 hours only the large intestine and, to a
minor degree, the cortical zone of the kidney displayed activity.
Tissue distribution studies were performed in female rats after
intra-gastric administration of 14C-Quinoline Yellow; single animals
were sacrificed after 1/2, 1, 4, 8, 24 and 48 hours and radioactivity
measured in the stomach, small intestine, caecum, large intestine,
liver, kidney, bladder, brain, muscle, ovary, lung, pancreas, splen,
thyroid, blood and carcass. The results indicated that only a small
proportion of the dose was absorbed from the gastro-intestinal tract
and this was primarily associated with the liver, kidney and bladder.
The maximum proportion of the dose found in these organs was: liver,
0.4% after 4 hours; ca 1.0% after 8 hours; bladder ca 0.02% after 8
hours. When the results were expressed as concentration factors
(radioactivity/g tissue) there appeared to be a selective
concentration of activity in the thyroid which persisted up to 48
hours; a relatively high concentration was found in the ovaries in the
first 24 hours but not after 48 hours. The total amount of activity
absorbed from the gastro-intestinal tract was estimated to be 3 to 4%
of the administered dose (Anon, 1978).
In a complementary study carcasses of male rats which had been
used to determine blood levels of activity in the studies described
above were dissected and residual tissue levels determined
corresponding to 1/2, 1, 4, 8, 24 and 48 hours after dosing.
Similarly, activity was measured in the tissues of male rats used in
the excretion balance studies 120 hours after dosing. The results
confirmed that activity was selectively concentrated in the thyroid
(Anon, 1978).
Studies of blood levels and excretion of 14C-Quinoline Yellow
were performed in beagle dogs after intravenous or intragastric
administration. After i.v. administration of 0.2 mg 14C-Quinoline
Yellow/kg body weight, the disappearance of radioactivity corresponded
to a two-compartment pharmaco-kinetic model with elimination
coefficients of 0.1971h-1 and 0.0163h-1. Following intra-gastric
administration of 0.44 mg 14C-Quinoline Yellow/kg body weight the
peak blood levels were observed after between 1 and 4 hours.
Approximately 22% of an i.v. dose of 14C-Quinoline Yellow was
excreted in the faeces in this period. After intra-gastric dosing,
1-4% of the label appeared in the 0-72 hours urine, mainly between 8
and 48 hours, and 42-60% was excreted in faeces within 72 hours.
Residual tissue levels after 72 hours were low and did not indicate
any specific tissue accumulation, particularly in the thyroid (Anon,
1978).
Metabolism
Chromatographic examination of bile, urine, faeces and plasma of
rats given intra-gastric doses of 14C-Quinoline Yellow indicated that
the colour was metabolised to only a small extent. In the urine,
between 10 and 15% of the activity was associated with an unidentified
metabolite which was more polar than the unchanged colour.
Similar experiments in beagle dogs, in which urine, faeces and
plasma were examined, indicated that Quinoline Yellow is metabolised
to only a small extent in this species.
TOXICOLOGICAL STUDIES
Long-term studies
A long-term chronic toxicity/carcinogenicity study was carried
out in the OFI mouse following in utero exposure. Four groups of
mice, containing 105 animals of each sex in the control and 65 of each
sex in the treatment groups, were fed diets 0, 0.1%, 0.3% and 1.0%
Quinoline Yellow in the diet from age 4-5 for a 9 week period prior to
mating (Fo generation). The animals were then mated monogamously with
partners from the same treatment groups and the females maintained on
their respective experimental diets throughout gestation and
lactation. The number of live and still-born pups was recorded and the
litter size reduced to 8 on the third day after parturition. On day 21
after parturition, animals were selected from the litters of the
appropriate treatment groups to provide groups of 100 animals of each
sex (controls) or 50 animals of each sex (test groups). These animals
comprising the F1 generation were housed singly and maintained on
their respective diets for 21 months in the case of males, and 23
months in the case of females. Body weight and food intake were
measured weekly for the first 3 months, twice a months from 3 to 6
months and monthly thereafter. Haematological examinations were
performed after 3, 6, 23 and 18 months of treatment and at termination
of the study. All animals dying or moribund animals sacrificed during
the study and those at terminal sacrifice were autopsied and abnormal
tissues were samples for histological examination. In addition, a
histological examination was carried out on all the animals from the
control and top dose groups at termination. The organs examined
histologically were: liver, gall bladder, kidneys, heart, lungs, brain
(cerebrum), gonads, seminal vesicles, epididymis/uterus, prostate/
vagina, salivary gland, peripheral nerve, adrenal, pituitary,
Harderian gland, oesophaagus, stomach, duodenum, nose, spleen,
jejunum, ileum, caecum, colon, urinary bladder, trachea, vena cava,
aorta, pancres, thymus, skin, mammary gland, skeletal muscle, optic
nerve, femur, eyes, thyroid, lymph nodes, spinal column. Organ weights
were recorded of: brain, heart, liver, spleen, kidneys, gonads,
stomach, jejunum, caecum (full and empty).
The growth rats and mortality rates during the course of the
study showed no significant dose-related effects; the mortality rates
at termination were, for males and females respectively, 60% and 71%
in controls, 50% and 72% in the 0.1% groups, 54% and 58% in the 0.3%
group and 68% and 68% in the 1% dose group.
The number of animals bearing palpable masses remained low (about
20%) and the incidence and time of onset was similar in all groups. On
comparing the top dose animals with controls at termination, there was
no important difference in the tumour types observed nor in the
overall incidence of tumours. Systematic histological examination of
all the tissues samples in the top dose group and controls at
termination and of any abnormal tissue or rumour observed in all
groups showed no treatment-related toxic effects (Coquet et al.,
1981).
Comments
Quinoline Yellow is absorbed from the gastro-intestinal tract to
only a small extent in rats and dogs, and most of an orally
administered dose is excreted unchanged. No adverse effects of
treatment were seen in the two-generation long-term study in mice. In
particular there was no observed effect on thyroid function or
histopathology and no evidence of carcinogenicity.
EVALUATION
Level causing no toxicological effects
Mouse: 1% of the diet, equal to 1.500 mg/kg/
Estimate of an acceptable daily intake for man
0-10 mg/kg bw.
REFERENCES
ANON (1978) Etude de la distribution chez le rat du jaune de
quinoleine ou E104 marqué au 14C. Unpublished report of the
Laboratoire d'Etudes du Métabolisme des Médicaments (Laboratory for
the Study of Drug Metabolism), Commissariat à l'Energie Atomique,
France.
COQUET, B., RONDOT, G., NEWMAN, A.J., GENOUX, P., JAHCHAN, A., MARY,
M.C., & BLANC, J.P. (1981) Carcinogenicity study in the OFI Mouse with
Colouring Agent E104 Quinoline Yellow. IFREB Report No. 110202 -
October 2, 1981. Unpublished Report of the EEC Colours Group.
See Also:
Toxicological Abbreviations
Quinoline yellow (FAO Nutrition Meetings Report Series 46a)
Quinoline yellow (WHO Food Additives Series 6)
Quinoline Yellow (WHO Food Additives Series 8)
Quinoline yellow (WHO Food Additives Series 13)
QUINOLINE YELLOW (JECFA Evaluation)