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Description of key information

In the rat ADME study 14C 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE administered orally was extensively absorbed (at least 82%), readily distributed, extensively metabolized, and excreted mainly in the urine. This is in line with the findings of the in vitro permeability study across the intestinal barrier indicating that 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE is considered to be highly absorbed in the human intestine. Dermal absorption was relatively slower and lower (8.79%) after a 30-min exposure period and moderate (16.8%) after a 24 hour exposure period. When absorbed, the test item was extensively metabolized and was excreted almost similarly in both urine and feces. The major biotransformation pathway was N-acetylation mainly in combination with oxidation and with glucuronidation. The metabolic pathways observed in the ADME study are in line with those observed in the in vitro metabolism studies with human keratinocytes (HaCaT) and hepatocytes; that is, N-acetylation was found to be the major route of metabolism. In human hepatocytes, N-acetylation of 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE was observed at all concentrations tested and also occurred in combination with glucuronidation. In both the human cell types no parent compound was found at the lowest concentration in the 24 hour incubations, indicating a complete metabolism of 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE. Taken together the findings indicate that the metabolism of 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE is similar in rodents and humans and that the major metabolic pathway is Phase II conjugation via N-acetylation.

Key value for chemical safety assessment

Absorption rate - oral (%):
82
Absorption rate - dermal (%):
17

Additional information

The oral bioavailability of 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE based on the blood AUC was high (93%) compared to the AUC after i.v. administration. When calculated from the urine data from the mass balance groups, the oral bioavailability was also determined to be high and was 84% at 12 mg/kg bw (Table ).

The average dermal absorption of 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE, when calculated from the urine data from the mass balance groups, was low, and was 9% at 11 mg/kg bw (0.5 hours exposure) and 17% at 11.5 mg/kg bw (24 hours exposure).

After i.v. and oral administration, elimination, mainly via the urine, was fast, with 85% of the total amount being excreted within in the first 48 h. The elimination after dermal doses was relatively slow, with 62% and 50% of the absorbed radioactive dose recovered by 48 h after a 0.5 h and 24 h exposure, respectively.

Table :       Overview of the mass balance data from the ADME study with 1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE in rats

 

Group No.

 

1-HEXYL-1H-PYRAZOLE-4,5-DIAMINE HEMISULFATE Dose Level / Concentration

 

  Dosing route  

 

   Absorption (%)  

 

   Excretion via urine/feces (%)

(relative to administered dose)

 1  

11.9 mg/kg bw

 

    i.v.  

 

   100  

 

  69 / 12

 2  

 12 mg/kg bw  

 

    oral   

 

     82   

 

    69 / 15

 3  

11 mg/kg bw;

0.186 mg/cm² (0.5 hours exposure)  

 

   dermal  

 

    9*   

 

 3 / 4

 4  

11.5 mg/kg bw; 0.208 mg/cm² (24 hours exposure)   

 

     dermal  

 

 17*  

 

  8 / 6

              

*: Percentage of the dose recovered from: excretion + exhaled air + cage-wash + carcass.