CHLORAMPHENICOL
First draft prepared by
Dr R. Fuchs
Institute for Medical Research and Occupational Health
University of Zagreb, Zagreb, Croatia
1. EXPLANATION
Chloramphenicol (CAP) is a broad spectrum antibiotic used in cattle,
swine and poultry in dose ranges of 22-66 mg/kg bw. Absorption of the
drug by the oral or parental route of administration is rapid, with
maximum blood concentrations reached in 1 to 5 hours. The major route of
excretion in pigs and cattle is in the urine.
CAP had been previously evaluated at the twelfth and thirty-second
meetings of the Committee (Annex 1, references 17 and 80). At the
thirty-second meeting the Committee was unable to establish an ADI
because it was not possible to give an assurance that residues in foods
of animal origin would be safe for human consumption; it was concluded
that human exposure to CAP can cause aplastic anaemia.
This monograph addendum summarizes the information on CAP that has
become available since the previous evaluation.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Biotransformation
Isolated liver cells from rats and rainbow trout were used to study
biotransformation of labelled CAP. After 2 hours in suspension, 85 and
25% of the dose was biotransformed by rat and trout hepatocytes,
respectively, and in both species primarily by glucuronidation. Three
major phase I metabolites, identified as CAP-oxamic acid, CAP base, and
CAP alcohol, were found in the hepatocyte suspensions. In the rat the
pattern of metabolites produced in vitro was significantly different
from the metabolites reported in vivo, CAP-arylamine and -arylamide
being identified in rat urine. The authors concluded that these
metabolites resulted from the action of the intestinal microflora and,
to a lesser extent, from the activity of tissue nitroreductase. In the
trout, no CAP-oxamic acid was detected in urine. The gills are a more
likely route of elimination of this metabolite in the trout (Cravedi &
Baradat, 1991).
Quantitative analysis of goat urinary metabolites of CAP indicates
that the glucuronide prevails (36.5%). The sulfate (22.5%) and phosphate
(7.9%) contribution to the detoxification of CAP are also important (Wal
et al., 1988).
In human patients with normal hepatic function, approximately 90% of
a CAP dose was conjugated to the glucuronide in the liver, and excreted
by the kidneys. Only about 5-15% was excreted by glomerular filtration
as unchanged CAP in urine. Minor metabolites have also been identified.
The mean elimination half-life was approximately 4 hours in adults and
children, but can be 9-12 hours in newborns. In patients with hepatic
dysfunction or renal insufficiency conjugation of CAP and elimination of
glucuronide conjugates were slower. Renal impairment did not modify the
elimination rate of the active and potentially toxic free drug (Goodman
& Gilman, 1991).
Several drug interactions have been reported involving enzyme
induction by phenobarbital, phenytoin and rifampicin. Inhibition of CAP
glucuronidation by paracetamol in neonates was suspected, but was later
refuted in a large study (Paap & Nahata, 1991). No significant
alteration of CAP half-life, area under the curve or peak concentration
was observed in adult patients after paracetamol treatment (Stein et
al., 1989).
A study performed in 225 children showed that large variations in
CAP metabolism and rate of elimination can lead to under/overdosage,
especially in neonates and young infants . The authors concluded that
CAP concentrations should be monitored every 48 hours in babies under 1
year of age (Rhodes & Henry, 1992)
No new information was available on metabolites produced by
intestinal bacteria, but it was stated that nitroreduction derivatives
may play an important role in haematological toxicity. (See "Special
studies on haematotoxical effects", sec. 2.2.2). There is no clear
evidence that CAP nitroreduction takes place in vivo in animals or
humans without the presence of intestinal bacteria. Whether this
metabolism occurs in the bone marrow, especially in susceptible
subjects, or whether toxic metabolites may find their way to the bone
marrow is also unknown at this time (Jimenez et al., 1990).
New data on CAP pharmacokinetics in food-producing animals were
available. The authors concluded that meat and offal from treated
animals contain CAP and non-genotoxic metabolites (Milhaud, 1993a).
