Iodomethane

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

8 February 2001 to 18 January 2002

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.8340 (Oral and Inhalation Pharmacokinetic Test)

Deviations:

no

Test guideline 3

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Iodomethane

EC Number:

200-819-5

EC Name:

Iodomethane

Cas Number:

74-88-4

Molecular formula:

CH3I

IUPAC Name:

iodomethane

Details on test material:

- Name of test material (as cited in study report): Iodomethane- Analytical purity: 99.7%- Lot/batch No.: 007403- Expiration date of the lot/batch: June 2002- Radiochemical purity (if radiolabelling): Lot no. 2962258 and 2962351 - 97.9 - 99.9%- Specific activity (if radiolabelling): Lot no. 2962258 - 43 mCi/mmol; 2962351 - 49 miCi/mmol- Locations of the label (if radiolabelling): Carbon atom- Expiration date of radiochemical substance (if radiolabelling): Not stated

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male

Administration / exposure

Route of administration:

other: Oral and inhalation

Vehicle:

water

Remarks:

(oral route only)

Duration and frequency of treatment / exposure:

Single exposure. For inhalation 6 hour exposure

Doses / concentrations

Remarks:

Doses / Concentrations:Oral: 1.5, 24 mg/kgInhalation: 25, 233 ppm

No. of animals per sex per dose / concentration:

12 animals/group

Control animals:

yes, concurrent vehicle

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Iodomethane was well absorbed following oral administration. In the supplemental study 51.71% and 60.81% of a 1.0 and a 35 mg/kg bw dose respectively were eliminated as carbon dioxide, 30.04% and 33.40% in urine and 20.85% and 26.91% was retained in the carcass. Only approximately 1.7% was eliminated in faeces. These results show that iodomethane was quantitatively absorbed at both dose levels. Absorption was also quantitative after inhalation exposure with 46.95%, 28.73% and 26.72% of the radioactivity being eliminated as carbon dioxide, in urine or being retained in the carcass, respectively, after exposure to 21 ppm. Corresponding figures following exposure to 209 ppm were 39.40%, 26.50% and 23.83%, respectively, again showing that absorption was linear over this dose range (Table 1).

Details on distribution in tissues:

Radioactivity was present in all tissues at all times but there was a decline between 0 or 1 and 168 hours after exposure (Table 2). As iodomethane is converted into carbon dioxide radioactivity will enter the carbon pool and endogenous metabolites will become labelled, the presence of radioactivity in all tissues analysed would therefore be predicted and the residues are unlikely to be of toxicological significance.In the oral dose groups blood concentrations of radioactivity increased during 4 hours after dosing and in the inhalation groups blood concentrations of radioactivity remained relatively constant for 2 hours after exposure before decreasing. Concentrations of iodomethane equivalents were approximately proportional to dose and blood concentrations were similar in rats given an oral dose of 24 mg/kg bw or exposed to 25 ppm by inhalation(Table 3). Elimination kinetics were at least bi-exponential with an initial half life of approximately 5-7 hours and a terminal half life of 115-140 hours.

Details on excretion:

Rats that received the 1.5 mg/kg dose eliminated 34.99% and 29.02% as carbon dioxide and in urine, respectively, only 0.13% of the dose was eliminated as exhaled volatiles and a further 13.12% was present in the carcass 168 hours after dosing. Similar results were obtained at the high oral dose of 24 mg/kg bw. 12.77% was eliminated as carbon dioxide, 35.27% in urine, and 0.22% as exhaled volatiles. A further 11.92% of the dose was present in the carcass. Recovery was 82.6% and 65.4% of the radioactivity at the low and high dose, respectively. (Table 1). The percentage of the dose eliminated as carbon dioxide appeared to be lower following inhalation exposure, only 2.98% and 2.75% of a 25 ppm and 233 ppm exposure was trapped as 14CO2 whereas the corresponding amounts in urine were 34.68% and 33.63%. The radioactivity in exhaled volatiles and in the carcass was similar to the percentages found after oral administration. However, the recovery of radioactivity from rats exposed by inhalation was only 56.3% and 54.4% at the low and high concentration respectively.Failure to trap all the exhaled carbon dioxide was considered to be the cause of the low recovery. This conclusion was supported by additional experiments. In the supplemental study 51.71% and 60.81% of a 1.0 mg/kg bw dose and a 35 mg/kg bw dose respectively were eliminated as carbon dioxide, 30.04% and 33.40% in urine and 20.85% and 26.91% was retained in the carcass. The total recovery was 104.9% and 123.5% in rats receiving 1.0 and 35 mg/kg bw respectively. Higher recoveries were also obtained after exposure by inhalation in the supplementary study.

