Summary of
FDA Information:Approval Date: January 30, 1998
Freedom of
Information Summary
NADA 041-061
I. GENERAL INFORMATION:
NADA 041-061
Sponsor: Pfizer Animal Health
Exton, Pennsylvania 19341
Generic Name: Carbadox Type A Medicated Article
Trade Name: MECADOX ® 10
Marketing Status: Over-the-counter (OTC)
Effect of
Supplement: This supplement provides for
the codification of
a revised tolerance for
residues of
carbadox in edible tissues.
II. INDICATIONS FOR USE
In swine, MECADOX® 10 is indicated for
the control of
dysentery and
bacterial enteritis and
for
growth promotion.
III. DOSAGE:
A. DOSAGE FORM
MECADOX® 10 is a Type A Medicated Article used in the
preparation of
finished Type C feeds.
B. ROUTE OF ADMINISTRATION
MECADOX® 10 is administered orally in the
finished feed.
C. RECOMMENDED DOSAGES:
Carbadox is administered ad libitum in a final feed at a concentration of
55 ppm. Medicated feed is not to be fed to swine weighing more than 75 pounds body weight.
The finished feed is not to be fed to swine within 10 weeks of
slaughter.
The Type A Medicated Article is not to be mixed in complete feeds containing less than 15% crude protein.
NOTES
IV. EFFECTIVENESS:
Not Given
V. ANIMAL SAFETY:
Not Given
VI. HUMAN FOOD SAFETY:
A. Toxicity Studies
The 36th Meeting of
the Joint FAO/WHO Expert Committee on Food Additives (JECFA) has evaluated the toxicology data for
carbadox and
its major metabolites.
These data clearly show that the
endpoint of
toxicological concern for
carbadox is carcinogenicity. Studies relating to the carcinogenic potential of
carbadox and
its metabolites are summarized.
Carbadox
Genotoxicity Studies
Carbadox was
evaluated by the sponsor and
others in standard genotoxicity batteries. Positive results were
seen in the
Ames test with Salmonella typhimurium TA1535, TA100, TA98 (+/- S9) and
equivocal results were
seen in the
Ames test in Salmonella typhimurium TA1536, TA1537, TA1538 and
C340. Mutagenicity Ames test was
positive for
E. coli WP2hcr, TA100 (+/- S9), and
TA 98 and
negative for
TA1535, TA1537, and
TA1538.
The host-mediated assay was
positive for
S. typhimurium and
negative for
TA1534 and
TA1952.
The repair test (Bacillus subtillis [rec] and
S. typhimurium [urv]) and
the fluctuation test (Klebsiella pneumoniae and
E. coli) were
positive.
The mutagenicity test (Saccharomyces cerevisiae D4), micronucleus test (rat bone marrow), repair test (Bacillus subtillis M45) and
chromosomal damage tests (mouse bone marrow and
in vitro human lymphocytes) were
positive.
The dominant lethal test in CD-1 mice was
negative (Pfizer Central Research, undated; Negishi et al., 1980; Ohta et al., 1980; Voogd et al., 1980; Beutin et al., 1981; Yoshimura et al., 1981; and
Cihak and
Srb, 1983).
Long-term/Carcinogenicity Studies
Rats
One hundred twenty Charles River C-D rats were
divided into
6 groups (10/sex/dose) and
received carbadox in the
diet at rates providing 100, 50, 25, 10, 5 and
0 mg carbadox/kg b.w./day for
26 months. Hematology and
urinalysis were
evaluated in 5 rats/sex/dose at 3, 6, 12, 18 and
25 months. Rats were
sacrificed at 14 and
112 weeks and
received gross necropsies. Tissues were
examined histopathologically (Stebbins, 1964).
At the interim sacrifice (14 weeks), rats in the
100 mg /kg b.w./day group showed decreased weight gain and
food consumption, reduced hemoglobin, RBCs and
neutropenia. Microscopic changes included pulmonary hemorrhage and
edema, adrenalcortical hemorrhage and
degeneration, splenic hemosiderin and
thymic atrophy. Rats in the
50 mg /kg b.w./day group showed decreased weight gain and
food consumption. Microscopic changes included pulmonary hemorrhage and
edema, adrenal cortical hemorrhage, necrosis and
degeneration, splenic hemosiderin and
renocorticomedullary fatty metamorphosis. All of
the rats in the
100 and
50 mg /kg b.w./day groups were
sacrificed at 14 weeks. In the remaining treatment groups, 3 rats/sex/dose were
sacrificed at 14 weeks. In the 25 mg /kg b.w./day group, rats had reduced weight gain, slight adrenal cortical atrophy, degeneration/necrosis and
renal tubular fatty change. Rats in the
5 and
10 mg /kg b.w./day groups had no clinical, gross or
microscopic changes reported at 3 months (Stebbins, 1964).
