## Appendix 8

D evelopment of the Chronic Screening Level for Carbonyl SulfideAppendix 8

- Development of the Chronic Screening Level f or Carbonyl Sulfide

Although the health effects data for carbonyl sulfide (COS) are very limited, a series of studies (ref 1,2,3) conducted by the National Toxicology Program have shown that the maj or concern regarding exposure to COS is its potential for neurotoxicity. These studies have shown consistently and at the same range of COS concentrations that the brain is a target organ for COS toxicity. A summary of the effects and levels at which the y are observed is presented below. Since health appropriate effects benchmarks have not been derived by our preferred sources of

dose

- response data including IRIS, ATSDR and Cal EPA, the EPA has used the data from the

above mentioned studies to derive a c hronic screening benchmark level for COS. The rationale for this screening analysis is presented below.

A chronic screening level of 163 ug/m 3 was developed for carbonyl sulfide (COS) from a No Observed Adverse Effects Level (NOAEL) of 200 ppm based on brain lesions and neurophysiological alterations in rodents as cited in the references below.

The NOAEL value of 200 ppm was converted to a value of 490,000 ug/m 3 as follows:

1 ppm of COS = 2.45 mg/m 3 (Molecular Weight = 60.08)

200 ppm x 2.45 mg/m 3 = 490 mg/m 3 = 490,000 ug/m 3

A total uncertainty factor (UF) of 3,000 was applied to this effect level: 10x for extrapolation for interspecies differences, 10x for consideration of intraspecies variability, 10x for extrapolation

from subchronic to chronic du ration, and 3x for database insufficiencies.

10 x 10 x 10 x 3 = 3,000

(490,000 ug/m 3 ) / 3,000 = 163 ug/m 3

S ummary of Findings from NTP Studies on Carbonyl Sulfide (COS)

Experimental Design:

Several studies were conducted using F344 rats exposed to c arbonyl sulfide (COS) by inhalation at various exposure concentrations and durations. Details are available in the references cited

below.

Results Synopsis:

Pathology : Brain lesions at 400 and 500 ppm after exposure for 2 weeks. NOAEL = 300 ppm [Ref erence 1] Brain lesions at 400 ppm after exposure for 12 weeks. NOAEL = 300 ppm [Reference 1

, Reference 3 ]Biochemistry [Reference 1] :

Inhibited cytochrome oxidase activity in posterior colliculus and parietal cortex at 200, 300, and 400 ppm COS after ex posure for 3, 6, and 12 weeks.

Neurophysiology : Changes in Brainstem Auditory Evoked Responses (BAERs) at 400 ppm after 2 weeks

exposure. [Reference 1] Changes in somatosensory evoked potentials (SEPs) at 400 ppm after 2 or 12 weeks. [Reference 2] Change s in BAERs at 300 and 400 ppm COS for 12 weeks. NO A EL = 200 ppm. [Reference 2]

Behavior : Changes in Functional Observational Battery (FOB) at 400 and 500 ppm with 2 week

exposure [ Reference 1] , and motor activity and FOB altered by 400 ppm COS with 2

wee k exposure. [Reference 2] Some chang es in FOB at 200, 300, and 400 ppm after 6 weeks exposure, with recovery indicated by 12 weeks. [Reference 1]

Summary

NOAEL of 200

- 300 ppm selected based on brain pathological lesions and neurophysiological alteration s. Behavioral effects were observed at 400 ppm, and observed in some studies but not

others at 200

- 300 ppm. Biochemistry changes were observed in brains of rats at all dose levels including 200 ppm, the lowest dose evaluated. A NOAEL was not determined for biochemical changes.

References : 1. Morgan, D.L., Little, P.B., Herr, D.W., Moser, V.C., Collins, B., Herbert, R., Johnson, G.A., Maronpot, R.R., Harry, G.J., and Sills, R.C.: Neurotoxicity of carbonyl sulfide in F344 rats following inhalation exposure f or up to 12 weeks. Toxicol. Appl. Pharmacol . 200(2):131

- 145, 2004.

2. Herr, D.W., Graff, J.E., Moser, V.C., Crofton, K.M., Little, P.B., Morgan, D.L., and Sills, R.C.: Inhalational exposure to carbonyl sulfide produced altered brainstem auditory and

somatose nsory

- evoked potentials in Fischer 344N rats. Toxicol. Sci. 95(1):118

- 135, 2007.

3. Sills, R.C., Morgan, D.L., Herr, D.W., Little, P.B., George, N.M., Ton, T.V., Love, N.E., Maronpot, R.R., and Johnson, G.A.: Contribution of magnetic resonance microscopy in the

12

- week neurotoxicity evaluation of carbonyl sulfide in Fischer 344 rats. Toxicol. Pathol

. 32:501

- 510, 2004.

Other Studies : 1. Sills, R.C., Harry, G.J., Valentine, W.M., and Morgan, D.L.: Interdisciplinary neurotoxicity inhalation studies: Carbon disulfi de and carbonyl sulfide research in F344

rats. Toxicol. Appl. Pharmacol . 207(Suppl 2):S245

- S250, 2005. Formatted: Numbered + Level: 1 + Numbering Style: 1, 2, 3,

... + Start at: 1 + Alignment: Left + Aligned at: 0.25" + Indent

at: 0.5"

Deleted: ¶