The plasma concentration of CAP was followed in 8 mature cats, after
ocular application of 1% CAP ophthalmic ointment at eight-hour intervals
for 21 days. It was estimated that the daily dose applied was 2.7
mg/cat/day. On day 21 of treatment the plasma concentration of CAP in
these treated cats was measured at 0.09 µg/ml (Conner & Gupta, 1973).
2.2 Toxicological studies
2.2.1 Special studies on genotoxicity
The results of recent genotoxicity assays with CAP are summarized in
Table 1.
In a recent literature review of the genetic and genotoxic potential
of CAP, the author concluded that reports of studies for many important
genetic endpoints, for example, gene mutations or the induction of
unscheduled DNA synthesis in mammalian cells could not be found despite
widespread use of CAP in human medicine. The only consistent findings
were of chromosomal effects on somatic cells. These effects may reflect
the CAP-induced blockade of the cell cycle and of macromolecule
synthesis (Rosenkranz, 1988).
The results of a battery of genotoxicity studies with CAP in
mammalian cell systems showed that at concentrations (2-4 mM) markedly
higher than those (0.08-0.15 mM) reported in humans following exposure
to a maximal therapeutic dose, CAP produced a minimal amount of DNA
fragmentation in both V79 cells and metabolically competent rat cells. A
level of DNA-repair synthesis indicative of a weak but positive response
was detected in primary cultures of liver cells obtained from 2 of 3
human donors, and a borderline degree was present in those prepared from
rats. The promutagenic character of CAP-induced DNA lesions was
confirmed by a low but significant increase in the frequency of
6-thioguanine resistant clones of V79 cells, which were absent in the
presence of co-cultured rat hepatocytes. Administration of a single oral
dose of 1250 mg/kg bw CAP to rats (1/2 the LD50) failed to induce an
increased incidence of either micronucleated hepatocytes or
polychromatic erythrocytes. The authors concluded that CAP should be
considered intrinsically capable of producing a very weak genotoxic
effect, but only at concentrations about 25 times higher than those
occurring in patients treated with the maximum therapeutic dose
(Martelli et al., 1991).
Chromosomal aberrations and sister-chromatid exchanges (SCE) in
human lymphocyte cultures treated with CAP, in bone marrow cells of
treated mice, and in Chinese hamster cells (V79), were studied. No
aberrations were induced by short-term treatment of human lymphocytes
exposed in the G1 and G2 phases. A high frequency of aberrations,
exclusively of the chromatid type, were induced during a whole cell
cycle. Aberrant metaphases were detected at the end and a few hours
after the end of treatment; at later times, aberrant cells reached
control values. Doses producing chromosomal aberrations slightly
increased SCEs both in human lymphocytes and in V79 cells. In mouse bone
marrow cells, CAP induced a high mitotic delay and few structural
aberrations. Intrachromosomal vacuoles were observed, which indicated a
possible effect on chromosome condensation (Sbrana et al., 1991).
The genotoxic potential of different CAP concentrations (5, 20, 40,
and 60 µg/ml) was investigated in bovine fibroblast primary lines by SCE
assay. All doses caused a significant increase in the number of SCEs, in
relation to the control dose (Arruga et al., 1992).
Cytotoxic and genotoxic effects of CAP and six metabolites were
investigated in human peripheral blood lymphocytes (PBL). Raji lymphoma
cells were included in the study to assess the effectiveness of a nitro
reduction step in the toxicological action of CAP and its derivatives.
As a model of target cells involved in aplastic anaemia, an immortalized
lymphoblastoid cell line originating from human bone marrow (RiBM) was
used. The metabolites were nitroso-CAP, dehydro-CAP, dehydro-CAP base,
CAP base, CAP glucuronide, and CAP alcohol. CAP and its metabolites were
assayed in a large range of concentrations (1 x 10-5 M to 4.10-3 M)
on the 3 cell types. The cytotoxic effect was determined by inhibition
of 3H-thymidine incorporation in DNA. The genotoxic effect was
evaluated by the induction of DNA single strand breaks detected by the
method of alkaline elution.
