No. 1031 - Miljøstyrelsen
No. 1031 - Miljøstyrelsen
No. 1031 - Miljøstyrelsen
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10<br />
CAS no Synonym<br />
Test Exposure<br />
route<br />
556-67-2 D4 evaluation of D4 as<br />
inhibitor of human<br />
cytochrome P450<br />
enzymes<br />
556-67-2 D4 in vitro dermal absorption,<br />
Flow-<br />
Through Diffusion<br />
Cell System<br />
Species / model Conc. Exposure<br />
period<br />
in vitro human liver microsomes<br />
from 7<br />
individuals<br />
in vitro percutaneous<br />
556-67-2 D4 absorption potential oral gavage rat (♀,♂), Fisher<br />
344<br />
556-67-2 D4 physiologically based<br />
pharmacokinetic<br />
modelling (PBPK)<br />
556-67-2 D4 physiologically based<br />
pharmacokinetic<br />
modelling (PBPK)<br />
human skin neat D4 and formulated<br />
D4 (antiperspirant)<br />
Result/Effects NOAEL /<br />
LOAEL<br />
0.32 - 2.9 µM no data non competitive inhibitor of rat CYP2B1/2 (estimated Ki=0.11<br />
mM)<br />
non competitive inhibitor of human CYP2B6 (estimated<br />
Ki=3.6 mM)<br />
competitive inhibitor of human CYP1A2 (estimated Ki=12<br />
mM)<br />
non competitive inhibitor of human CYP2D6 and CYP3A4/5<br />
(estimated Ki=14 and 11 mM)<br />
either competitive or non competitive inhibitor of CYP2C19<br />
(estimated Ki=6.4 or 11 mM)<br />
little or no capacity to inhibit rat CYP1A2 and human CYP2A6,<br />
CYP2C9 and CYP4A9/11 activity<br />
activator of human CYP2E1<br />
little or no capacity to to function as metabolism-dependent<br />
inhibitor of any of the P450 enzymes examined (except rat<br />
CYP1A1/2 and human CYP3A4/5<br />
300 mg/kg 14C-D4 single exposure<br />
inhalation human 10 ppm 14C-D4 one hour<br />
during altering<br />
periods of rest<br />
and exercise<br />
inhalation,<br />
dermal, oral,<br />
i.v.<br />
24 hours 0.50% of neat D4 absorbed (91.6% recovered from analysed<br />
sample)<br />
0.49% of formulated D4 (103.2% recovered from analysed<br />
sample)<br />
carrier has an impact on absorption<br />
peak levels of radioactivity delayed relative to parent D4<br />
by 24 hr most of the radioactivity in blood could be attributed<br />
to metabolites<br />
most of D4 absorbed from corn oil and neat D4 was metabolised<br />
and excreted via urine<br />
hepatic extraction calculated from model parameters was<br />
0.65 to 0.8 (clearance nearly flow-limited)<br />
decreased retension of inhaled D4 during periods of exercise<br />
was explained by altered ventilation/perfusion characteristics<br />
and a rapid approach to steady-state conditions<br />
high lipophilicity coupled with high hepatic and exhalation<br />
clearance<br />
increased confidence in the utility of the model for predicting<br />
human tissue concentrations of D4 and metabolites during<br />
inhalation exposures<br />
rat no data no data pharmacokinetics of D4 delivered by inhalation or dermal<br />
routes is similar, and is different from the i.v. or oral delivery<br />
route<br />
EPA DCN/Ref.<br />
not relevant 86990000017<br />
1998<br />
not relevant 86980000163<br />
1998<br />
not relevant 86980000184<br />
1998<br />
not relevant Ready MB et al,<br />
2003<br />
not relevant Sarangapani R et<br />
al<br />
2003