Iodine/046905 Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 1of4 Non-Guideline Study Study Profile version 07/04 

### EPA Reviewer: Jonathan Leshin, Ph.D. 

### RASSB, Antimicrobials Division (7510P) SecondaryReview: Michelle Centra, Pharmacologist 

### RASSB Antimicrobials Division (7510P) TXR#: 1003330 

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# ff**Templa~\,e/Sion** 02/06 

# II DataEvaluation Record 

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STUDY TYPE: Subchronic Oral Toxicity (liquid)- human; Non-Guideline Study 

### PC CODE: 046905 

### DPBARCODE: 408676 

### TESTMATERIAL (PURITY): Iodine 

### SYNONYMS: None 

### CITATION: Paul, T., Meyers, B., Witorsch, R.J., et al (1988) The effects ofsmall increases in dietary iodine onthyroid function in euthyroid subjects. University of Massachusetts Medical School MRID 48358603. Metabolism, 37(2) pp 121-124 

### SPONSOR: National Institute ofDiabetes and Digestive and Kidney Diseases 

### INVESTIGATORS' EXECUTIVE SUMMARY: In a 14-day oral toxicity study (MRID 48358603), iodine was selfadministered by patients as a 0.5 ml solution ofsodium iodide every 12 hours. The males in the study received 750**~g**twice daily and the women received either125, 250 or 750**~g** twice daily (250, 500 and 1500**~g** total). All doses were co-administered with 5 mg ofascorbic acid. The subjects were nine euthyroid men (26-59) and 23 euthyroid women (23-44). Five additional men were age matched controls, receiving no additional iodine. Some women were studied attwo dose levels, at least one year apart. This dosing was in addition to their normal unadjusted diets. No changes in weight, symptoms ofthyroid dysfunction, orother adverse effects were reported. Following the administration of 1500**~g,** there were small but significant decreases inT4 and T3 concentrations and compensatory increases in serum TSH and TSH response to TRH. These changes, while significant, remained withinthe normal range and are not considered adverse. No effects were seen inthe 250 and 500**~g** dose groups. This study is considered quantitative. There is no LOAEL associated withthis non-guideline study; the NOAEL is 

### 1500 J.Lg/day.lodine/046905 Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 2 of4 Non-Guideline Study Study Profile version 07/04 

### I. MATERIALS AND METHODS A. MATERIALS: 1. TestMaterial: Description: CAS # ifTGAI: Iodine Nal 74-88-4 

### 2. Vehicle and/orpositive control: Deionizedwater 

### 3. Testanimals: Humans Diet: Typical American Subject Information: 9 euthyroid men (26-56 yo) and 23 euthyroid women (23-44 yo), no evidence or history of thyroid disease, no antithyroid antibodies detected, not pregnant 

### B. STUDY DESIGNAND METHODS: All subjects had initial evaluations for the study. A 24 hr urine sample was collected for baseline urinary iodine and creatinine excretions. Urinary creatinine was measured to help ensure that a 24 hrurine collection was completed. On day 0, blood was collected for a baseline serum protein bound iodine (PBI) and total iodine (TI), thyroxine (T4), triiodothyronine (T3) and thyrotropin (TSH) as well resin T3 uptake and free T4 index (FT4I). Thyrotropin releasing hormone (TRH) was administered via IV andblood was drawn at 15, 30, 45 and 60 minutes for measurement of TRH induced TSH. All subjects were treated with various doses ofiodine in 0.5 ml ofdeionized water containing 5 mg ofascorbic acid, every 12 hours for 14 days. Men received 750 Jlg and women received either750, 250, or 125 Jlg twice daily. Some women were studied at two dose levels at least one-- year apart. A 24 hoururine sample was collected on day 7 and on day 8, priorto morning iodine ingestion, a sample ofblood was drawn for analysis. A final 24 hrurine sample was collected on day 14 and the TRHtest was repeated on day 15. Five additional age matched men were studied as above, butnot given iodine supplements. No changes in anyparameters were seen in these subjects. 