Three CAP metabolites, nitroso-CAP, dehydro-CAP, and dehydro-CAP
base presented significant cytotoxic and genotoxic effects in the 3
cellular models. CAP and the 3 metabolites were devoid of cytotoxic and
genotoxic effect in all 3 models, up to a concentration of 1 x 10-3 M.
At higher concentrations a cytotoxic effect was observed for CAP and
CAP-base in human lymphocytes and RiBM cells, and for CAP only in Raji
cells. No DNA damage could be detected with these compounds.
Table 1. Results of genotoxicity assays on chloramphenicol
Test system Test object Concentration Results Reference
DNA fragmentation V79 cells 4mM weak Martelli et al.,
positive 1991
DNA fragmentation Rat hepatocytes 2 mM weak Martelli et
positive al., 1991
DNA repair assay Cultured human 2 mM weak Martelli et
and rat positive al., 1991
hepatocytes
Mutation to TGr V79 cells 2 mM weak Martelli et
positive al., 1991
Micronucleus test Rat liver bone 1250 mg/kg negative Martelli et
marrow cells al., 1991
Chromosomal Human 2.4-4.8 positive1 Sbrana et al.,
aberrations lymphocytes mg/ml 1991
Chromosomal
aberrations Mouse bone 50 & 100 positive Sbrana et al.,
marrow cells mg/kg 1991
SCE Human 2.4-3.2 weak Sbrana et al.,
lymphocytes mg/ml positive 1991
SCE V79 cells 3-12 mg/ml weak Sbrana et al.,
positive 1991
SCE Bovine 5-60 µg/ml positive Arruga et al.,
fibroblasts 1992
DNA single stand PBL2, Raji >1 x 10-4M positive4 Decloitre et al.,
breaks lymphoma c. 1993
RiBM3
1 Negative in G1 and G2 phases.
2 Human peripheral blood lymphocytes.
3 Immortalized lymphoblastoid cell line originated from human bone
marrow.
4 Only for 3 CAP metabolites: nitroso-CAP, dehydro-CAP and
dehydro-CAP base.
The authors concluded that nitroso-CAP, dehydro-CAP, and dehydro-CAP
base were able to induce a cytotoxic effect at concent-ration superior
to 1 x 10-6 M and a genotoxic effect at 1 x 10-4 (no effect
concentration 2 x 10-5) in human cells. Human bone marrow-derived
cells were less sensitive than human peripheral lymphocytes and Raji
cells (Decloitre et al., 1993).
In a literature review and analysis of in vitro studies of the
toxic effects of CAP and its metabolites the authors concluded that the
essential problem is the evaluation of the lowest concentration capable
of inducing genetic lesions. In their view, CAP has a very low or
genotoxic capacity and, for those of its metabolites which are more
active, 3 to 4 logs of concentration separate the possible genotoxic
concentrations in serum from the concentrations that could result from
the ingestion of residues in food of animal origin (Frayssinet et al.,
1993).
2.2.2 Special studies on haematological effects
CAP was administered intravenously for 8-17 days to 5 newborn calves
at a daily dosage of 100 mg/kg bw High levels of serum CAP were observed
throughout the study, despite a marked increase in elimination rate seen
with increasing age. Adverse effects included severe hypotension
following rapid i.v. administration and severe gastrointestinal
dysfunction. Minor haematological effects were observed in only one
animal, which included a slight decrease in packed cell volume and
haemoglobin without any related changes in the bone marrow. Based on
these results the authors concluded that it was unlikely that
haematological effects would be an important limiting factor in CAP use
in cattle (Burrows et al., 1988).
