Document ID: EPA-HQ-OPP-2006-0599-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-06-03T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

					WASHINGTON, D.C.  20460

		

					OFFICE OF PREVENTION PESTICIDES AND

       											 TOXIC SUBSTANCES

DATE:	November 6, 2006											

MEMORANDUM

SUBJECT:	IODINE AND IODOPHOR COMPLEXES – Revised Report of the
Antimicrobials Division Toxicology Endpoint Selection  Committee (ADTC).

	

FROM:	Timothy F. McMahon, Ph.D.

Chair, ADTC

Antimicrobials Division (7510P)

Michelle Centra, Pharmacologist

		Executive Secretary, ADTC

		Antimicrobials Division (7510P)

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

			

TO:		Mark Hartman, Acting Branch Chief

Diane Isbell, Acting Team Leader

Heather Garvie, Chemical Review Manager

Michelle Centra, Risk Assessor

Regulatory Management Branch II

		Antimicrobials Division (7510P)

				

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

On February 23, 2005, the Antimicrobials Division Toxicology Endpoint
Selection Committee (ADTC) met to consider the available toxicology data
for Iodine and Iodophor Complexes in support of the reregistration
eligibility decision document (RED.  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;
Melba Morrow, D.V.M.; Najm Shamim, Ph.D.; 

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

DATA PRESENTATION:                                      
______________________________

			Tim McMahon, Ph.D., Chair

DRAFT DOCUMENT PREPARATION:                 
______________________________

		Tim McMahon, Ph.D., Chair

FINAL DOCUMENT PREPARATION:		______________________________

							Michelle Centra, Executive Secretary

COMMITTEE MEMBERS	(Signature indicates concurrence unless otherwise
stated)

Stephen Dapson				                                                   		 
                                                

Jonathan Chen				                                                   		  
                                              

Roger Gardner				                                                   		  
                                              

Tim McMahon (chair)			                                                  
		                                                

Melba Morrow				                                                   		   
                                           

John Redden				                                                   		    
                                          

Sanyvette Williams-Foy			                                               
   		                                               

Tim Leighton				                                                   		

Michelle Centra				                                                   		

Najm Shamim				                                                   		

 

 INTRODUCTION

Regulatory History and Use Patterns for Iodine in Pesticide Products

Products containing iodine as the active ingredient were initially
registered in the United States by the U.S. Department of Agriculture
beginning in 1948.  Approximately 2 million pounds of iodine are sold
annually in the United States for use in antimicrobial products. 
Currently there are 69 products containing iodine or an iodophor complex
as the active ingredient registered by the Agency

Iodine and the iodophor complexes are used   SEQ CHAPTER \h \r 1 for a
variety of indoor antimicrobial uses.  They all function as
microbiocides by releasing iodine.    SEQ CHAPTER \h \r 1 As active
ingredients in formulated products, iodine and iodophor complexes are
used as a water disinfectant, slimicide, germicide, antimicrobial,
broad-spectrum disinfectant (bactericide/germicide), fungicide/fungistat
(trichophyton), microbiocide/microbiostat (slime-forming bacteria),
sanitizer (food-contact surfaces), tuberculocide, virucide
(antimicrobial), sporicide and preservative for emergency drinking water
purification, fresh food sanitization, food-contact surface
sanitization, hospital surface disinfection, materials preservation, and
commercial and industrial water cooling tower systems.  

Currently, iodine and iodophor complexes are divided into the following
groups and sub-groups: iodine, potassium iodide, sodium iodide,
hydriodic acid and, the iodophor complexes that consist of the following
subgroups: 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 products release only
limited amounts of iodine for their labeled applications.

Tolerance Exemptions

The tolerance exemption for residues of iodine and iodophor complexes
per se is established under 40 CFR 180.940 (69 FR 23124, Apr.28, 2004). 
Ten tolerance exemptions exist for iodine and iodophor complexes when
used as ingredients in antimicrobial pesticide formulations under 40 CFR
180.940 (Table 1).



		Table 1.  Tolerance Exemptions in 180.940, 40 CFR for Iodine

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

1Residues 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.

