Iodine/046905 

Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 1 of 4 

Non-Guideline Study 

Study Profile version 07/04 

EPA Reviewer: Jonathan Leshin, Ph.D. 

RASSB, Antimicrobials Division (7510P) 

Secondary Review: Michelle Centra, Pharmacologist 

RASSB Antimicrobials Division (7510P) 

TXR#: 1003330 

Signature: 

Date: 

~ 

~Z/1 Signature~iL~ 

Date: *'3 f ff Templa~\,e/Sion 02/06 

II Data Evaluation Record II 

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

PC CODE: 046905 DP BARCODE: 408676 

TEST MATERIAL (PURITY): Iodine 

SYNONYMS: None 

CITATION: Paul, T., Meyers, B., Witorsch, R.J., et al (1988) The effects of small increases 

in dietary iodine on thyroid function in euthyroid subjects. University of 

Massachusetts Medical School MRID 48358603. Metabolism, 37(2) pp 121-124 

SPONSOR: National Institute of Diabetes and Digestive and Kidney Diseases 

INVESTIGATORS' EXECUTIVE SUMMARY: 

In a 14-day oral toxicity study (MRID 48358603), iodine was self administered by patients as a 

0.5 ml solution of sodium 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 of ascorbic 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 at two dose levels, at least one year 

apart. This dosing was in addition to their normal unadjusted diets. 

No changes in weight, symptoms of thyroid dysfunction, or other adverse effects were reported. 

Following the administration of 1500 ~g, 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 within the normal range and are not considered adverse. No 

effects were seen in the 250 and 500 ~g dose groups. 

This study is considered quantitative. There is no LOAEL associated with this non-guideline 

study; the NOAEL is 1500 J.Lg/day. 
lodine/046905 

Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 2 of 4 

Non-Guideline Study 

Study Profile version 07/04 

I. MATERIALS AND METHODS 

A. MATERIALS: 

1. Test Material: 

Description: 

CAS # if TGAI: 

Iodine 

Nal 

74-88-4 

2. Vehicle and/or positive control: Deionized water 

3. Test animals: 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 DESIGN AND 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 hr urine collection was completed. On day 0, blood was collected for a baseline serum protein 

bound iodine (PBI) and total iodine (TI), thyroxine (T 4), triiodothyronine (T 3) and thyrotropin 

(TSH) as well resin T3 uptake and free T4 index (FT4I). Thyrotropin releasing hormone (TRH) 

was administered via IV and blood was drawn at 15, 30, 45 and 60 minutes for measurement of 

TRH induced TSH. 

All subjects were treated with various doses of iodine in 0.5 ml of deionized water containing 5 

mg of ascorbic 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 hour urine sample was collected on day 7 and on day 8, prior to morning iodine 

ingestion, a sample of blood was drawn for analysis. A final 24 hr urine sample was collected on 

day 14 and the TRH test was repeated on day 15. 

Five additional age matched men were studied as above, but not given iodine supplements. No 

changes in any parameters were seen in these subjects. 

II. RESULTS 

A. Serum inorganic, protein-bound and urinary iodines: 

In the subjects receiving the 1500 Jlg daily iodine, there was an increase in mean 24 hr urinary 

iodine excretion from 211 ± 41 Jlg 1124 hr to 1360 ± 74 Jlg I/24 hr on day seven and 1308 ±58 

Jlg I/24 hr on day 14. This increase in iodine excretion approximated the additional iodine 

supplementation. Iodine lost through other mechanisms (sweat, feces, salivary gland, choroid 

plexus and gastric mucosa) could not be evaluated. At this dose level, the increase in iodine 

uptake induced a small, but significant upward change in serum total iodine, but no change in 

I *' _,._..-. 
lodine/046905 

Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 3 of 4 

Non-Guideline Study 

Study Profile version 07/04 

protein bound iodine. This indicates there was an increase in the level of serum inorganic iodine 

levels. 

In the subjects receiving 250 or 500 j..lg daily iodine, there was an increase in urinary iodine 

excretion (186 ± 37 j..lg daily to 314 ± 39 j..lg by day 14 for the 250 j..lg dose, 177 ± 21 j..lg daily to 

506 ± 33 j..lg daily for the 500 j..lg dose), but no change in serum iodine, protein bound iodine or 

inorganic iodine. 

B. Serum thyroid hormones: 

The 1500 j..lg dose caused small but significant decreases in serum T3, T4 and FT4l and a 

significant increase in TSH concentrations by day 15. The 250 and 500 j..lg daily doses did not 

significantly affect the serum levels of these factors. These results are seen in Table 1. 

T a bl e 2 : S erum th lyroi 'd h ormone concen t ra f Ions b e :t ore an d a ft er 10 . d'd 1 e a d miDIS .. t ra f IOn 

Iodide dose 

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 

The maximum increase in TRH stimulated TSH was greater in subjects receiving 1500 j..lg. This 

increase in TSH in response to TRH was also significant when integrated TSH response (j..lU/ml 

X min) over one hour were calculated. The response was greater in women than 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 of iodine administration of the maximum increase in serum TSH 

concentration following the intravenous administration of 500 llg TRH. The numbers in 

parenthesis represent the number of subjects in each group. Statistical significance was 

determined using a Student's paired t-test. 
Iodine/046905 

40 

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0 

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0 

Doys 

QControl 

ol 

0 15 

p value < 0.001 

~ 0.75 mo 1 q 12 h 

FEMALES (9) 

0 15 

<0.005 

Subchronic (90-day) Oral Toxicity Study (non-rodents) (1988) I Page 4 of 4 

Non-Guideline Study 

Study Profile version 07/04 

Table 2: Effect of 500 or 250 Jlg iodine administered daily to euthyroid women on the TSH 

response t o TRH 

Delta Max Serum TSH (!!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 self administered 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 

women received either 125, 250 or 750 11g twice daily. All doses were co-administered with 5 

mg of ascorbic 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 at two dose levels, at least one year apart. This dosing was in addition to 

their normal unadjusted diets. No changes in weight, symptoms of thyroid 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 within the normal range and 

are not considered adverse. No effects of any kind were seen in the 250 and 500 11g dose groups. 

This study is considered quantitative. There is no LOAEL associated with this non-guideline 

study; the NOAEL is 1500 Jlg/day.