CAP, tetracycline and gentamicin have been shown in vitro to have
detrimental effects on bovine polymorphonuclear lymphocytes (PMNL). To
evaluate their effects on bovine PMNL in vivo, three Holstein dairy
cows received intramammary infusions of one of these antibiotics into
two quarters and an infusion of phosphate buffered saline into one of
the remaining untreated quarters. A fourth cow received intramammary
infusions of phosphate buffered saline solution (10 ml/treatment) only.
Dosages administered were 5 g/infusion of CAP and 500 mg/infusion of
gentamicin and tetracycline. Each dose was dissolved in 10 ml of
phosphate buffered saline. Each cow was treated once a month for four
consecutive months. CAP at a dose of 5 g per treatment failed to show
stronger effects than tetracycline on the basis of PMNL lymphocyte
morphologic features or phagocytosis ability (Paape et al., 1990a).
The activity of CAP against bovine neutrophils was assessed in an
in vitro model This activity was compared to florphenicol and
thiamphenicol, two analogs of CAP in which the p-nitro group is replaced
by a methyl sulfonyl group. All drugs altered neutrophil morphology
(lack of pseudopodia), but only CAP depressed phagocytosis and
completely blocked respiratory burst activity of neutrophils at
concentrations of 2000 and 4000 µg/ml, but not at 10 µg/ml. At
concentration of 4000 µg/ml CAP also blocked chemolumin-escence
activity. (Paape et al., 1990b).
Sequence analysis of the 3' end of the 16S rRNA gene of
mitochondrial DNA revealed a single base change (Guanine to Adenine) at
position 3010, in a patient who had recovered from CAP-induced aplastic
anaemia. A link between this mutation and CAP-induced aplastic anaemia
was ruled out by investigating three other similar patients that died,
none of whom had the mutation. The authors concluded that the relatively
high frequency of this mutation in the population (14% in Europeans),
made its role as a potential determinant of a person's susceptibility to
CAP-induced aplastic anaemia unlikely (Mehta et al., 1989).
Burst-promoting activity (BPA) measured in the sera from 31 children
with aplastic anaemia was significantly higher when compared with
healthy children. BPA elevation is a biological compensation for the
haematopoietic disorder, and the authors stated that its measurement in
patients with aplastic anaemia may be helpful in evaluating the
haematopoietic condition. However, none of the three patients suffering
from CAP-induced aplastic anaemia exibited increased BPA (Wang et al.,
1990).
Three CAP metabolites known to be produced by intestinal flora,
dehydro-CAP, nitroso-CAP, and nitrophenyl-CAP, are much more toxic to
bone marrow in vitro than CAP itself. The author concluded that the
p-nitro group of CAP is the structural feature underlying aplastic
anaemia. In predisposed subjects this group undergoes nitroreduction,
leading to the production of toxic intermediates (nitroso,
hydroxylamine), resulting in stem cell damage. Nitroso-CAP in
macromolecular concentrations inhibits myeloid growth irreversibily and
arrests cells in the G2 phase of the cycle. The fact that the parent
compound thiamphenicol appears free of irreversible toxicity may be
related to the lack of p-nitro group in the molecular structure (Yunis,
1988).
Colony stimulating factors (CSFs) completely reversed the inhibitory
effects of CAP on different cell strains (CFU-GM, KG-1, HL-60). In
contrast, inhibition by dehydro-CAP and nitroso-CAP was not affected by
CSFs and CSFs were inhibited by dehydro-CAP and nitroso-CAP, but not by
CAP or nitrophenyl-CAP. The authors suggested that the dual
toxic-inhibitory effect of some intestinal metabolites of CAP on
haematopoietic growth and on CSF production render them very potent as
potential mediators of CAP-induced aplastic anaemia (Jimenez et al.,
1990).
2.3 Observations in humans
The most serious adverse effect of CAP in humans are its ability to
cause a reversible dose-related bone marrow suppression or serious,
generally irreversible, aplastic anaemia, which is not considered to be
dose-related. The aplasia usually develops after a latency period, and
the affected people are considered to have some biochemical
predisposition. The incidence of the disease varies significantly and is
rather low, 1 in approximately 30 000 or more courses of therapy, but
the fatality rate is high when bone-marrow aplasia is complete. There is
a possible higher risk of acute leukemia in those who recover (Goodman &
Gilman, 1992).