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

Current Regulatory Standards for Iodine

The National Academy of Sciences has set the Recommended Dietary
Allowance (RDA) of iodine for adult men and women at 150 µg/day.  For
infants, the Adequate Intake (AI) is used as the RDA and is 110 µg/day
of iodine for infants aged 0 to 6 months and 130 µg/day of iodine for
infants aged 7 to 12 months.  The RDAs for children are in the range of
90-150 µg/day of iodine (1-8 years: 90 µg/day; 9-13 years: 120
µg/day; 14-18 years: 150 µg/day).  The RDAs for pregnant and lactating
women are 220 µg/day and 290 µg/day of iodine, respectively. 

A Tolerable Upper Intake Level (UL), the maximum level of daily intake
that is likely to pose no risk of adverse effects, has been established
at 1,100 µg/day for adult men and women based on serum thyroptropin
concentration in response to varying levels of ingested iodine.  The ULs
for children range from 200 - 600 µg/day of iodine (1-3 years: 200
µg/day; 4-8 years: 300 µg/day; 9-13 years: 600 µg/day).  The ULs for
adolescents and pregnant and lactating women ages 14-18 years is 900
µg/day of iodine and for pregnant and lactating women ages 19-50 years
is 1,100 µg/day of iodine.  For infants (0-12 months), no UL was
determined.  However, to prevent high intake of iodine, it is
recommended that the only source of this essential nutrient for infants
be from food and formula. (NAS, 2001).

In 1978, the Food and Drug Administration deemed potassium iodide a safe
and effective means by which to block uptake of radioiodines by the
thyroid gland in the event of a radiation emergency under certain
specified conditions of use.  The recommended daily doses for different
risk groups were revised in 2001 using data on thyroid cancer resulting
from the Chernobyl reactor accident in 1986.  These values range from
16,000 µg (16 mg) to 130,000 µg (130 mg) of potassium iodide.  

 

There are no primary drinking water standards (MCL) for iodine or its
oxidized or reduced forms, as iodine is used only in emergency
disinfection of water and not in treatment of municipal water supplies.
In addition, there are no Health Advisories (HA), secondary drinking
water standards, or ambient water quality standards associated with
iodine, iodate and iodide.  

For comparison purposes, the various levels of existing and/or
background exposure to iodine/iodide are given in Table 2.

  SEQ CHAPTER \h \r 1 Table 2: Existing Iodine Background Exposure
Levels	

Exposure Scenario	Exposure Level

RDA set by the National Academy of Sciences for adult men and women.	150
µg/day (0.0021 mg/kg/day)

Tolerable Upper Intake Level set by the National Academy of Sciences for
adult men and women	1100 µg/day (0.016 mg/kg/day)

US Estimated dietary adult intake established by the U.S. Department of
Agriculture Continuing Survey of Food Intakes by Individuals (1994-1996)
	190 to 210 µg/day for women 

240 to 300 µg/day for men

 



II.  PHYSICAL/CHEMICAL PROPERTIES

IODINE 

		  SEQ CHAPTER \h \r 1 1.  Chemical Overview 						

The chemical Iodine  (PC Code: 046905) is most commonly used in:
sanitation, animal feed and pharmaceutical production.

	2.  Chemical Identification

Name:				Iodine

Chemical Family: 	Halogen 

Common/Trade Names:	None

CAS Number:		7553-56-2

Molecular Formula:	I2	

3.  Physical/Chemical Properties

The following characteristics have been reported for iodine: 

Technical Grade Active Ingredient (TGAI):

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

C

Boiling point:                                      185.24C

Water Solubility:	330 mg/L at 25C

Log Kow			0.40

Vapor Pressure:		0.305 mm Hg at 25oC 

	B.	POTASSIUM IODIDE

	1.  Chemical Overview 						

The chemical Potassium iodide (PC Code: 075701) is most commonly used
in: sanitation, animal feed, catalysts, and for treatment of radioiodide
poisoning resulting from nuclear accidents.