Toxicokinetic parameters

Toxicokinetic parameters:

half-life 1st: 5-7hrs

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The major metabolite of iodomethane was carbon dioxide which accounted for approximately 40-60% of the dose irrespective of the route of exposure in the supplementary study. Urine contained two major metabolites which were identified by LC-MS/MS as N-(methylthioacetyl)glycine and S-methyl glutathione. Small amounts of methylthioacetic acid, methyl mercapturic acid and S-methyl cysteine were detected in some samples. The amounts of metabolites were determined in urine samples that contained ≥ 5% of the dose and the results are shown in Table 4. Neither the route of administration nor dose had any significant effect on the proportions of the metabolites.

Any other information on results incl. tables

Table 1: Excretion of radioactivity (mean % dose) by male rats exposed to iodomethane

Study	Target dose	Route of administration	Exhaled carbon dioxide	Urine	Carcass	Faeces	Total recovery*
Main	1.5 mg/kg	Oral	34.99	29.02	13.12	2.66	82.6
	24 mg/kg	Oral	12.77	35.27	11.92	2.47	65.4
	25 ppm	Inhalation	2.98	34.68	14.39	1.58	56.3
	233 ppm	Inhalation	2.75	33.63	13.85	1.40	54.4
Supplemental	1.0 mg/kg	Oral	51.71	30.04	20.85	1.74	104.9
	35 mg/kg	Oral	60.81	33.40	26.91	1.73	123.5
	21 ppm	Inhalation	46.95	28.73	26.72	1.32	104.8
	209 ppm	Inhalation	39.40	26.50	23.83	0.74	91.4

*Recovery for main groups includes radioactivity in tissues, GI tract and contents, blood, exhaled volatiles and cage wash and for the supplemental groups includes cage wash

Table 2: Concentration of radioactivity (µg equiv./g) in tissues of male rats exposed to iodomethane

Tissue	Oral			Inhalation
	Time (h)	1.5 mg/kg bw	24 mg/kg bw	Time (h)	25 ppm	233 ppm
Spleen	1	1.24	29.0	0	43.4	152
	6	1.40	24.7	6	12.6	66.7
	168	0.319	5.50	168	2.49	16.3
Kidney	1	1.28	17.3	0	50.5	319
	6	2.40	36.8	6	19.7	134
	168	0.406	7.34	168	3.70	24.1
Liver	1	12.1	204	0	24.5	187
	6	2.70	54.6	6	16.8	153
	168	0.377	7.27	168	3.15	23.9
Brain	1	0.471	5.97	0	21.9	121
	6	0.680	10.3	6	12.6	93.5
	168	0.154	2.62	168	1.30	9.12
Thyroid	1	0.807	17.9	0	106	198
	6	1.14	19.7	6	34.9	136
	168	0.367	18.7	168	2.57	21.7
Lung	1	0.752	11.1	0	75.2	189
	6	1.05	18.0	6	21.5	85.9
	168	0.258	4.28	168	2.40	16.5
Nasal turbinates	1	0.549	9.90	0	51.7	138
	6	1.02	16.0	6	14.3	72.4
	168	0.342	5.85	168	3.01	18.6
Fat	1	0.107	3.53	0	3.20	23.1
	6	0.152	2.52	6	1.49	10.5
	168	0.103	1.26	168	0.524	4.29
GI tract	1	11.7	78.8	0	24.3	192
	6	3.42	36.2	6	11.8	113
	168	0.207	3.76	168	1.79	10.6
GI tract contents	1	1.12	37.6	0	4.32	24.4
	6	0.812	16.0	6	3.38	15.3
	168	0.026	0.493	168	0.194	1.15