The remaining rats were
evaluated from
3 months up to and
including the 26-month sacrifice. In the 25 mg /kg b.w./day group, one female rat died at 51 weeks with no drug-related changes noted. All 13 remaining rats were
sacrificed at 73 weeks due to palpable abdominal masses. At necropsy, all rats had multiple hepatic nodules. Ten of
13 rats were
diagnosed microscopically as having benign nodular hyperplasia while the remaining 3 rats were
determined to have malignant transformation bases on metastatic foci in other organs. In the 10 mg /kg b.w./day group, one rat died after 67 weeks with reticuloendothelial neoplasia, a common tumor of
aged rats.
The remaining rats in the
group were
sacrificed between the 64th and
112th week. Eleven of
13 rats were
found to have hepatic benign nodular hyperplasia. In the 5 mg /kg b.w./day group, one male died at 20 weeks due to pulmonary abscesses.
The remaining 13 rats died or
were
sacrificed between the 61st and
112th week. Five of
the rats were
found to have hepatic benign nodular hyperplasia. One control rat was
sacrificed at 33 weeks with a forestomach papilloma and
pulmonary atelectasis.
A second male died at 93 weeks with myocarditis, nephrosclerosis and
peribronchitis.
The remaining rats were
sacrificed between the 80th and
112th week. None of
the control animals were
observed to have hepatic benign nodular hyperplasia (Stebbins, 1964).
In a study
to determine the level of
carbadox tolerated by rats chronically, 120 Charles River rats received 2.5, 1.0 or
0 mg/kg b.w./day of
carbadox in the
diet. Hematology, urinalysis and
ophthalmoscopic examinations were
done at 3, 6, 12, 18 and
24 months on 5 rats/sex/dose. Interim sacrifices of
5 rats/sex/dose were
conducted at 54 weeks with the remainder of
the rats being sacrificed at 106 weeks. All evaluated gross necropsies and
microscopic parameters were
within normal limits at 54 weeks. At two years in the
2.5 mg /kg b.w./day group, 7/27 rats displayed hepatic benign nodular hyperplasia and
peliosis hepatis. Additionally, the
2.5 mg /kg b.w./day group showed an increase in total mammary tumors. In the 1.0 mg /kg b.w./day group, 1/29 rats had hepatic benign nodular hyperplasia and
3/29 displayed peliosis hepatis. In the control group, 3/29 rats had hepatic benign nodular hyperplasia and
2/29 displayed peliosis hepatis.
The 1.0 mg /kg b.w./day dose was
tolerated by rats for
2 years with no adverse effects (Sigler, 1969).
In a third study
, rats (14/sex/group) were
treated with 25 mg/kg b.w./day carbadox or
one of
two lots of
desoxycarbadox in the
feed for
10 months to compare the oncogenic activity of
carbadox and
desoxycarbadox. An equal sized group served as untreated controls. Two to four rats were
sacrificed at 30, 60, 90, 191 and
309 days. Animals received a gross necropsy at sacrifice and
liver and
adrenals were
evaluated histopathologically.
A moderate decrease in body weight occurred in both sexes receiving carbadox. At necropsy, all groups treated for
10 months showed evidence of
hepatic changes including necrosis and
nodule formation. Changes in the
carbadox-treated group were
less severe than the changes in the
desoxycarbadox groups. All desoxycarbadox-treated rats and
2/18 of
the carbadox-treated rats showed evidence of
hepatocellular carcinoma.
There was
a significant increase in adrenal cortical hemorrhage in all treatment groups. In this study
, carbadox induced tumors in rats (King, 1976).
Monkeys
The long-term toxicity of
carbadox in primates was
assessed. Twenty-eight monkeys were
divided into
4 groups of
7 animals (3 or
4 per sex) and
were
dosed with carbadox orally in gelatin capsules. Doses were
20 mg/kg b.w./day (as 5 mg/kg b.w./day QID), 10 mg/kg b.w./day (as 5 mg/kg b.w./day BID) or
5 mg/kg b.w./day and
controls. Animals were
evaluated at 1, 3, 6, 12 and
24 months. Animals were
sacrificed at 3 months and
2 years. Elevated transaminase levels were
detected at the
3- and
6-month evaluations.