	2.  Chemical Identification



Name:				Potassium iodide

Chemical Family: 	Halogen 

Common/Trade Names:	None

CAS Number:		7681-11-0

Molecular Formula:	KI	

3.  Physical/Chemical Properties

The following characteristics have been reported for potassium iodide: 

Technical Grade Active Ingredient (TGAI):

Molecular Weight:	166.02

Color:				Colorless or white

Physical State:		Solid; crystals, granules, or powder

Specific gravity:		3.12

Dissociation Constant:	N/A: Completely ionized in aqueous 		

	                                                         medium

pH:				No data available

Stability:			Stable, but turn yellowish over prolonged  

					period of time

C

Boiling point:                                     	1323C

Water Solubility:	1429 g/L at 25C

pH;				Aqueous Solution: neutral to basic: 7-9

Log Kow:			0.04

Vapor Pressure:		9.9 x 10-18 mm Hg

	C.	SODIUM IODIDE

	1.  Chemical Overview:

The chemical Sodium iodide is currently not formulated into pesticide
products.

	2.  Chemical Identification:

Name:				Sodium Iodide

Chemical Family:		Halogen

	Common/Trade Name:		None

	CAS Number:			7681-82-5

	Molecular Formula:		NaI

3.  Physical/Chemical Properties:

 

The following Characteristics have been reported for Technical Grade
Active Ingredient (TGAI):

Molecular Weight:	149.89

Color:				White, which on prolonged exposure to air turns    

							brown as it releases Iodine

Physical State:		Solid

Melting Point:		321 oC

Boiling Point:		732 oC

Specific Gravity:		3.67

pH:				Basic in aqueous medium: 8-9.5

Stability:			Delinquent, absorbs moisture from air and becomes

                            			brown

Water Solubility:		22 g/L

Dissociation Constant:	N/A: Completely ionized in water.

Log Kow			0.04

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

Vapor Pressure:		9.9 x 10-18 mm Hg

	D.	HYDRIODIC ACID

	1.  Chemical Overview 						

The chemical Hydriodic acid (PC Code:  is most commonly used in:
sanitation, animal feed, catalysts, and for treatment of radioiodide
poisoning resulting from nuclear accidents.

	2.  Chemical Identification

Name:				Hydriodic acid (aqueous solution of hydrogen 

					Iodide)

Chemical Family: 	Halogen 

Common/Trade Names:	Hydrogen iodide

CAS Number:		10034-85-2

Molecular Formula:	HI	

	3.  Physical/Chemical Properties

The following characteristics have been reported for potassium iodide: 

Technical Grade Active Ingredient (TGAI):

Molecular Weight:	127.91

Color:				Colorless (gas); Pale yellow (aqueous soln.)

Physical State:		Gas dissolved in aqueous solution

Specific gravity:		1.54-1.7	                                            
  

Odor:				Pungent

Stability:			Stable, but when exposed to sunlight, turns a

  					light brown color 

C	(57% solution)		 						

Water Solubility:	100% soluble up to a 57% solution in water

pH				not available			

Vapor Pressure:		not available

Note: Hydriodic acid is highly irritating to the eyes and skin.

	E.	IODOPHOR COMPLEXES

As the antimicrobial registered uses of Iodine/KI/NaI/Hydriodic acid may
be in the form of an iodophor complex, the Antimicrobials Division has
included some important physical/chemical characteristics and also some
important relevant information of all the applicable polymeric units
used as iodophors in this section.

	1. Surfactant-Iodine Complexes		

Propoxyethoxy (PO/EO) Copolymer Carriers or
Polypropoxypolyethoxyethanol-Iodine Complexes

		a. Butoxypolypropoxypolyethoxyethanol (PC Code: 046901)

For iodophor production, so-called block copolymers are used to
synthesize the surfactant-iodine complex.  The final polyalkylene glycol
(PAG) is not a single compound but is a mixture of polymer chains which
has an approximate normal distribution around the desired molecular
weight. The molecular weights used in iodophor production range from
2000 to 4000 a.m.u. 

			b. Polypropoxypolyethoxyethanol (PC Code: 046904)

With the exception of the initiator, these polymers are synthesized by a
reaction similar to the butoxypolypropoxypolyethoxyethanol carriers. 

