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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1983
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Limit of detection of formaldehyde production rate measurement is not specified. Only in vitro metabolisation of methylal in formaldehyde by rat nasal and liver microsome was studied.

Data source

Reference
Reference Type:
publication
Title:
Formaldehyde production promoted by rat nasal cytochrome P-450-dependent monooxygenases with nasal decongestants, essences, solvents, air polluants, nicotine, and cocaine as substrates
Author:
Dahl AR & Hadley WH
Year:
1983
Bibliographic source:
Toxicology and Applied Pharmacology 67, 200-205

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Metabolization of 32 compounds to formaldehyde in rat nasal cavity was assessed. These compounds were screened as substrates of cytochrome P-450-dependant-monooxygenase. Methylal is 1 of the 32 tested compounds.

GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Methylal (J.T. Baker, Phillipsburg, N.J.)

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Lovelace Inhalation Toxicology Research Institute colony
- Age at study initiation: not specified
- Weight at study initiation: 200-280 g
- Fasting period before study: not specified
- Housing: Sanicell bedding (Paxto Products)
- Individual metabolism cages: yes/no
- Diet (e.g. ad libitum): standard rat chow (Wayne LabChows,Allied Mills, Chicago) ad libitum
- Water (e.g. ad libitum): water ad libitum
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 27°C
- Humidity (%): 60%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: not specified

Administration / exposure

Route of administration:
other: rats microsomes preparations were incubated with methylal
Vehicle:
other: not relevant
Details on exposure:
Microsome preparation
Microsomes from rat nose and livers were collected and resuspended in 20% glycerol in Tris buffer pH 7.4 at a protein concentration of 4 mg/mL for nasal microsomes and 20 mg/mL for liver microsome. Microsomes were frozen with nitrogen, stored in capped vials and stored at -75°C.
Microsomes were diluted with 0.1 MTris buffer (pH 7.4) to get specific cytochrome P-450 contents of 55 to 100 pmol/mg microsomal protein for nasal microsomes and 400 to 600 pmol/mg microsomal protein for liver microsomes. Protein concenteration was measured with method of Lowry and concentration of dithionite reduced carbon monoxide adduct of cytochrome P-450 was measured on an Aminco DW-2A spectrophotometer.

Duration and frequency of treatment / exposure:
Not relevant
Doses / concentrations
Remarks:
Doses / Concentrations:
Not specified
No. of animals per sex per dose:
Not specified
Control animals:
no
Positive control:
An assay with aminopyrine was performed to check microsomes activity.
Details on study design:
Not relevant
Details on dosing and sampling:
METABOLITE CHARACTERISATION STUDY
An amount of 0.5 to 1.5 mg of proteinper sample was used for liver microsomes and 0.3 to 0.8 mg for nasal microsomes. Initial methylal (used as substrate) concentration was 2 mM. Methylal was added to incubation flasks in water solution. Each assay was run in duplicate. Formaldehyde concentration was measured with the method of Axelrodasmodified by Hadley et al (1974).
Statistics:
Not specified

Results and discussion

Preliminary studies:
Not specified
Main ADME results
Type:
metabolism
Results:
Methylal is in vitro metabolized to formaldehyde by rat nasal microsomal cytochrome P-450-dependant-monooxygenase

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not specified
Details on distribution in tissues:
Not specified
Details on excretion:
Not specified

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Methylal is metabolized to formaldehyde at a rate of 270 ± 90 pmol/mg microsomal protein/min following incubation of nasal microsomes with 2mM methylal for 30 minutes at pH 7.4. In comparison this rate decreased at 70 to 200 pmol/mg microsomal protein/min after incubation with liver microsome.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no data
Methylal is metabolized to formaldehyde at a rate of 270 ± 90 pmol/mg microsomal protein/min following incubation of nasal microsomes with 2mM methylal for 30 minutes at pH 7.4. In comparison this rate decreased at 70 to 200 pmol/mg microsomal protein/min after incubation with liver microsome.
Executive summary:

Metabolization of 32 compounds to formaldehyde in rat nasal cavity was assessed. These compounds were screened as substrates of cytochrome P-450-dependant-monooxygenase. Methylal is 1 of the 32 tested compounds.

Methylal is metabolized to formaldehyde at a rate of 270 ± 90 pmol/mg microsomal protein/min following incubation of nasal microsomes with 2mM methylal for 30 minutes at pH 7.4. In comparison this rate decreased at 70 to 200 pmol/mg microsomal protein/min after incubation with liver microsome.