Iodomethane

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1 June 2004 to 7 November 2004

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Type of study / information:

Refer to methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The objective of this study was to evaluate the toxicokinetic behaviour of iodomethane in rats exposed by inhalation. Key study endpoints included evaluation of glutathione status in selected target tissues, inorganic serum iodide and haemoglobin adducts as measures of internal dose and clinical chemistry, haematology, thyroid hormone status, liver UDP-glucuronyltransferase (UDPGT) activity and pulmonary function as measures of exposure or toxicity

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:

Test Material: IodomethaneDescription: Pale yellow liquidLot/Batch #: 41055110Purity: >98%Stability of test compound: Confirmed for the study duration

Results and discussion

Any other information on results incl. tables

OBSERVATIONS:

Clinical signs of toxicity:

No details reported.

Bodyweight:

Only terminal body weights were reported, therefore no assessment has been made.

Food consumption:

No details reported.

BLOOD AND URINALYSIS:

Haematological findings:

No adverse changes in haematological parameters were reported.

Clinical chemistry findings:

Cholesterol was mildly to moderately increased in animals exposed to 25 or 100 ppm (means of 119% and 161% respectively of control group means). These increases were due to increases in both HDL and non-HDL fractions, with these fractions being 120% and 199% of control at 25 ppm and 147% and 170% of control group means at 100 ppm. Triglyceride levels were decreased in the 25 or 100 ppm treated animals (means were 71% and 48% of control group means respectively). These changes were considered treatment related and potentially adverse due to the magnitude of change.

TSH concentrations were significantly increased in both the 25 and 100 ppm groups (186 and 360% of control, respectively). Serum T₃and T₄concentrations were significantly decreased at exposure concentrations of 100 ppm (68.4% and 61.7% of control respectively). Serum rT₃concentrations and hepatic UDP glucuronyltransferase activity were not statistically different.

Iodomethane induced GSH depletion was observed in all tissues sampled. Generally the timing of maximum depletion for each tissue corresponded to the time periods during or shortly after inhalation exposure, which occurred between collection times of 0 and 6 hours and 24 and 30 hours for the first and second days of exposure, respectively. The magnitude of depletion generally increased with increasing iodomethane concentration. Maximum depletion was observed in olfactory and respiratory epithelia of 24% and 14% of control at 100 ppm exposure for 6 hours respectively. Depletion was less pronounced in blood, kidney and liver.

A substantial increase in serum iodide was observed in rats exposed to 25 or 100 ppm iodomethane. In the 25 ppm group mean peak concentration of 25600 ng/mL and 34100 ng/mL occurred at the 6 and 30 hour collection times, respectively. These samples corresponded to the end of the 6 hour exposure period for day 1 and day 2 of the exposure regimen. By 24 or 48 hours the concentrations had declined to 1260 ng/mL and 742 ng/mL, respectively.

For the 100 ppm group peak concentrations were 60300 ng/mL and 83200 ng/mL at 3 and 30 hour collection times, respectively. The concentrations had declined to 8170 ng/mL and 4500 ng/mL by 24 and 48 hour collection times, respectively.

The concentration of S-methylcysteine was quantified in rat globin following exposure to 0, 25 and 100 ppm of iodomethane. Average concentrations were as follows: control group: 161.2±23.8; 25 ppm: 201.6±34.3 and 100 ppm: 345.7±50.4 nmol/g globin thus the over the concentration range tested, the increase in S-methylcysteine was essentially linear, although not directly proportional with iodomethane exposure concentration.

Summary of selected clinical chemistry data ± standard deviation

Group / ppm	TSH (ng/dL)	T3 (ng/dL)	T4 (μg/dL)	rT3 (ng/dL)
1. 0	5.9±1.4	74.1±11.4	3.4±0.5	0.067±0.049
2. 25	10.9±7.7*	65.9±9.2	3.1±0.8	0.119±0.024
3. 100	21.1±11.2*	50.8±14.4#	2.1±0.9	0.039±0.037
Percentage of controls
Gps I / III	186±138	89±19	90±26	177±132
Gps I/ V	360±210	68±22	62±27	58±69

* Statistically significant difference from control by (p<0.05) by Dunn’s test and Jonckheere-Terpstra trend test

# Statistically significant difference from control by (p<0.05) by Jonckheere-Terpstra trend test and Dunnett’s test

 

Summary of serum iodide data ± standard deviation

Collection time (hour)	0 ppm (ng/mL)	25ppm (ng/mL)	100ppm (ng/mL)
0	17±NA	NA±NA	NA±NA
1	17±NA	5070±721	22900±1620
3	19±NA	9510±3800	60300±2860
6	22±NA	25600±1940	53800±4480
9	39±NA	18400±1550	52500±8230
24	19±NA	12600±83.9	8170±1850
25	14±NA	5900±576	27200±13700
27	14±NA	10800±1100	55200±3050
30	4.1±NA	34100±8170	83500±7840
33	13±NA	24700±1310	58300±6520
48	14±NA	742±141	4500±396
0 - 48	17±9	NA±NA	NA±NA

 

PULMONARY FUNCTION EVALUATION:

Inhalation exposures to 25 or 100 ppm iodomethane for 6 hours did not alter the overall pattern of breathing frequency compared with the control rats.

Applicant's summary and conclusion

Conclusions:

The objective of this study was not to identify a NOAEL, but provide toxicity and dosimetry endpoints which could be used in support of physiologically-based pharmacokinetic modelling and product safety assessment.

Executive summary:

The objective of this study was to evaluate the toxicokinetic behaviour of iodomethane in rats exposed by inhalation. Key study endpoints included evaluation of glutathione status in selected target tissues, inorganic serum iodide and haemoglobin adducts as measures of internal dose and clinical chemistry, haematology, thyroid hormone status, liver UDP-glucuronyltransferase (UDPGT) activity and pulmonary function as measures of exposure or toxicity.

 

Male rats (10/group) were exposed to iodomethane (viawhole body inhalation) for 6 hours/day over two days, with scheduled necropsy the following day post the end of exposure. Intended exposure concentrations were 0, 25 and 100 ppm. Significant treatment related changes resulting from 25 and 100 ppm exposures were minimal to mild increases in total cholesterol concentrations and minimal to mild decreases in triglyceride concentrations.

 

Serum T₃and T₄concentrations were significantly decreased at exposure concentrations of 100 ppm, with TSH concentrations significantly increased at both exposure levels. Serum rT₃concentrations and hepatic UDPGT activity were not altered under the conditions of the study. Iodomethane exposure caused time and concentration dependent reductions in tissue GSH concentrations. Depletion was less pronounced in blood, kidney and liver than in olfactory and respiratory epithelia. Substantially increased inorganic serum iodide levels were observed in animals exposed to iodomethane in a concentration and time dependent manner. Inhalation exposures to 25 and 100 ppm iodomethane for 6 hour did not alter the overall pattern of breathing frequency compared to the control rats.

 

The objective of this study was not to identify a NOAEL, but provide toxicity and dosimetry endpoints which could be used in support of physiologically-based pharmacokinetic modelling and product safety assessment.