Phenoxypolyethoxyethanol Carriers (Phenoxypolyethoxyethanol-iodine
complexes)

		a. Nonylphenoxypolyethoxyethanol (PC Code: 046903)

Nonylphenoxypolyethoxyethanols (nonylphenol polyethoxylates; NPE; CAS
No. 9016-45-9 or 26027-38-3) are commonly used surfactants in industrial
cleaners, pesticide adjuvants, and, for the most commonly made 9-mole
ethoxylate, spermicides.  The C9 chain of the nonylphenol (NP) is
comprised of approximately 25-30 isomers with varying chemical branches.
As with the EO/PO polymers discussed above, the final products are not a
single compound but are mixtures of chains which have an approximate
normal distribution around the desired molecular weight. 
Nonylphenoxypolyethoxyethanol is a blue liquid with a specific gravity
of 1.01 and has a listed pH of 9.5 ± 2.  

Polyvinylpyrrolidone Carriers (Polyvinylpyrrolidone-iodine complexes)

		a. Polyvinylpyrrolidone (Povidone) (PC Code: 046914)

Povidone (PVP; CAS No. 9003-39-8) is a synthetic polymer principally
consisting of linear 1-vinyl-2-pyrrolidone groups, produced as a series
of products having mean molecular weights ranging from about 10,000 to
about 1 million a.m.u. or greater.  The monomer molecular weight is 11.1
a.m.u.  In addition to its use in disinfectants, it is used as a
dispersing agent, and has been used as a tablet binder, coating agent,
and viscosity-increasing agent in pharmaceutical preparations.  The
chemical formula is (C6H9NO)x.

 

PVP is an odorless faintly yellow powder and is soluble in water,
ethanol, and chloroform and insoluble in ether.  PVP has a specific
gravity of 1.1-1.3 and a pH ranging from 3.0 to 7.0 in a 1:20 solution. 
The melting point is 100oC.  The amide region of the pyrrolidone
substituent absorbs in the UV region at wavelengths below 235 nm. 

	2.	 AMINO ACID-IODINE COMPLEX

Tetraglycine hydroperiodide (PC Code: 046923)

For the amino-acid iodophor used in emergency water disinfection,
tetraglycine hydroperiodide is formed by a catalyst driven reaction of
the essential amino acid glycine, to produce the complex:
2[(CH2NH2COOH)8 • (HI)2 2.5I2].

	3. IODINATED RESIN COMPLEX

Quat Amine divinylbenzene/ styrene copolymer  (Anion exchange resin is a
complex and iodine is binding to it ( iodophor) (PC Code: 046905)

 

Triosyn® resin is produced by thermally fusing pure iodine crystals
under high pressure with a specialized quaternary amine
divinylbenzene/styrene polymer. During this process, a stable
electrochemical bond is formed between the iodine and the polymer,
allowing no free release of iodine in the media employed. This
electrochemical bond serves as a demand-release mechanism that allows
iodine molecules to be released from Triosyn® resin in the presence of
microorganisms and in amounts required to eliminate the source of the
demand. Upon contact with a microorganism, ionic molecular iodine is
transferred from Triosyn® resin, to the more strongly charged surface
proteins of the microbe. The iodine immediately devitalizes the
microorganism by removing electrons from the organism's surface proteins
which are necessary for life and reproduction.  This process provides
disinfectant properties to items such as tent fabric and outdoor paint.
There is little human contact with the poymeric Triosyn® resin.

In addition, when iodine is present in the iodophor (matrixed in one of
the polymeric structures discussed above, the vapor pressure of iodine
decreases considerably.  For example, iodine present at a level of 300
ppm in an iodophor, has a considerable reduction in vapor pressure from
0.3 mm Hg to 6.6 x10-6 mm Hg.

III. DOSE-RESPONSE ASSESSMENT

The ADTC considered the following three issues for reregistration
eligibility of iodine-containing pesticide products:

	Issue 1

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). 