The monkeys tolerated 20 mg/kg b.w./day for
2 years with no adverse effects (Coleman, 1967).
Summary
Using data from
these studies, a low-dose linear statistical model was
used to determine an S0 of
106 ppt for
carbadox.
Desoxycarbadox
Genotoxicity Studies Desoxycarbadox was
evaluated by the sponsor in standard genotoxicity test batteries. Negative results were
seen in the
Ames tests with TA1535, TA1537, TA1538, TA100, TA98, TA1537+S9 and
TA1535 +S9.
The host-mediated assay was
negative for
TA1950, for
TA1950 in mice and
rats, and
TA1535 in rats.
The Ames test was
positive for
TA1535+/- TA100S9(rat) and
for
TA1535+S from
rat and
mouse.
The Ames test was
negative TA1535+S9 from
hamster, dog and
monkey.
The chromosomal damage test was
negative for
human lymphocytes and
rat bone marrow in a 5-day test.
The chromosomal damage test was
positive for
rat bone marrow in a 9 month feeding test.
The cell transformation test in BALB/C Swiss 3T3 was
positive (Pfizer Central Research, 1975; Holmes, 1976).
Long-term/Carcinogenicity Studies
Rats
A long-term study
was conducted by the sponsor to determine the tumorigenic potential of
desoxycarbadox, a carbadox metabolite. Four hundred Charles River C-D rats were
divided into
groups of
50/sex/dose. Desoxycarbadox was
administered continuously in the
diet at doses of
0, 5, 10 and
25 mg/kg b.w./day. Although treatment originally was
scheduled for
2 years, test material was
withdrawn from
all rats in the
25 mg/kg b.w./day and
50% of
the rats of
each sex in the
other two treatment groups on day 350 due to high morbidity and
mortality. Administration of
desoxycarbadox was
stopped completely on day 416.
The study
was terminated on day 447 (Reinert, 1976).
Clinical examinations revealed a number of
treatment-related signs including tumors in the
mammary region in both sexes, small cutaneous nodules, and
enlargement of
the liver with nodules preceded by weight loss and
polyphagia.
There was
a dose-related decrease in weight gain and
a dose-related decrease in survival. Clinical chemistry parameters were
evaluated. Desoxycarbadox resulted in increases in plasma enzyme activity, urea and
bilirubin, abnormalities consistent with hepatic disorders.
The results were
highly variable and
nonreversible following drug withdrawal.
A dose related hypoglycemia was
noted in both sexes. Hematological parameters were
evaluated in 10 rats/sex/group at day 413 and
for
the remainder on day 447.
A moderate hypochromic microcytic anemia was
seen in the
25 mg/kg b.w./day groups and
a slight anemia was
seen in the
10 mg/kg b.w./day.
A neutrophilia also was
observed in the
25 mg/kg b.w./day (Reinert, 1976).
All rats received a gross necropsy. Histopathological examinations were
performed on all grossly abnormal tissue and
routinely on a standard array of
tissues.
There was
a dose-related increase in pigmentation of
the renal tubules and
nephrosis. An increased tumor incidence was
seen in all treatment groups. Desoxycarbadox is a potent hepatocarcinogen and
there were
dose-related increases in other tumors (Reinert, 1976).
Summary
Using data from
these studies, a low-dose linear statistical model was
used to determine an S0 of
61 ppt for
desoxycarbadox.
Hydrazine
Genotoxicity Studies
Hydrazine was
evaluated by several researchers in standard genotoxicity batteries. Positive results were
seen in the
Salmonella typhimurium Ames test, the
mouse lymphoma cell test and
the bacterial test using E. coli WP2 uvr A trp (Ames, 1971; von Wright and
Tikkanen, 1980; and
Rogers and
Back, 1981).
Long-term/Carcinogenicity Studies
Mice
A number of
long-term/carcinogenicity studies have been conducted in mice to evaluate the toxicity of
hydrazine.
These published studies are briefly summarized for
completeness.
Oral administration of
hydrazine to BALB/C female mice at 1.13 mg/day for
46 weeks produced a 100% incidence of
lung tumors (Biancifiori and
Ribacchi, 1962).
A 46% incidence of
lung tumors was
seen in female Swiss mice treated with hydrazine at a dose level of
0.25 mg/day for
5 days/week for
46 weeks. Control mice had a 10% incidence (Roe et al., 1967).
