DATE:	July 12, 2005											

MEMORANDUM

SUBJECT:	Iodine and Iodophor complexes- Report of the Antimicrobials
Division Toxicology Endpoint Selection Committee. 

	

FROM:	Timothy F. McMahon, Ph.D.

Chair, ADTC

Antimicrobials Division (7510C)

Michelle Centra, Pharmacologist

		Executive Secretary, ADTC

		Antimicrobials Division (7510C)

THROUGH:	John Redden, Roger Gardner;  Stephen Dapson, Ph.D., Karen
Hamernik, Ph.D., Melba Morrow, D.V.M., Jonathan Chen, Ph.D., Timothy
Leighton, Michelle Centra, Najm Shamim, Ph.D., Deborah Smegal; Myron
Ottley, Ph.D., Tim McMahon, Ph.D.

			

TO:		Mark Hartman, Acting Branch Chief

Ben Chambliss, Team Leader

Heather Garvie, Chemical Review Manager

Michelle Centra, Science Coordinator/Risk Assessor

Regulatory Management Branch II

		Antimicrobials Division (7510C)

				

PC Codes:  046905; 075701; 046901; 046904; 046921; 046918; 046903;
046915;   046914; 046923.

On February 23, 2005, the Antimicrobials Division Toxicology Endpoint
Selection Committee (ADTC) met to consider the available toxicology data
for Iodine in support of the reregistration eligibility decision
document (RED) for iodine.    The conclusions drawn at this meeting are
presented in this report.

Committee Members in Attendance

Members present were: Timothy F. McMahon, Ph.D. Stephen Dapson, Ph.D.;
Michelle Centra;  Jonathan Chen, Ph.D.; Timothy Leighton; John Redden;
Deborah Smegal; Melba Morrow, D.V.M.; Najm Shamim, Ph.D.; Myron Ottley,
Ph.D.

Member(s) in absentia: Roger Gardner; Sanyvette Williams, D.V.M.; Karen
Hamernik, Ph.D.

Data evaluation prepared by: Tim McMahon, Ph.D.

COMMITTEE MEMBERS	(Signature indicates concurrence unless otherwise
stated)

Stephen Dapson				                                                   		 
                                                

Jonathan Chen				                                                   		  
                                              

Roger Gardner				                                                   		  
                                              

Karen Hamernik				                                                   		 
                                               

Tim McMahon (chair)			                                                  
		                                                

Melba Morrow				                                                   		   
                                           

John Redden				                                                   		    
                                          

Sanyvette Williams-Foy			                                               
   		                                               

Tim Leighton				                                                   		

Michelle Centra				                                                   		

Najm Shamim				                                                   		

Deborah Smegal				                                                   		

Myron Ottley 				_________________________

 

INTRODUCTION tc \l1 "INTRODUCTION 

The reregistration eligibility decision document (RED) for iodine
encompasses several chemical forms of iodine. Included in this case are
iodine, potassium iodide, sodium iodide, and several iodophor complexes.
 These complexes consist of the following 1) iodine complexed with
propoxyethoxy copolymer carriers [subgroup A]; 2) iodine complexed with
phenoxypolyethoxyethanol carriers [subgroup B]; 3) iodine complexed with
polyvinylpyrrolidone carriers [subgroup C]; and 4) an iodinated resin
complex (quaternary amine divinylbenzene/styrene copolymer.  The iodine
complexes all function in a similar manner, in that the complex releases
molecular iodine when diluted to the use concentration specified on the
label.  Two products (Triosyn T50 and T50 powder, EPA reg. nos. 72897-1
and 72897-2) are manufacturing use products that consist of a solid
polymeric material containing iodine as the active ingredient. These
release only limited amounts of iodine for their applications, but are
also included in the RED document. 

There are a wide variety of uses for iodine and iodine complexes. Iodine
and iodine complexes are used primarily for emergency drinking water
disinfection. Potassium iodide is used to sanitize fresh fruits and
vegetables. The surfactant iodophor complexes are used primarily for
sanitizing food-contact surfaces in food processing plants and food
handling establishments, and for disinfection of environmental surfaces
in hospitals. 

Several tolerance exemptions exist for iodine and salts of iodine when
used as ingredients in antimicrobial pesticide formulations under 40 CFR
180.940:

Table 1.  Tolerance Exemptions in 180.940, 40 CFR



Tolerance Exemption  	

CAS No.	

