Methyl isothiocyanate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meet genrally accepted scientific principles, acceptable for assessment.

Data source

Reference

Reference Type:

publication

Title:

Metabolism in rats and mice of the soil fumigants metham, methyl isothiocyanate and Dazomet.

Author:

Lam WW, Kim JH, Sparks SE, Quistad GB, and Casida JE.

Year:

1993

Bibliographic source:

J.Agric.Food.Chem, 41 : 1497-1502.

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

13C was used to facilitate identification and quantification of MITC's metabolites.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Methyl isothiocyanate

EC Number:

209-132-5

EC Name:

Methyl isothiocyanate

Cas Number:

556-61-6

Molecular formula:

C2H3NS

IUPAC Name:

isothiocyanatomethane

Details on test material:

MITC was purchased from Aldrich Chemical Co. (Milwaukee, WI).

Radiolabelling:

yes

Remarks:

13C=S

Test animals

Species:

mouse

Strain:

Swiss Webster

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 20-25g
- Fasting period before study: no data
- Housing: no data
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum):no data
- Acclimation period:no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light):no data

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

DMSO

Details on exposure:

Total concentration : 0.05 mmol/kg bw

Duration and frequency of treatment / exposure:

a single administration

Doses / concentrations

Remarks:

Doses / Concentrations:
4.0 mg/kg bw

No. of animals per sex per dose / concentration:

3-4 animals/ group

Control animals:

no

Positive control reference chemical:

no data

Details on study design:

no

Details on dosing and sampling:

Mice were sacrified at 6, 24 and 48 hours for tissue analysis.

Statistics:

Yes, see table

Results and discussion

Preliminary studies:

no

Toxicokinetic / pharmacokinetic studies

Details on absorption:

no data

Details on distribution in tissues:

See table 2.
When the average residues in the 16 tissues examined are expressed as a percentage of the administered level, the values at 6, 24 and 48 h, respectively are 25, 13 and 10% for MITC.

Details on excretion:

See table 1.
Mice injected with 14CH3-labeled MITC excrete 80% of the radiocarbon in the urine within 48 hours. Feces are a minor route of excretion, accounting for only 4.8% of the administered radiocarbon. radiocarbon in whole carcasses 48h after dosing ranged from 6% for MITC.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

See table 3.
MITC have several metabolites in common in rats and mice. A principal detoxification step for MITC is the conversion to the GSH conjugate. MITC reacts readily with GSH without GST.
Mice metabolize MITC in mercapturate (2%), but there are large amounts of unidentified metabolites in mice. The vast majority of the unknown 14C is very polar (84.6%).

Any other information on results incl. tables

Table 1 : Radiocarbon recovery for mice 48ht after intraperitoneal administration of 14C labeled MITC at 0.05 mmol/kg

Excreta and retention	Radiocarbon recovery %
Urine	80.2+/-9.7^a
Feces	4.8+/-1.4^c
14 CO2	3.8+/-1.3^c
Carcass	5.9^d
Total	94.7
^an=5,^cn=3,^dn=1

Table 2 : Radiocarbon on the tissues (ppm equivalents) of mice at 6, 24, and 48h after intraperitoneal administration of 14C-MITC at 0.05 mmol/kg

Sample analyzed	MITC (4.0 mg/kg bw)
	6h	24h	48h
Blood	1.2^b	0.29^b	0.24^b
Bone	0.45^b	0.34^c	0.32^b
Brain	0.48^b	0.19^c	0.12^b
Fat	0.27^c	0.25^c	0.19^c
Hair	0.46^b	1.5^b	0.82^b
Heart	0.57^a	0.32^b	0.33^b
Intestine large	1.9^b	0.70^b	0.36^b
Intestine small	1.4^b	0.49^b	0.34^b
Kidney	1.6^b	0.66^b	0.50^b
Liver	2.2^a	0.87^c	0.76^b
Lung	1.3^b	0.51^b	0.51^b
Muscle	0.34^b	0.26^c	0.32^b
Skin and hair	0.88^c	0.69^b	1.1^a
Spleen	0.92^b	0.41^a	0.53^b
Stomach	0.99^b	0.48^b	0.34^b
Testes	0.32^b	0.28^b	0.24^a
^aStandard error (SE) < 10% ^bSE 11-25% ^cSE 26-50% ^dSE 51-75%

Table 3 : Urinary metabolites of mice after intraperitoneal administration of 14C-labeled MITC at 0.05 mmol/kg

Metabolite	Radiocarbon in urine (%) 0-48hr^c
Mercapturate	2.1
Methylamine	2.2
Unidentified polar^d	84.6
Other unidentified	11.1
^cN=2,^dHPLC solvent front

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
MITC is distributed in several tissues : 6h after absorption, 25% of MITC was found in 16 examined tissues in mice.
Several metabolites were found but the majority were polar. MITC and metabolites were excreted in urine (80%).

Executive summary:

Isotopic labeling of methyl isothiocyanate (MITC), and 13C=S provided the materials for metabolite identification by 13CNMR and quantitation by HPLC analysis and radiocarbon counting. Mice were treated intra­peritoneally and the metabolites studied at 48 h. Most of the 13C=S label for MITC in mice appears in urine (58-80%) or is retained in the body (8-12%), particularly the liver and kidney. From mice the mercapturate is a minor metabolite. Detoxification by conjugation with glutathione (GSH) appears to involve direct reaction for MITC.