Issue 1 Conclusion

Dietary exposure (food and water) could potentially occur from the
antimicrobial use of iodine and iodophor complexes on food contact
surfaces, on fruits and vegetables as a sanitizing wash, and in
emergency drinking water disinfection.  Using conservative assumptions
for the food contact sanitizer uses, the tolerance exemption noted in
180.940 for iodine and iodophor complexes with a limitation 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.  For adults, the estimated
food contact exposure (0.007 mg/kg/day) falls between the RDA of 150
µg/day (0.002 mg/kg/day) and the Tolerable Upper Intake Level (UL) of
1,100 µg/day (0.016 mg/kg/day).  For children ages 1-4 years and 4-8
years, the estimated exposure exceeds the established upper intake level
of 200 µg/day (0.01 mg/kg/day) and 300 µg/day (0.02 mg/kg/day) of
iodine, respectively.  

Based on evaluation of the available information, the ADTC determined
that there is no risk of concern from antimicrobial uses of iodine and
iodophor complexes for all age groups because: (1) the estimated oral
exposures represent worst-case scenarios from antimicrobial use of
iodine and iodophor complexes and it is highly unlikely that all iodine
residue from food contact use would be transferred to food.  The actual
levels of iodine persons may be exposed to at any given time from these
uses are more than likely to be lower than these highly conservative
estimates, (2) iodine is not the primary food contact surface
antimicrobial chemical but one of several used for such purposes, (3)
the use of potassium iodide to sanitize fresh fruits and vegetables is
limited to military personnel only, (4) iodine use in drinking water
disinfection is restricted to emergency situations only, (5) although
the dietary UL (the highest level of daily nutrient intake that is
likely to pose no risk of adverse health effects in almost all
individuals) for children is exceeded, exposure from the use of iodine
in emergency water disinfection is expected to be sporadic in nature and
of short duration.  Such sporadic increases in potential exposures to
iodine do not represent a risk of concern, especially in light of the
ability of the body to regain homeostasis through down-regulation of the
iodine transporter mechanism in the thyroid gland, (6) the benefits from
use of iodine and iodophor complexes in emergency water disinfection
outweigh any potential risks associated with this use.  In addition,
there are no primary drinking water standards (MCL) for iodine or its
oxidized or reduced forms as iodine is not used for disinfection of
municipal water supplies, there are no Health Advisories (HA), secondary
drinking water standards, or ambient water quality standards associated
with iodine, iodate and iodide.

Concentrations of iodine in surface water have been reported to range
from 4 to 336 µg/L. In aqueous solution, iodine is oxidized to iodate
or reduced to iodide, very little molecular iodine (I2) is present in
surface waters. Iodine in water exists as iodide and iodate at a 55:45
ratio.  Concentrations of iodine in rainwater have been reported to
range from 0.1 to15 µg/L.  In groundwater, the mean concentration is
less than 1 µg/L.  There are no primary drinking water standards (MCL)
for iodine or its oxidized or reduced forms as iodine is used only in
emergency disinfection of water and not in treatment of municipal water
supplies. In addition, there are no Health Advisories (HA), secondary
drinking water standards, or ambient water quality standards associated
with iodine, iodate and iodide  

Taking this into consideration, the ADTC concluded that the calculated
oral exposures to iodine and iodophor complexes from food contact
sanitization, fruit and vegetable sanitizer wash and emergency water
disinfection present no risk of concern.  Therefore, no oral
toxicological endpoints were selected and a qualitative risk assessment
is considered adequate for iodine and iodophor complexes.

	Issue 2

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).

		Issue 2 Conclusion

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 and a qualitative risk assessment
is considered adequate for iodine and iodophor complexes.

 

		Issue 3

With respect to iodine toxicity, is there a concern for susceptible
subpopulations (infants, children and individuals with certain disease
states at increased risk for thyroid dysfunction.

		Issue 3 Conclusion

		

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 has relied on the published scientific literature to assess
the potential developmental and reproductive toxicity of iodine. 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 following exposure.  

There are no endpoints of concern for oral, dermal, or inhalation
exposure to iodine and iodophor complexes based on the low toxicity
(subclinical effects) observed in the available human data.

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.

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.

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.

Therefore, the FQPA Safety Factor has been removed (i.e., reduced to 1X)
for iodine and iodophor complexes.