40 CFR 	

Limits



Iodine	

7553-56-2 	

180.940(a)(b)(c)1	

When ready for use, the total end-use concentration of all
iodide-producing chemicals in the solution is not to exceed 25 ppm of
titratable iodine



Potassium Iodide	

7681-11-0	

180.940(a)(b)(c)1	

When ready for use, the total end-use concentration of all
iodide-producing chemicals in the solution is not to exceed 25 ppm of
titratable iodine



Sodium Iodide	

7681-82-5	

180.940(c)1	

When ready for use, the total end-use concentration of all
iodide-producing chemicals in the solution is not to exceed 25 ppm of
titratable iodine



Hydriodic Acid	

10034-85-2	

180.940(b)(c)1	

When ready for use, the total end-use concentration of all
iodide-producing chemicals in the solution is not to exceed 25 ppm of
titratable iodine



1. Residues of chemical substances listed in Sec. 180.940 are exempted
from the requirement of a tolerance when used in accordance with good
manufacturing practice as ingredients in an antimicrobial pesticide
formulation, provided that the chemical substance is applied on a
semi-permanent or permanent food-contact surface (other than being
applied on food packaging) with adequate draining before contact with
food.  Under 180.940 (a) (b)(c), chemical substances when used as
ingredients in an antimicrobial pesticide formulation may be applied to
(a) food-contact surfaces in public eating places, dairy-processing
equipment, and food-processing equipment and utensils; (b) dairy
processing equipment, and food-processing equipment and utensils, and
(c) food-processing equipment and utensils. 

As noted above, in all cases, the  exemption states that “When ready
for use, the total end-use concentration of all iodide-producing
chemicals in the solution is not to exceed 25 ppm of titratable
iodine.”  Based on calculations made by the Antimicrobials Division
using current assumptions on food contact sanitizer uses, this
translates into a dose of  approximately  0.007 mg/kg/day for a 70 kg
adult, and 0.033 mg/kg/day for a 15 kg child. 

In addition to the above, the following exemption is listed in 180.1022:

180.1022 Iodine-detergent complex; exemption from the requirement of a
tolerance.

“The aqueous solution of hydriodic acid and elemental iodine,
including one or both of the surfactants (a)
polyoxypropylene-polyoxyethylene glycol nomionic block polymers (minimum
average molecular weight 1,900) and (b) ( -(p- nonylphenyl)-omega-
hydroxypoly (oxyethylene) having a maximum average molecular weight of
748 and in which the nonyl group is a propylene trimer isomer, is
exempted from the requirement of a tolerance for residues in eggs and
poultry when used as a sanitizer in poultry drinking water.”

Physical Properties:

Active ingredient:	iodine

	Molecular Weight:			253.809

	Color:				           	Bluish-black

	Physical State:			            Solid; scales or plates

	Specific gravity:			4.93

	Dissociation Constant:		No data available

	pH:				            No data available

	Stability:			            No data available

	Melting point:			            113.6oC

	Boiling point:                                      185.24oC

	Water Solubility:			330mg/L at 25oC

	Octanol-water Partition Coefficient:	2.49

	Vapor Pressure:			0.305 mm Hg at 25oC 

Active ingredient: potassium iodide

  SEQ CHAPTER \h \r 1 Molecular Weight:			166.02

Color:				            Colorless or white

Physical State:			            Solid; crystals, granules, or powder

Specific gravity:			3.12

Dissociation Constant:		No data available

pH:				            No data available

Stability:			            No data available

Melting point:			            680oC

Boiling point:                                      1323oC

Water Solubility:			1429 g/L at 25oC

Octanol-water Partition Coefficient:	No data available

Vapor Pressure:			No data available

Active ingredient: sodium iodide

  SEQ CHAPTER \h \r 1 Molecular Weight:	149.89

Color:			White, which on prolonged exposure to air turns brown as it
releases

			Iodine

Physical State:		Solid

MP:			321 o C

Specific Gravity:	3.25

pH:			8- 9.5

Stability:		Delinquent, absorb moisture from air and become brown

Water Solubility:	22 g/L

Log Kow		0.04

Henry Law Constant:	2.8 x10-23 atm-m3/mol

Vapor Pressure:	9.9 x 10-18 mm Hg

Both iodine and potassium iodide are naturally occurring chemicals in
the environment. Iodine is

an essential nutrient and an adequate intake of this nutrient is
required for production of thyroid 

hormones. Currently, the National Research Council (NRC) Recommended
Daily Allowance 

