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EC number: 696-364-9
CAS number: 133779-11-0
The genotoxic potential of orally
administered N-C12-18-alkyltrimethylenediamine (Coco-diamine) to induce
micronucleus formation in bone marrow erythrocytes was determined in
The study was conducted according to OECD
474 guideline and under GLP.
In the range-finding assay, three mice per
sex received orally administered Coco-diamine in corn oil at dosage
levels of 150, 300, 600, 1200, 2500, or 5000 mg/kg body weight/day
(mg/kg/day) to determine a maximum tolerated dosage (MTD) that would be
used in setting dosages for the definitive study. A control group of
three male and three female mice received corn oil only. All mice were
observed and dosed for two consecutive days. Mice surviving the dosing
regimen were euthanized 48 hours after the administration of the last
dose and evaluated for specific signs of cytotoxicity reflected in
All mice receiving dosages of 300 mg/kg/day
or greater died on study, while in the 150 mg/kg/day dosage group only
one male mouse died. Adverse clinical observations reported for the 150
mg/kg/day dosage group included decreased body weight in female mice. A
set number of erythrocytes in both bone marrow and peripheral red blood
cell (RBC) pools from mice surviving to euthanasia were examined and the
number of RNA-positive (polychromatic) erythrocytes was counted to
determine cellularity and the frequency of PCEs among erythrocytes.
Suppression of PCE/RBC ratio to approximately 65% of that of the corn
oil control group was observed in both pools from mice receiving doses
of 150 mg/kg/day. From this suppression and the minimal mortality
observed at 150 mg/kg/day, an MTD of approximately 125 mg/kg/day was
determined for Coco-diamine.
In the definitive assay, at least 10 mice
per sex per dosage group were orally administered Coco-diamine in corn
oil dosage levels of 31.3, 62.5, or 125 mg/kg/day for two consecutive
days. Five mice per sex per dosage group were euthanized 24 hours after
the final dose and the same number 48 hours after the final dose; all
were evaluated for cytotoxicity and micronucleus formation in bone
marrow erythrocytes. A corn oil vehicle control group (10 mice per sex)
and a benzene positive control group (10 male mice only) were treated
similarly and evaluated concurrently with test groups. Salient clinical
signs included rough fur and loose stools in all Coco-diamine dosage
groups. One test-substance-related death was observed in the 62.5
mg/kg/day dosage group. Cytotoxicity, as indicated by a slight decrease
in the PCE/RBC ratio was observed in both sexes in the top two dosage
groups of Coco-diamine. However, all Coco-diamine-treated groups, when
compared to that of the corn oil control group, had average micronucleus
counts approximately equal to that of the control groups. Background
micronucleus incidences in bone marrow' erythrocytes of male and female
mice treated with corn oil alone averaged 0.18% and 0.22%, respectively.
The benzene positive control induced micronucleus rates at least 5-fold
greater than that of the background.
In summary, Coco-diamine at dosages up to
and including the MTD of 125 mg/kg/day did not induce increased
incidences of micronuclei in the bone marrow erythrocytes of
Swiss-Webster mice. Therefore, Coco-diamine was considered to be
non-genotoxic under these test conditions.
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