Other manifestations of CAP toxicity have been reported. Prolonged
oral administration of therapeutic doses of CAP may induce bleeding,
either by bone marrow depression or inhibition of vitamin K synthesis
due to the reduction of intestinal flora that produce vitamin K. At dose
levels exceeding 25 mg/kg bw/day, "the grey syndrome" may occur in
premature and newborn infants, and also in adults and older children
given very high doses. The "grey syndrome" is characterized by abdominal
distention, vomiting, ashen colour, hypothermia, progressive pallid
cyanosis, irregular respiration, and circulatory collapse followed by
death in a few hours or days (Martindale, 1989). Haemolytic anaemia has
occurred in some patients with a genetic deficiency of
glucose-6-phosphate dehydrogenase activity. In 20 children with
glucose-6-phosphate dehydrogenase deficency who developed intravascular
haemolysis, CAP was involved in 5 cases (Choudry et al, 1990).
In a study of 45 pediatric patients who received CAP for the
treatment of central nervous system infections, anaemia occurred in 10,
leukopenia and neutropenia in 4, and eosinophilia in 16. The mean
cumulative dose of CAP ranged from 1.2 to 1.8 g/kg bw in patients with
adverse effects in comparison with 0.9 to 1.1 g/kg bw in those without.
This suggests that a high cumulative dose may be an important factor in
predisposing some patients to reversible haematological toxicity of CAP
(Nahata, 1989).
Contact sensitivity to CAP is rare in humans, most cases being
elicited by eye drops. The systemic administration of CAP is capable of
eliciting a reaction at sites previously exposed and sensitized (Urratia
et al., 1992).
Documentation on the ophthalmic use of CAP provides no evidence that
this route of administration is associated with the same toxicity risk
as CAP administered parenterally. In a study on 300 patients with
ophthalmic complaints treated topically with fusidic acid or CAP, the
incidence of side-effects was similar in both groups (Kairys & Smith,
1990).
A case of aplastic anaemia was reported in a patient treated with
i.v. CAP and cimetidine. The patient died 19 days after the initiation
of therapy. In an evaluation of nine cases of aplastic anaemia following
parenteral administration of CAP, the interval from the start of the
treatment to the onset of aplasia varied from 7 to 270 days. The
interval between the initial dose and death ranged from 18 days to 4.8
years. The authors concluded that the potential for aplastic anaemia
must be considered whenever CAP is used, regardless of the route of
administration (West et al, 1988).
A compilation of 576 cases of blood dyscrasia related to CAP
administration showed that aplastic anaemia was the most common type
reported, accounting for about 70% of the cases. The outcome was
apparently unrelated to the dose of CAP taken. However, the longer the
interval between the last dose and the appearance of first sign of the
blood dyscrasia, the greater was the mortality rate; nearly all patients
in whom this interval was longer than 2 months died (Goodman & Gillman,
1992).
The incidence of aplastic anaemia is particularly low in Hong Kong,
despite extensive use of CAP. Sales of CAP are between about 11 and
440-fold greater in Hong Kong than in several western countries and
Australia. In contrast, the certified death rate from aplastic anaemia
in Hong Kong is only 0.4 per 1000 deaths compared with 1.0 per 1000 in
England and Wales. The authors concluded that this low incidence may be
due to either genetic factors, inter-ethnic differences in the flora of
the gut, or relatively short treatment periods in Hong Kong (5 days in
most cases) (Kumana et al., 1988a).
The literature on the occurrence of medullary hypoplasia associated
with topical application of CAP in eye treatment is extremely limited,
despite the prevalence of this particular use. Based upon the analysis
of all known reported cases (4 cases reported from 1965-1982) the author
concluded that, even if usual per os doses of CAP could cause
medullary aplasia and if the prolonged administration of lower doses was
determined to be an added risk, an association between ocular use and
occurrence of blood dyscrasias could not be proven on the basis of cases
reported in literature (Ascari, 1989).