(RDA) for iodine is 150 ug/day (2.1 ug/kg/day for a 70 kg adult), with
additional allowances of 

25 and 50 ug/day during pregnancy and lactation respectively.  The
Environmental Protection Agency has also established an emergency
disinfection Drinking Water Level of 8000 to 16000 ug/L, equivalent to
approximately 229 to 1067 µg/kg/day for iodine. Therefore, exposures
from the antimicrobial uses of iodine and iodophors complexes should be
considered in this context.  That is, potential toxicological effects
should be characterized in the context of the magnitude of the expected
exposures from the antimicrobial uses in relation to the accepted daily
intake for iodine and current regulatory values established for iodine. 


The ADTC considered the following two issues for the reregistration
eligibility decision:

Do the antimicrobial uses of iodine and iodine complexes warrant a
qualitative or quantitative assessment?  The toxicological effects cited
in other regulatory assessments have not quantified risk because the
effect on which the regulatory value is based is reversible (subclinical
hypothyroidism). 

Specifically, with regard to dermal and inhalation exposures, should
dermal and inhalation exposure from the antimicrobial uses of iodine and
iodine complexes be quantified as to risk? The available dermal
absorption data show the magnitude of absorption to be low (generally
less than 1% from intact skin). In addition, the maximum  inhalation
exposure calculated from antimicrobial uses is estimated to be 0.008
ppm, more than 10-fold lower than the ACGIH TLV for iodine (0.1 ppm)

Conclusions/Recommendations

	Issue 1

The ADTC concluded that a qualitative assessment is appropriate for the
iodine reregistration 

case.  This conclusion is based partly upon the worst-case exposure
calculations made within 

the Antimicrobials Division for the inhalation and dermal exposures that
would result from the 

antimicrobial uses of iodine and iodine complexes.  As noted previously,
based on calculations 

made by the Antimicrobials Division using current assumptions on food
contact sanitizer uses,

the tolerance exemption noted in 180.940 for iodine of 25 ppm translates
into a dose of  

approximately 0.007 mg/kg/day for a 70 kg adult, and 0.033 mg/kg/day for
a 15 kg child and 

represent worst-case exposures.  These calculated oral exposures fall
between the RDA of 150 µg/day (0.002 mg/kg/day) and the Tolerable Upper
Intake Level of 1100 µg/day ( 0.016 mg/kg/day for the general
population as well as the tolerable upper limit for children 1-13 of
200-600 µg/day (0.01 – 0.04 mg/kg/day).    It is important to note
that the tolerable upper intake level is the highest level of daily
nutrient intake that is likely to pose no risk of adverse health effects
in almost all individuals (Institute of Medicine, 2003), and that
responses to intake of iodine between the RDA and the upper intake level
do not represent adverse responses, but biological responses.   Taking
this into consideration,  the ADTC concluded that the calculated oral
exposures from food contact sanitizer use of iodine and iodine complexes
represented no risk of concern.

It is important to note that an acute exposure to iodine that may
temporarily be 

above the RDA is usually a temporary effect to which the body readily
adapts through down-

regulation of the iodine transporter mechanism in the thyroid gland
(ATSDR, 2004).  

	

Issue 2

The ADTC, having considered the published data on dermal absorption and
toxicity of iodine, and the estimated worst-case exposures from dermal
and inhalation uses of iodine in antimicrobial pesticide formulations,
concluded that quantitative assessment of dermal and inhalation
exposures is not needed for iodine and iodine complexes.  The ADTC
agreed that the data for dermal absorption of iodine show a low
percentage of absorption (1%; ATSDR, 2004) and that calculated
worst-case inhalation exposures (0.008 ppm) are well below the ACGIH
published TLV for iodine vapor of 0.1 ppm. Therefore, dermal and
inhalation exposures from the antimicrobial uses of iodine and iodine
complexes present no risk of concern. 



       Susceptible subpopulations	

 It is known that with respect to iodine toxicity, certain disease
states (thyroid gland adenoma, autoimmune thyroid disease) may make
individuals with those conditions at increased risk for thyroid
dysfunction if exposed to excess iodine.  Pre-existing nutritional
deficiency of iodine in the diet may also result in an adverse reaction
when exposure to excess iodine is encountered.  In infants, thyroid
iodine uptake as a fraction of absorbed dose, is 3-4 times higher during
the first 10 days after birth but then becomes equivalent to adult
uptake values thereafter (ATSDR, 2004). While there are several studies
that examined susceptibility of infants and children to radioiodine
fallout as a result of thermonuclear bomb tests (ATSDR, 2004), these all
involved radioiodine exposures, complicating an interpretation of the
effect of iodine itself.  It should be noted that iodine deficiency is
of greater concern with respect to the health of infants and children,
as a lack of iodine can result in growth and developmental
abnormalities, particularly of the developing brain. 