In a study
with CBA/Cb/Se mice, hydrazine was
administered by gavage at a dose of
1.13 mg/day for
36 weeks. Treated mice had an incidence of
76% and
90% lung tumors for
males and
females, respectively. Control mice had an incidence of
3%. Hepatomas were
found in 62% of
males and
71% of
the females treated with hydrazine. Control mice had an incidence of
11% and
4% for
males and
females, respectively (Severi and
Biancifiori, 1968).
CBA mice were
divided into
groups of
40-59 mice /sex. Hydrazine was
administered by gavage daily for
150 days at rates of
45, 22, 11, 5.6 and
0 mg/kg b.w./day. Mice were
examined at natural death or
following sacrifice when
moribund. Control males had a hepatoma incidence of
10% while females had a 3.4% rate. Treated males had hepatoma rates of
60, 48, 28 and
3.8%, at 45, 22, 11, 5.6 mg/kg b.w./day, respectively. Treated females had hepatoma rates of
62.5, 66.6, 8 and
0%, respectively (Biancifiori, 1970).
Hamsters
Golden hamsters were
divided into
three groups of
23, 35 and
56 animals. Animals received 60 doses of
3.0 mg hydrazine via intubation over a 15-week period, 100 doses of
2.8 mg hydrazine via intubation over a 20-week period, or
no hydrazine, respectively. Hepatic lesions, including fibrosis, reticuloendothelial cell proliferation and
bile duct proliferation, were
found in 60-80% of
the treated hamsters but in none of
the control animals (Biancifiori, 1970).
Negative tumorigenicity results were
obtained in a chronic study
in golden hamsters. Fifty hamsters/sex received hydrazine in the
drinking water at 2.3 mg/day for
a lifetime (Toth, 1972).
Rats
A chronic oral study
was conducted in Cb/Se rats. Hydrazine was
administered daily by stomach tube at doses of
18 mg/rat to 14 males and
12 mg/rat to 18 females. Dosing continued for
68 weeks. Lung tumors were
found in 21 and
27% of
the dosed male and
female rats, respectively. Control groups (28M, 22F) had no lung tumors. Hepatic tumors were
found in 30% of
the treated males while no hepatic tumors were
found in treated females or
controls (Severi and
Biancifiori, 1968).
Summary
Based on these published data, FDA has concluded that hydrazine induces tumors in animals. Using a low-dose linear statistical model, an S0 of
11 ppb is calculated.
Methyl Carbazate
Genotoxicity Studies
Methyl carbazate was
evaluated in standard genotoxicity batteries. Negative results were
seen in the
Ames tests and
the chromosomal damage test. Results in the
host-mediated assay were
equivocal (Pfizer Central Research, 1975; Holmes, 1976).
Long-term/Carcinogenicity studies
Rats
The chronic oral toxicity of
methyl carbazate, a metabolite of
carbadox, was
studied by the sponsor in the
rat. Wistar rats were
divided into
groups of
12/sex/dose and
received methyl carbazate at target doses of
1 and
10 mg/kg b.w./day in feed for
10 months. Necropsies were
performed on all animals and
histology was
conducted on a standard array of
tissues and
all tissues with grossly observed tumors.
Three males and
three females in the
high dose group died before termination. No histopathological evidence of
toxicity or
evidence of
elevation in tumors was
reported.
The administration of
methyl carbazate to rats at dose levels of
1 and
10 mg/kg b.w./day produced no evidence of
carcinogenic potential (Rutty, 1972).
In a second study
conducted by the sponsor, Wistar rats were
divided into
groups of
24/sex and
were
treated with target doses of
0, 2.5, 5 and
10 mg/kg b.w./day in the
feed for
710 days. Clinical examinations were
conducted weekly. Blood samples for
clinical chemistry were
obtained at terminal sacrifice and
from moribund animals. Hematology was
conducted on samples from
moribund and
dead rats as well as from
an interim sacrifice of
6 rats at 12 months. Rats were
sacrificed and
necropsied at 710 days. Histopathology was
performed on all gross lesions and
on a standard array of
tissues.
There were
no treatment-related effects noted in any parameters evaluated in the
study
.
There was
histological evidence of
widespread chronic respiratory disease in all groups. Methyl carbazate had no adverse effect when
given to rats in the
diet for
2 years (Ferrando, 1980).
Summary
On the basis of
these studies, the
agency has concluded that methyl carbazate does not induce tumors in animals.
Quinoxaline-2-Carboxylic Acid (QCA)
Genotoxicity Studies
Quinoxaline-2-carboxylic acid was
evaluated by the sponsor in a standard genotoxicity battery. Negative results were
seen in the
Ames tests with Salmonella typhimurium, TA1535, TA1537, TA1538 and
TA1535+S9 tests.