IV. HAZARD CHARACTERIZATION OF IODINE

Animal Data

	Acute Toxicity

The acute toxicity of iodine (99.5% a.i.) is low for dermal toxicity
(Toxicity Category III), but shows higher toxicity for acute oral
toxicity (Toxicity Category II), inhalation toxicity (Toxicity Category
II), and primary dermal irritation (Toxicity Category I).  Iodine is not
a dermal sensitizer.  Table 2 presents the acute toxicity of iodine (PC
Code 046905).

Table 2.  Acute Toxicity of Iodine Technical Grade Active Ingredient
(TGAI)

Guideline	

Study Type	

MRID No.	

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	Non sensitizer
using Buehler method	N/A

N/A = Not applicable

Human Data

	Subchronic Toxicity 

The human studies summarized below are available literature in which the
lowest observable iodine exposure levels were associated with adverse
effects in humans.  Since approximately 90% of the body iodine content
resides in the thyroid (ATSDR, 2004), the focus of the human studies
were on the adverse thyroid effects.  The ATSDR established an acute
(1-14 days) MRL (Minimum Risk Level) for iodine of 0.010 mg/kg/day,
based on the established NOAEL of 0.024 mg/kg/day in healthy adult
humans (reversible subclinical hypothyroidism).  Although the NOAEL is
derived from acute studies of healthy adults, supporting studies
indicate that the NOAEL would be applicable to children and elderly
adults.  Therefore, an uncertainty factor was not used to adjust the
NOAEL to account for human variability and sensitivity.  The supporting
literature was from two fourteen-day repeat-exposure studies (Gardner et
al., 1988; Paul et al., 1988).  

In a fourteen-day oral toxicity study in humans (Gardner et al., 1988),
thirty euthyroid male volunteers ranging in age from 22-40 were randomly
assigned to receive 500, 1,500, or 4,500 µg iodide/day (0.011, 0.026,
0.069 mg/kg/day, respectively).  The day before admission, a 24-hour
urine sample was collected from all of the volunteers for iodide and
creatinine measurements.  When admitted, the volunteers had fasted for
eight hours.  Baseline measurements of serum T4, T3, T3-charcoal uptake,
TSH, protein-bound iodide and total iodide were taken.  Following these
initial evaluations, all of the volunteers received a single IV bolus
dose of 500 µg TRH.  Blood samples were collected at 15-minute
intervals for one hour to determine TSH measurements.  After completion
of the initial TRH test, the volunteers received their first iodide
administration. The iodide was administered twice daily for 14 days.  On
day 15, all of the procedures performed on day 1 were repeated.  All
test subjects maintained their normal diets throughout the study.

None of the volunteers reported any adverse effects during iodide
administration.  While there were no significant changes in serum
thyroid hormone concentrations in the 500 µg/day group, administration
of 1,500 and 4,500 µg/day reduced significantly mean serum T4.  There
were no changes in serum T3 at any of the doses administered.  Mean
serum TSH concentrations increased in the groups receiving 1,500 and
4,500 µg/day, but not in the group receiving 500µg/day.  The NOAEL was
500µg/day.  The LOAEL was 1,500 µg/day, based on reversible
subclinical hypothyroidism.