In a critical study of the risk of developing acute bone marrow
aplasia associated with the use of CAP, the author of the paper
referenced in this paragraph concluded that CAP, even administered in
small doses per os (1 g/day for 3-6 days) can cause bone marrow aplasia
and induce as side effects, malignant myelo-dysplasia or paroxystic
nocturnal haemoglobinuria. The repetition of treatments or the
chronicity of small doses is an additional risk. However, the potential
risk associated with small doses (of the eye drop type), cannot be
determined because a test case has not been documented (Najean, 1988).
During the past 30 years numerous epidemiological studies have been
performed to assess the incidence of bone marrow aplasia in populations
and to determine whether an association exists between the use of CAP
and the etiology of aplastic anaemia. The author of the paper referenced
in this paragraph concluded that in the past decade a remarkable decline
in the reported incidence of aplastic anaemia occurred when careful
diagnostic criteria have been applied to population surveys and the
proper clinical data have been collected for statistical evaluation. In
these studies, the incidence of CAP as an associated etiology has
decreased to an unmeasurable level. The widespread use of topical ocular
CAP throughout Europe in the past decade suggests that this mode of
application is associated with minimal if no cases of aplastic anaemia
(Gardner, 1990).
A multicentric prospective study in France between 1984 and 1987
recorded 250 cases of aplastic anaemia, with an annual incidence of 1.5
per million inhabitants. This is similar to the incidence in other
European regions, but lower than those published for the United States.
The fatality rate was estimated to be 17% at 3 months and 34% at 1 year
after diagnosis. As to the etiology of the disease 74% were declared
idiopathic, 13% presumably associated to drug toxicity, and 5% related
to hepatitis. The authors concluded that retrospective studies lead to a
much higher incidence rate than prospective studies. In their view, the
most accurate method to assess the incidence of aplastic anaemia in a
well defined population is by prospective identification of cases with
confirmation by follow-up (Mary et al., 1990).
The results of a large case-control study on the etiological factors
of aplastic anaemia conducted in France between 1984 and 1988 failed to
show any association between aplastic anaemia in humans and exposure to
CAP through ophthalmic use. However, the authors stated that the
frequency of the consumption of CAP made the quantification of its risk
impossible to estimate accurately using case-control methods. For
ophthalmic use of CAP, the ability of an epidemiological survey to
accurately assess an association with aplastic anaemia is unclear
(Baumelou et al., 1993).
In a report evaluating correlations between the incidence of
aplastic anaemia in different countries and the available information
about CAP use for medical, ophthalmic, or veterinary purposes, the
authors observed that no relationship could be demonstrated between
ophthalmic and veterinary uses of CAP and incidence of aplastic anaemia
(Mary & Baumelou 1993).
Based on the previous three reports and the status of knowledge on
aplastic anaemia available from the literature, an independent expert
concluded that there was no evidence that humans may be at risk of
developing aplastic anaemia when exposed to doses of CAP associated with
ophthalmic use or levels found as residues in food resulting from
veterinary uses (Mary, 1993).
A case report of acute myeloblastic leukemia associated with
previous CAP use and the onset of malignancy two years later, apparently
induced by oral CAP treatment (250 mg every six hours for 12 days), has
been described (Shah, 1988). Two more cases from India were reported
where the authors claimed that treatment with CAP in two children
resulted in hypoplastic anaemia which later turned into acute leukaemia
(Mitra, 1989). Another case of acute myeloid leukaemia with a rapid,
fatal outcome was reported from India in a 65-year old man following
treatment with 6 hourly doses of 500 mg of CAP for 8 days (Mappilacherry
& Chandra, 1990). Similar observations available from China (Shu et al.,
1988) have been debated by other authors (Kumana et al., 1988b),
leading to inconclusive evidence.
