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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP study, well documented and scientifically fully reliable. For the sake of clarity individual Robust Summaries were prepared for the intravenous and the oral rat and mouse studies. These studies were assigned key studies in the OECD/ICCA program as they provide essential information on the behavior of formamide in rodents.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Toxicokinetics of formamide in the rat following single oral administration.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Formamide
EC Number:
200-842-0
EC Name:
Formamide
Cas Number:
75-12-7
Molecular formula:
CH3NO
IUPAC Name:
formamide
Details on test material:
Formamide was obtained from Aldrich, purity was given as 99.5%.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
Males: 36, 300, and 600 mg/ kg bw
Females: 36, 300, and 600 mg/ kg bw
No. of animals per sex per dose / concentration:
24
Control animals:
other: not required
Positive control reference chemical:
not required
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling: 5, 10, 15, and 30 minutes, 1, 1.5, 2, 5, 8, 12, 20, 30, 48, 72, and 96 hr postdose.
Statistics:
Formamide plasma concentrations were calculated using internal standard response factors and established standard curve parameters. Sample mean, standard deviation, and relative standard deviation were calculated using commonly accepted practices.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The authors concluded: Formamide was rapidly and completely absorbed following oral administration to male and female rats. Peak plasma levels were reached within 1 to 2 hours after oral gavage.
Details on distribution in tissues:
not examined
Details on excretion:
Across all doses a mean combined male and female elimination t1/2 of 15.3 +/- 3.1 hr was calculated from the data contained in the result table.
The pharmacokinetic parameters DNAUC and clearance were comparable between male and female animals at all dose levels, suggesting linear kinetics after oral administration of formamide over the dose range 36 to 600 mg/kg bw. Comparison of the estimated peak plasma levels across dose levels supports this.
Toxicokinetic parameters
Toxicokinetic parameters:
half-life 1st: 15.3 h

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables


Observations: there was no clinical sign of health effects in any of the animals at any dose level.

Table:  pharmacokinetic parameters for formamide following a single oral administration to rats


============================================================
              36 mg/kg bw       300 mg/kg bw    600 mg/kg bw
------------------------------------------------------------
Parameter     male  female     male  female     male  female
------------------------------------------------------------
-
DNAUC         33     26        37     26        41      32 
        
F             1.3    1.2       1.4    1.2       1.6     1.4

Cmax          50     51       301    269       823     753 
tmax          1.9    1.5       2.4    1.5       1.7    1.3 
t1/2 abs      0.35   0.28      0.42   0.26      0.28   0.19     

t1/2 elim     14.8   11.0      18.8   12.6      18.5  15.8  
Cl             39     46        38     45        39      44 

V            662    648       913   1025       684     755 
 
MRT           23     19        25     18        24      20 
MAT            4.8    1.5       7.1    0.9       5.6    3.4 
============================================================
DNAUC (µg hr/mL)/dose)  =  dose normalized area under the curve
F                             
     = absolute bioavailability
Cmax      (µg/mL)              =  max. plasma concentration
tmax      (hr)                 =  time to max. plasma concentration
t1/2 abs  (hr)                 = absorption half-life
t1/2 elim (hr)                 = elimination half-life 
Cl        (mL/hr kg)           = clearance 
V         (mL/kg)              = distribution volume
MRT       (extravascular, hr)  = mean residence time
MAT       (hr)                 = mean absorption time

============================================================

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Executive summary:

 The authors concluded:

Absorption: Formamide was rapidly and completely absorbed following oral administration to male and female rats. Peak plasma levels were reached within 1 to 2 hours after oral gavage. 

Excretion: plasma half-live time was 15.3 hours across all doses in both sexes. The pharmacokinetic parameters DNAUC and clearance were comparable between male and female animals at all dose levels, suggesting linear kinetics after oral administration of formamide over the dose range 36 to 600 mg/kg bw. Comparison of the estimated peak plasma levels across dose levels supports this.  Clearance of formamide was approx. 39 mL/hr kg bw in males (and 45 hours in females) irrespective of the dose level.

Comparison of the pharmacokinetic parameters after intravenous and oral dosing suggests that the elimination half-lives are slightly longer for the oral route which may have resulted in an overestimation of the AUC and finally bioavailability. However, clearance was not changed. Other explanations of t1/2 values to be greater is saturation of protein binding or saturation of tubular reabsorption (according to the authors observed when the compound is excreted largely unchanged).

 

Bioavailability: The authors offered possible explanations for the finding that the absolute bioavailability (F) was greater than 1 (i.e. bioavailability was greater after oral than after i.v. administration): 

 

- formamide undergoes rapid first pass lung clearance after injection which would result in less than the injected amount reaching the general circulation (F<1). This effect could be greater after i.v. injection than after oral administration, consequently the actual amount of drug reaching the general circulation would be greater after oral dosing than intravenous (AUC oral > AUC i.v.). 

- enterohepatic cycling; this is often (but not always) accompanied by a biphasic plasma concentration-time curve. No such secondary peak was detected in this study. Oral and intravenous doses were not equivalent, therefore the dose normalized AUCS after intravenous and oral dosing cannot be compared to establish enterohepatic cycling. 

 

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