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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
calculation (if not (Q)SAR)
Remarks:
Migrated phrase: estimated by calculation
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards and is reported in sufficient detail.

Data source

Reference
Reference Type:
publication
Title:
Toxicokinetic modelling of methyl formate exposure and implications for biological monitoring.
Author:
Nihlén A and Droz P-O
Year:
2000
Bibliographic source:
Int Arch Occup Environ Health 73, 479-487.

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
A toxicokinetic model to describe human inhalation exposure, and to predict the urinary excretion of the metabolites methanol and formic acid, was developed. The model was validated against human experimental data.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
human

Administration / exposure

Route of administration:
inhalation
Duration and frequency of treatment / exposure:
6 hour(s)
Doses / concentrations
Remarks:
Doses / Concentrations:
Males: 100 ppm
No. of animals per sex per dose:
Males: 40

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parameters
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 0.1 min

Metabolite characterisation studies

Metabolites identified:
yes

Any other information on results incl. tables

1. Prediction of individual urinary metabolite level time course 
Assuming an 8-h inhalation exposure to 100 ppm MFT the model predicted 8-h MeOH level of 0.119 mM which fitted well with
the measured average 0.113 mM. Further the model predicted FA levels of 0.76 mmol/g creatinine, compared to the average
measured 0.70 mmol/g creatinine. 

The rate constants used were derived from 16 subjects exposed to 100 ppm MF:

KMF (oxidation and hydrolysis of MF) = 6.7 (6.1-7.3) 1/min, and 
FMF (fraction of hydrolysis) = 97 (95-100)%.


2. Predictions of urinary metabolite excretion after 8-h exposure to MF

2.1. Methanol
The model predicted a linear relation between the urinary concentration of MeOH and increasing MF exposure levels in
the range 0 - 150 ppm MF, both at rest and at light work load. The predicted levels of urinary MeOH were higher at
the end of the work-shift compared to the level before shift. The prediction fitted well with values measured after 8 h
occupational MF exposure (Berode et al., 2000).

2.2. Formic acid
A nonlinear relationship was noted between formic acid in urine after a 8-h work-shift and increasing concentrations of MF
in the air. The curve was relatively flat at background levels and up to approx. 50 ppm, and much steeper at MF concentrations >50 ppm.


2.3 Urinary metabolite time course
The model was used to calculate the urinary concentration vs. time curve for MeOH and FA. During the 8-h work shift
the concentrations increased and declined thereafter. FA returned to background levels within 2-4 h after the end of
exposure. The elimination of MeOH was much slower, as background levels were not reached until 8-12 h after the
end of exposure.

Table: Urinary exretion ; selected values (human exposure during 0-8 hours):


=====================================================
MF in air    Time       urinary FA       urinary MeOH      
(ppm)       (hours)  (nmol/g creat.)         (mM)

-----------------------------------------------------
Background    0           0.30               0.054

50 ppm        8           1.0                0.14
             12           0.3                0.08
             24           0.3                0.054  

100 ppm       8           2.4                0.24
             12           0.4                0.125
             24           0.3                0.054  
=====================================================

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:

Conclusion:

The authors developed a TK-model that fitted well into measured data and allows prediction of time-concentration curves for metabolites of methyl formate. Background levels for urinary methanol (MeOH; 0.054 mM) and formic acid (0.30 nmol/g creatinine) were provided. A mean rate constant for the global oxidation and hydrolysis metabolism of methyl formate in human subjects (n=16) was provided (6.7 (6.1-7.3)), which compares to a halflife time as follows: t1/2= ln 2/k (1st order reaction) = 0.69/6.7 = 0.01 minutes. Hydrolysis of methyl formate to formic acid and MeOH accounts for 97 (95-100) %. Oxidation is therefore a minor metabolic pathway. Formic acid is more rapidly eliminated compared to MeOH.

Both urinary formic acid and MeOH could be used as markers for biomonitoring. MeOH is more suitable at lower exposures, whereas formic acid is more sensitive at higher exposures. Both paramters were clearly increased after an 8 -hour exposure period at 50 ppm and at 100 ppm, but the increase at 50 ppm was relatively small compared to the background level. 50 ppm is currently the German OEL.