The Agency is not in possession of submitted data on potential
developmental or reproductive toxicity of ingested iodine and has
examined the available scientific literature on this subject.  A
retrospective study conducted by ATSDR in 2000 on pregnancy outcomes and
infant deaths among residents living near the Hanford Nuclear site
during 1940-1952 found no significant association with exposure to
radioiodine and infant or fetal death. Another study examined pregnancy
health and reproductive outcomes of women exposed to radioiodine from
the Chernobyl nuclear power plant. Although this study suggested some
association of exposure to radioiodine and congenital abnormalities and
neonatal respiratory disorders, the contribution of radioiodine itself
to these effects is highly uncertain from this study.  Additional
published scientific studies on developmental toxicity of iodine were
available by Arrington et al (1965) and Lee and Satow (date not
available). In the Arrington et al. study, Long-Evans female rats were
administered dietary iodine as sodium or potassium iodide at doses of 0,
30, 60, or 120 mg/kg/day on gestation days 6-15.  The only effect
observed in this study was a decrease in fetal body weight at the high
dose.  There was no evidence of teratogenicity in this study. In the Lee
and Satow study, Donryu strain rats were administered potassium iodide
by gavage on gestation day 9 only at doses of approximately 75, 300,
900, 1500, or 1800 mg/kg/day, and sacrificed on day 18.   The abstract
reported an increased incidence of resorptions at 300 mg/kg, and also
reported anomalies in treated rats (without respect to incidence),
consisting of ventricular septal defects, aberrant right subclavian
artery, incomplete lung development, and growth retardation. There were
no data in this abstract to verify these findings nor was there any
discussion of parental toxicity.   

	The ADTC concluded that based on the available data, there is no
concern for increased susceptibility of infants and children to the
exposures from antimicrobial uses of iodine and iodine complexes. This
is based on the following observations:

The available hazard data show no evidence of increased susceptibility
to developing offspring. 

The chronic Minimal Risk Level as determined by ATSDR (0.01 mg/kg/day)
is based upon exposure of groups of children, the effect being
subclinical hypothyroidism, a reversible condition. 

3)  The MRL value itself (0.01 mg/kg/day) is higher than the National
Research Council       recommended dietary allowance of 0.002 mg/kg/day
for a 70 kg adult and 0.006 mg/kg/day for children ages 1-8 years. By
definition, no adverse effects are expected below the MRL. 

4)   The tolerable upper limit for children is estimated at 0.01-0.04
mg/kg/day for children aged 1-13  years. This value is in excess of the
estimated dietary exposures occurring from the uses of iodine.  It
should also be noted that the lower end of the tolerable upper limit for
children is equal to the MRL. References

1) ATSDR, 2004: Toxicological profile for Iodine. U.S. Department of
Health and Human Services. 

2) Institute of Medicine, 2003: Dietary Reference Intakes for Vitamin A,
Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese,
Moybdenum, Nickel, Silicon, Vanadium, and Zinc. National Academy Press,
Washington D.C.

3) Flury, F. and Zernik, F.: Schadliche Gase. J. Springer, Berlin (1931)
in: ACGIH, 2001: Iodine.

4) Casarett, L.J. Toxicology of the Respiratory System. In: Toxicology.
The Basic Science of Poisons. Pp. 201-224. L.J. Casarett and J. Doull,
Eds. Macmillan, New York (1975). Acute Toxicity of Iodine Technical

Guideline No.	Study Type	MRID#	Results	Toxicity Category

870.1100	Acute Oral- Rats	42326704	LD50 = 315 mg/kg	II

870.1200	Acute Dermal – Rats	42326705	LD50 = 3,333 mg/kg	III

870.1300	Acute Inhalation – Rats	42961002	LC50 = 0.363 mg/L	II

870. 2500	Primary Dermal Irritation – Rabbits	42326706	Corrosive;
severe edema, erythema, and eschar	I

870.2600	Dermal Sensitization- Guinea Pigs	42326707	No sensitization
using Buehler method	N/A



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