The chromosomal aberration test in in vitro human lymphocytes also was
negative (Pfizer Central Research, 1975).
Long-term/Carcinogenicity Studies
Mouse
Charles River CD mice (50/sex/dose) received QCA in feed for
19 months at levels to deliver 0, 25, 50 and
100 mg/kg b.w./day. Hematology and
clinical chemistry were
evaluated once, prior to sacrifice. Necropsies were
performed on all animals and
histopathological examinations were
conducted on a standard array of
tissues. No treatment-related effects were
noted in any parameter during the study
. Cumulative mortalities and
incidences of
tumors were
comparable for
the control and
treatment groups. Oral administration of
QCA to mice for
19 months produced no evidence of
toxicity (Faccini et al., 1979).
Rats
Nine male and
9 female Charles River C-D rats were
divided into
groups of
3 rats/sex/dose. Rats received QCA in the
feed for
2 years at levels to provide 100, 50 or
0 mg/kg b.w./day. Rats received clinical examinations weekly and
routine ophthalmoscopic, hematology and
urinalysis examinations. Terminal sacrifice was
performed on day 735 of
the study
. All rats received gross necropsies and
standard tissues were
evaluated microscopically. No treatment-related changes were
reported and
QCA was
tolerated at up to 100 mg/kg b.w./day when
given to rats via feed (Coleman, 1971).
In a study
to determine whether QCA has tumorigenic potential, Charles River Sprague-Dawley rats (20/sex/dose) were
treated with QCA in the
diet for
two years at doses to provide 0, 10, 25, and
50 mg/kg b.w./day. Rats received clinical examinations weekly and
routine ophthalmoscopic, hematology and
urinalysis examinations. At 12 months, 5 rats/sex/dose and
at 24 months all remaining rats were
sacrificed, received a gross necropsy and
standard tissues were
examined histopathologically. No treatment-related effects were
noted for
any of
the evaluated parameters. Cumulative tumor rates were
comparable for
control and
treated rats. QCA in doses of
10, 25, and
50 mg/kg b.w./day over a two year period does not produce any toxicity or
elevated tumor incidence (Pfizer Central Research, 1971).
Summary
Thus, quinoxaline-2-carboxylic acid is not a carcinogen in animals.
B. Definition of
"No Residue"
Neither an ADI nor a safe concentration of
total residues is calculated for
carbadox. Carbadox, and
its metabolites desoxycarbadox and
hydrazine, were
determined to be carcinogenic in animals. Methyl carbazate and
quinoxaline-2-carboxylic acid were
also tested in short-term genotoxicity assays and
carcinogenicity studies and
these compounds are not carcinogens.
Pursuant to 21 CFR § 500.84(c)(2), FDA considers that "no residue" of
a compound remains in edible tissue when
the residue of
carcinogenic concern in the
total diet of
people does not exceed S0.
The S0- is defined in 21 CFR §§ 500.82(b) and
500.84 (c)(1) as the concentration of
total residue of
carcinogenic concern of
the test compound in the
total diet of
test animals that corresponds to a maximum lifetime risk of
cancer in the
test animals of
1 in 1 million. For carbadox and
each of
the carcinogenic metabolites, an S0 was
calculated using a low-dose linear extrapolation statistical model. An S0 of
106 parts per trillion, 61 parts per trillion, and
11 parts per billion was
calculated for
carbadox, desoxycarbadox, and
hydrazine, respectively. Based on these results, an S0 of
61 parts per trillion (ppt) is determined for
the total residues of
carcinogenic concern for
carbadox in the
total diet. As provided in 21 CFR § 500.82(b), this concentration, i.e., the
S0, represents no significant increase in risk of
cancer to people.
Because the total human diet is not derived from
food producing animals, a correction for
food intake is made in determining the concentration of
residues of
carcinogenic concern that will be permitted in edible animal tissue, 21 CFR § 500.84(c)(2). FDA designates as Sm the permitted concentration of
residues of
carcinogenic concern in a specific edible product, 21 CFR §§ 500.82(b) and
500.84 (c)(2). Given a 1500 g total daily diet in humans, it is assumed that up to 500 g is due to the consumption of
meat. Of this 500 g total daily meat consumption, 300 g is assumed to be comprised of
muscle, 100 g comprised of
liver, 50 g comprised of
kidney, and
50 g comprised of
fat.
Thus, for
any calculated S0,
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