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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Objective of study:
toxicokinetics
Principles of method if other than guideline:
The study was performed to examine the absorption of methanol after oral administration and the rate and the extent of methanol absorption during inhalation exposure in rats and mice.
GLP compliance:
not specified
Radiolabelling:
no
Species:
other: rats and mice
Strain:
other: Sprague-Dawley and CD-1
Sex:
female
Route of administration:
other: oral:gavage and inhalation: vapour
Vehicle:
other: water and unchanged
Details on metabolites:
After oral administration of 100 and 2500 mg methanol/kg to female rats, gastrointestinal absorption was 100% within minutes (abs. half-life 1.5 min and 7.6 min, respectively).
The maximum elimination rate is about twice as high in mice as in rat: 117.0 ± 3 and 60.7 ± 1.4 mg/hour/kg.
After inhalation at exposure concentrations from 1.3 to 6.7 mg/L (corresponding to 1000 to 5000 ppm), the mean fractional respiratory absorption of methanol in rats and mice was found to about 85%. At exposure concentrations from 13.3 to 26.6 mg/L (corresponding to 10000 - 20000 ppm), the mean fractional respiratory absorption of methanol tended to be lower (approximately 70%) in rats, but not in mice.
Blood levels in rats were about 1000 mg/L (observed: 1047 ± 298 mg/L; predicted: 1018 mg/L) at 6.7 mg/L methanol (corresponding to 5000 ppm; 8 hour exposure). Blood levels in mice were about 3500 mg/L (observed: 3580 ± 599 mg/L; predicted: 4188 mg/L) at 6.7 mg/L methanol (corresponding to 5000 ppm; 8 hour exposure).
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Objective of study:
toxicokinetics
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
- only females were studied; determination of the amount of test substance only in urine and blood; no analysis of metabolites
GLP compliance:
not specified
Radiolabelling:
no
Species:
mouse
Strain:
CD-1
Sex:
female
Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
8 hours for one day
Remarks:
Doses / Concentrations:
3.3; 6.7 and 13.0 mg/L (corresponding to 2500; 5000 and 10000 ppm)
No. of animals per sex per dose:
Mice were exposed individually and in groups of 8 to 9 animals per dose.
Control animals:
yes
Details on metabolites:
Mice exposed to methanol in air at concentrations of 3.3 - 13 mg/L (corresponding to 2500 to 10000 ppm) absorbed the substance rapidly. Blood methanol concentrations were approximately 500 - 3000 mg/L at 1 hour and 500 - 4000 mg/L at 6 hours exposure.
Total 8 hours ventilation decreased slightly with increasing exposure concentration. The calculated values of the fraction of inhaled methanol absorbed was approx. 85% in mice. No statistically significant differences between exposed groups were observed for the fractional absorption.
Measured ventilation, fractional absorption, and systemic kinetic parameters were combinded in a semiphysiologic pharmacokinetic model that yielded accurate predictions of blood methanol concentrations during and after an 8 hours exposure. Model predictions for the mouse were compared to previously developed inhalation toxicokinetic model for the rat.
The comparison demonstrated that at similar methanol vapour concentrations, mice evidenced a two- to threefold higher blood methanol cencentration than rats, despite the fact that V(max) for methanol elimination in the mouse is twofold higher than that in the rat. The fractional absorption was higher in mice (approx. 85%) than in rats (56 - 87%) (p. 251; Perkins et al., 1995).
At the teratogenic exposure concentration in mice of 6.7 mg/L (corresponding to 5000 ppm), the following blood levels would be achieved mouse: 2313 ± 338 mg/L (exposed as group; Perkins et al., 1995); rat: 1047 ± 298 mg/L (Pollack and Brouwer, 1996).
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Objective of study:
toxicokinetics
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
- only females were studied; determination of the amount of test substance only in urine and blood; no analysis of metabolites
GLP compliance:
not specified
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
8 hours for one day
Remarks:
Doses / Concentrations:
1.3; 6.7; 13.0; 20.0 and 26.6 mg/L (corresponding to 1000; 5000; 10000; 15000 and 20000 ppm)
No. of animals per sex per dose:
3 - 4
Control animals:
yes
Details on metabolites:
Blood methanol concentrations were approximately 100 - 4000 mg/L after 8 hours exposure to 1.3 to 26.6 mg/L methanol vapour.
The influence of inhaled methanol exposure on total 8 hours ventilation remained fairly constant during exposure for each rat. The mass of methanol extracted from the air and the mass in the blood pluss mass eliminated were on balance approximately equal during the course of the experiment regardless of concentration. The total amount of methanol taken up by the animal increased as exposure concentration increased, the relationship, however, was not proportional, which suggests that the fraction absorbed differed across exposure concentrations. The fraction absorbed decreased as exposure concentration increased: fractional absorption of inhaled methanol (1.3 to 26.6 mg/L) was 87% to 60%.