### II. RESULTS A. Serum inorganic, protein-bound andurinaryiodines: In the subjects receiving the 1500 Jlg daily iodine, there was an increase in mean 24 hrurinary iodine excretion from 211 

### ±41 Jlg 1124 hrto 1360

### ±74 Jlg I/24 hr on day seven and 1308 ±58 Jlg I/24 hr on day 14. This increase in iodine excretion approximatedthe additional iodine supplementation. Iodine lostthrough othermechanisms (sweat, feces, salivary gland, choroid plexus and gastric mucosa) could not be evaluated. Atthis dose level, the increase in iodine uptake induced a small, but significantupward change in serumtotal iodine, butno change in

I *' _,._..-.lodine/046905 Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 3 of4 Non-Guideline Study Study Profile version 07/04 proteinbound iodine. This indicates there was an increase inthe level ofserum inorganic iodine levels. Inthe subjectsreceiving 250 or 500 j..lg daily iodine, there was an increase inurinary iodine excretion (186 

### ± 37 j..lg daily to 314 

### ± 39 j..lg byday 14 for the 250 j..lg dose, 177 

### ± 21 j..lg daily to 506 

### ± 33 j..lg daily for the 500 j..lg dose), butno change in serum iodine, proteinbound iodine or inorganic iodine. 

### B. Serum thyroid hormones: The 1500 j..lg dose caused small but significant decreases in serumT3, T4 and FT4l and a significant increase in TSH concentrationsby day 15. The 250 and 500 j..lg daily doses did not significantly affect the serum levels ofthese factors. Theseresults are seeninTable 1. T 

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1500 J.lg 500 J.lg 250 J.lg •, p<0.02 **, p<O.OI ***, p<O.OOI n 18 9 9

NS- not significant Serum T4 (llg/dl) Serum FT41 DayO Day 15 DayO Day 15 7.3 ±0.2 6.7 ± 0.2*** 7.0 ± 0.2 6.4 ± 0.2*** 7.8 ± 0.4 7.9 ± 0.6 7.1 ±0.3 7.1 ±0.3 7.9±04 7.5 +0.3 7.6 ± 0.3 6.9 ± 0.2



### C. TSH, stimulated and unstimulated: Serum T3 (ng/dl) Serum TSH (llU/ml) DayO Day 15 DayO Day 15 181 ±4 173 ± 4* 1.9 ± 0.2 2.8 ± 0.4** 148 ± 5 144±4 2.1 ± 0.3 2.4 ± 0.4 134±3 135 ± 4 2.3 ± 0.4 2.7 ± 0.5

Themaximum increase in TRH stimulated TSH was greater in subjects receiving 1500 j..lg. This increase in TSH inresponseto TRHwas also significant when integrated TSHresponse (j..lU/ml X min) over onehourwere calculated. The response was greater in womenthan in men, both before and after iodine administration. There was no effect from the 500 and 250 j..lg doses. Data is shown in Figure 1 and Table 2. 

### Figure 1: The effect ofiodine administration ofthe maximum increase in serum TSH concentration following the intravenous administration of500 llgTRH. The numbers in parenthesis representthe numberofsubjects in each group. Statistical significance was determined using a Student's pairedt-test.Iodine/046905

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0 15 <0.005 Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 4 of4 Non-Guideline Study Study Profile version 07/04

Table 2: Effect of500 or250 Jlg iodine administered daily to euthyroid women on the TSH t TRH response o DeltaMax SerumTSH (!!U/ml) Integrated Serum TSH response

Iodide dose n (1-!U/ml x min) DayO Day 15 DayO Day 15 500 llg 9 18.4 ±2.8 20.7 ±2.8 975 ± 151 1088 ± 159 250 llg 9 19.1 ±3.9 21.6 ±5.8 1008± 196 1170 ±298



### III. INVESTIGATORS' DISCUSSION AND CONCLUSIONS: In a 14-day oral toxicity study iodine was selfadministered by patients as a 0.5 ml solution of sodium idodide every 12 hours. The males in the study received 750 11g twice daily and the womenreceived either 125, 250 or 750 11g twice daily. All doses were co-administeredwith 5 mg ofascorbic acid. The subjects were nine euthyroidmen (26-59) and 23 euthyroid women (23- 44). Five additional menwere age matched controls, receiving no additional iodine. Some women were studied at two dose levels, at least one year apart. This dosing was in addition to their normal unadjusted diets. No changes in weight, symptoms ofthyroid dysfunction, or other adverse effects were reported. Following the administration of 1500 11g, there were small but significant decreases in T4 and T3 concentrations and compensatory increases in serum TSH and TSH response to TRH. These changes, while significant, remained withinthe normal range and are not considered adverse. No effects ofany kind were seen in the 250 and 500 11g dose groups. This study is considered quantitative. There is no LOAEL associated withthis non-guideline study; the NOAEL is 1500 Jlg/day.