The use of CAP is strictly regulated in different parts of the
world. It is specifically prohibited in all food-producing animals in
the USA and Australia (Page, 1991). There are no data to implicate the
presence of residues of CAP in foods consumed by humans as a cause of
aplastic anaemia (Woodward, 1991).
3. COMMENTS
Additional genotoxicity data together with new epidemiological data
addressing the occurrence of aplastic anaemia in humans were available.
In addition, the Committee re-evaluated previous data on CAP, which were
summarized in the toxicological monograph published after the
thirty-second meeting (Annex 1, reference 81).
Rapid and extensive absorption of CAP occurred after oral
administration to laboratory animals and humans. It is distributed to
all major organs and tissues. In contrast to oral absorption, the
systemic uptake of the drug from ophthalmic application appeared to be
poor. The major route of excretion in animals and humans is urinary (up
to 90% of the administered dose, of which 15% is excreted as parent
compound and the rest in the form of metabolites). A number of
metabolites are formed, the major one being the glucuronide.
Single i.v. doses of CAP were moderately toxic to mice (LD50
1300-1800 mg/kg bw). There were no repeat-dose studies available to the
Committee.
The Committee concluded that adequate carcinogenicity studies were
not available, and an evaluation report was not presented (Annex 1,
reference 104, section 2.3). IARC came to the same conclusion in 1982,
1987, and 1990 (IARC, 1990).
The original genotoxicity studies and the new data suggested that
CAP and its metabolites were genotoxic in a number of in vitro test
systems, and in an in vivo study for chromosomal aberrations in mice.
The only negative study was a rat micronucleus test.
In rabbits given CAP orally at doses of 0, 500, 1000, or 2000 mg/kg
bw/day over days 6-15, 6-9, or 8-11 of gestation, high incidences of
fetal deaths occurred. There was no evidence of a teratogenic effect.
The NOEL was 500 mg/kg bw/day. In a series of studies in the rat,
embryolethality occurred even at the lowest dose tested, 500 mg/kg
bw/day. When mice were given oral doses of 500-2000 mg/kg bw/day CAP,
embryotoxicity occurred at all doses, but there was no evidence of a
teratogenic effect.
Adequate reproduction studies were not available, and an evaluation
report was not presented to the Committee (Annex 1, reference 104,
section 2.3).
The original epidemiological evidence reviewed by the Committee
suggested that treatment of humans with CAP was associated with the
induction of blood dyscrasias, particularly aplastic anaemia. The
Committee considered the new epidemiological data on aplastic anaemia,
which showed that the total incidence was of the order of 1.5 cases per
million people per year. Only about 15% of the total number of cases was
associated with drug treatment and among these CAP was not a major
contributor. These data gave an overall incidence of CAP-associated
aplastic anaemia in humans of less than one case per 10 million per
year. In considering epidemiological data derived from the ophthalmic
use of CAP, the Committee concluded that systemic exposure from this
form of treatment was not associated with the induction of aplastic
anaemia. However, it was not possible to quantify the actual systemic
exposure from ophthalmic use.
The Committee noted the extremely low overall incidence of aplastic
anaemia and the lack of association between the ophthalmic use of CAP
and aplastic anaemia. It concluded that human exposure to CAP residues
in food of the same order as exposure resulting from systemic uptake
after ophthalmic use would not cause any demonst-rable alteration in the
incidence of the disorder.
Toxicological considerations overshadowed any level of concern for
microbiological effects.
4. EVALUATION
The Committee was unable to establish an ADI for CAP due to the lack
of information to assess its carcinogenicity and effects on reproduction
and because the compound was genotoxic in a number of in vitro and in
vivo test systems.
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See Also:
Toxicological Abbreviations
Chloramphenicol (WHO Food Additives Series 53)
Chloramphenicol (WHO Food Additives Series 23)
CHLORAMPHENICOL (JECFA Evaluation)
Chloramphenicol (IARC Summary & Evaluation, Volume 50, 1990)