 

Table 3: Concentration of radioactivity (µg equiv/g) in blood of male rats exposed to iodomethane

Oral			Inhalation
Hours	1.5 mg/kg bw	24 mg/kg bw	Hours	25 ppm	233 ppm
1	0.861	11.7	0	8.54	61.2
2	0.927	12.4	2	8.54	61.9
4	1.03	16.1	4	7.87	60.0
6	0.963	15.8	6	6.76	54.2
12	0.663	11.1	12	5.41	44.3
24	0.418	7.03	24	4.15	32.2
48	0.322	5.33	48	3.47	24.1
168	0.175	2.91	168	1.95	12.9

 

Table 4: Proportions of the major metabolites identified in rat urine

Sample	% dose in sample	% (N-(methylthioacetyl) glycine	% S-methyl glutathione
Oral dose, 1.5 mg/kg 6-12h sample	12.72	4.23	8.49
Oral dose , 24 mg/kg 6-24 h sample	23.56	12.65	10.92
Inhalation dose, 25 ppm, 0-24 h sample	29.21	15.67	13.54
Inhalation dose , 233 ppm, 0-24 h sample	24.29	14.17	10.12

 

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study resultsIodomethane is completely absorbed following oral administration or inhalation exposure of male rats and metabolites are rapidly eliminated in exhaled air and urine. Oxidation to carbon dioxide is the major metabolic pathway but methylation of glutathione also occurs leading to elimination of methyl glutathione and N-(methylthioacetyl)glycine in urine. Small amounts of methylthioacetic acid, methyl mercapturic acid and S-methyl cysteine are also present in urine. Only small proportions of the dose are eliminated as exhaled volatiles or in faeces. Radioactivity from [14C] iodomethane is present in tissues and blood but, as the radioactivity enters the one carbon pool, it is incorporated into endogenous metabolites which explains the presence of radioactivity in blood, tissues and carcass. The absorption, distribution, metabolism and excretion of iodomethane is unaffected by the route of administration or dose level in the range used in this study.

Executive summary:

Groups of male rats were exposed to [¹⁴C] iodomethane by oral administration at dose levels of 1.5 and 24 mg/kg bw or by inhalation to 25 and 233 ppm for 6 hours. Urine, faeces, carbon dioxide and exhaled volatiles were collected up to 168 hours after exposure. Blood samples were also collected at intervals up to 168 hours and tissues were removed for analysis from rats that were killed 0 or 1, 6 and 168 hours after the end of exposure. Samples were analysed for radioactivity and urine was analysed by LC and LC-MS/MS to identify metabolites.

 

Iodomethane was completely absorbed following oral administration or inhalation exposure to male rats and metabolites were rapidly eliminated in exhaled air (40-60%) and urine (26-34%), approximately 20-27% of the dose was retained in the carcass. Oxidation to carbon dioxide was the major metabolic pathway but methylation of glutathione also occurred leading to elimination of methyl glutathione (4-16%) and N-(methylthioacetyl)glycine (8-14%) in urine. Small amounts of methylthioacetic acid, methyl mercapturic acid and S-methyl cysteine were also present in urine. Only small proportions of the dose were eliminated as exhaled volatiles or in faeces. Radioactivity from [¹⁴C] iodomethane was present in tissues and blood but, as the radioactivity enters the one carbon pool, it was incorporated into endogenous metabolites which explains the presence of radioactivity in blood, tissues and carcass.

 

The absorption, distribution, metabolism and excretion of iodomethane was unaffected by the route of administration or dose level in the range used in this study.