Comparison of rat and mouse: The same environmental methanol vapour concentration lead to very different blood methanol levels and these were higher in mice although the maximum elimination rate was about twice as high in as in rats (Pollack and Brouwer 1996).
At an concentration in mice of 6.7 mg/L (5000 ppm, which was teratogenic in mice), the following blood levels were estimated: mouse 2313 ± 338 mg/L (exposed as group; Perkins et al., 1995); rat 1047 ± 298 mg/L (Pollack and Brouwer, 1996).
In conclusion, the same environmental methanol vapour concentration leads to very different blood methanol level. Therefore, risk assessment for methanol should be based on blood concentrations following inhalation exposure, not on exposure concentrations itself. The differences between the teratogenic potential of methanol in rats versus mice, with mice being approximately two-fold more sensitive than rats may be due to the differences in blood concentrations.

Description of key information

Based on experimental data, the test substance is fast adsorbed and metabolised, so it has no bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - inhalation (%):
60

Additional information

Methanol is readily absorbed after inhalation, ingestion and dermal contact and distributed rapidly throughout the body. The clearance from the body is mainly due to metabolism (up to 98%), with more than 90% of the administered dose exhaled as carbon dioxide. Renal and pulmonary excretion rates contribute to only about 2 – 3%. The metabolism and toxicokinetics of methanol varies by species and dose. In humans, the half-life time is approximately 2.5 – 3 hours at doses lower than 100 mg/kg bw. At higher doses, the half life can be 24 hours or more (IPCS/WHO, 1977; Kavet and Nauss, 1990).

The mammalian metabolism of methanol occurs mainly in the liver, where methanol is initially converted to formaldehyde, which is in turn converted to formate. Formate is converted to carbon dioxide and water. In humans and monkeys, the oxidation to formaldehyde is mediated by alcohol dehydrogenases and basically limited to the capacity of those enzymes. In rodents, the oxidation to formaldehyde predominantly employes the catalase-peroxidase pathway which is of less capacity than the ADH-pathway in humans but on the other hand produces oxygen radicals which may be involved into the developmental effects in rodents which - in contrast to humans - tolerate high methanol levels without signs of CNS or retinal toxicity. The last oxidation step, conversion of formate to carbon dioxide employes formyl-tetrahydrofolate synthetase a co-enzyme, is of comparably low capacity in primates which leads to a low clearance of formate, possibly also from sensitive target tissues (such as CNS and the retina) (DFG 1999; IPCS/WHO, 1997; Dorman et al., 1994; Medinsky et al., 1997, Medinsky and Dorman, 1995; Mc Martin et al., 1977).

In humans, when exposed to methanol via inhalation up to an air concentration 65 mg/m3, no increase of blood methanol is expected. Up to 260 mg/m3 (single or repeated exposure) the methanol blood level is likely to increase only 2- to 4- fold above the endogenous methanol concentration in humans, but still remains significantly below 10 mg/L (Lee et al., 1992; NTP, 2003). Up to air concentrations of 1600 mg/m3 the blood methanol levels increase to a similar extent in rats, monkeys, and humans. However, above this concentration rats show a steep exponential increase which apparently reflects the saturation of the catalase-dependent pathway. A smaller exponential increase was observed in monkeys, whereas in humans there appears to be a linear relationship between air concentrations and blood methanol levels.

Baseline levels of formate in blood are about 3 to 19 mg/L (0.07 – 0.4 mM) in humans. Toxic blood formate concentrations are reported to be 220 mg/L and higher (> 5 mM formate). Inhalation of about 1200 mg methanol/m3 for 2.5 hours contributed only insignificantly to the internal formate pool in monkeys (in the μM-range). This also hold true for folate-deficient conditions. After repeated inhalation of 2600 mg/m3 for 6 hours/day, 5 days/week, for 1 or 2 weeks, monkeys showed no discernible increase in formate concentrations in blood (estimated body burden 200 to 300 mg/kg bw/d). Formate accumulation, however, has been observed in primates upon bolus administration of more than 500 mg Methanol/kg bw (Horton et al., 1992; Medinsky and Dorman, 1995). The critical methanol dose that saturates the folate pathway in humans is estimated to be ≥ 200 mg/kg bw. Based on data produced in monkeys, metabolic saturation in humans is also less likely to happen upon inhalation where the dose is distributed over several hours (DFG 1999; IPCS/WHO, 1997; Burbacher et al., 1999).

There is a strong link between saturation (zero-order) kinetics and the onset of acute toxic effects. Exposure levels in humans above 5000 ppm (750 mg/kg bw in the course of 8 hrs) are prone to a zeroorder kinetic and a strong accumulation of methanol in the blood. Transient blindness has been reported for exposure levels between 1000 and 5000 ppm. (This saturation point could be reached after oral uptake at lower dose levels.) 10.000 ppm are still tolerated in rodents but would be highly detrimental in humans.