In another fourteen-day oral toxicity study in humans (Paul et al.,
1988), a group of nine euthyroid men ranging in age from 26-56 and 23
euthyroid women ranging in age from 23-44 volunteered for study. 
Baseline urinary iodine and creatinine excretion were determined from a
24-hour urine collection.  On day 0, blood samples were collected for
determination of baseline serum protein bound iodine, total iodine, T4,
T3 and TSH concentrations.  TRH was administered in a single intravenous
dose of 500 µg.  Blood samples were subsequently obtained at 15, 30,
45, and 60 minutes after the injection for the measurement of TSH. The
male subjects then received 750 µg iodine orally twice daily for 14
days, while the female subjects received 125, 250, or 750 µg iodine
twice daily for 14 days.  On day 7 of administration, a 24-hour urine
collection was obtained for urinary iodine and creatinine levels. Just
before iodine administration on day 8, blood samples were taken for the
various serum iodine analyses.  Another 24-hour urine collection was
obtained on day 14 and the TRH test described above was repeated on day
15.  Small, but significant decreases in serum T4 and T3 concentrations
were observed following ingestion of 1,500 µg iodine/day.  Likewise, a
significant increase in the TSH concentration was recorded following
administration of 1,500 µg iodine/day. Serum T4, T3, and TSH
concentrations were not significantly affected by the administration of
250 or 500 µg iodine/day.  The serum TSH response to TRH following
administration of 1,500 µg iodine/day was significantly greater than
that observed on day 0.  However, the administration of 250 or 500 µg
iodine/day did not significantly affect the serum TSH response to TRH. 
The absence of significant effects on pituitary-thyroid function
following administration of 250 or 500 µg iodine/day suggest that small
increases in iodine intake should not affect short-term thyroid
function.  However, it is uncertain whether the subtle changes observed
following administration of 1,500 µg iodine/day would be sustained over
longer periods of administration and whether such changes, if sustained,
would have adverse effects on the thyroid.  The NOAEL was 500 µg
iodine/day.  The LOAEL was 1,500 µg iodine/day, based on reversible
subclinical hypothyroidism.

In a twenty-eight day human oral toxicity study (Namba et al., 1993),
ten euthyroid male volunteers aged 35-39 were chosen for study.  The
diet of the volunteers was restricted for one week prior to the start of
the study.  All subjects were subsequently given nine tablets of
licorice lecithin-bound iodine (27 mg iodine; 0.39 mg iodine/kg/day)
daily for four weeks.  After administration was complete, the
individuals were closely followed for four additional weeks.  Blood and
urine samples were collected from each subject before treatment, on days
1, 2, 3, 5, 7, 14, 21, and 28 of treatment, and two and four weeks after
treatment.  The rise in serum TSH following iodide administration
elicited reversible thyroid hypertrophy in normal individuals.
Therefore, a change in serum TSH levels within the normal range may be
sufficient to control thyroid volume and function.  The NOAEL was less
than 0.39 mg iodine/kg/day.  The LOAEL was 0.39 mg iodine/kg/day, based
on subclinical hypothyroidism with gland enlargement.

In a ninety-day human toxicity study (LeMar et al., 1995), eight (seven
males, one female) healthy volunteers aged 35-47 were selected for
participation in the study.  All subjects were euthyroid and none had
any history of thyroid disease, chronic disorders, or had used any
iodine-containing medications.  The participants were orally
administered water purification tablets of tetraglycine hydroperiodide
(liberating 8 mg iodine/tablet; 0.46 mg iodine/kg/day) four times daily
for ninety days.  Serum and urinary iodine increased dramatically at one
week and remained elevated when measured at days 28 and 90. 
Pretreatment radioactive iodine uptake values ranged from 8-26%.  After
one week, the uptake values dropped to 0-2.3% and remained decreased
through 90 days.  There were no statistically significant changes in
serum T4 or T3 levels, although both fell slightly.  Conversely, serum
TSH levels increased significantly by day 7 and remained elevated
through the end of treatment on day 90. Thyroid volume also increased
significantly by day 35, with a mean increase in thyroid volume of 37%
relative to baseline. The thyroid enlargement that occurred in response
to iodine exposure was TSH-dependent and reversible.  The NOAEL was less
than 0.46 mg iodine/kg/day.  The LOAEL was 0.46 mg iodine/kg/day, based
on subclinical hypothyroidism with gland enlargement.

	

Chronic Toxicity and Carcinogenicity

The ATSDR established a chronic MRL (Minimum Risk Level) for iodine of
0.01 mg/kg/day, based on the established NOAEL of 0.010 mg/kg/day
(subclinical hypothyroidism with gland enlargement).  The supporting
literature was from an eleven-year study (Boyages et al., 1989; Li et
al., 1987) of two populations in an iodine excess or sufficient area of
China.  Thyroid status was compared in groups of children, ages 7–15
years, who resided in two areas of China where drinking water iodide
concentrations were  either 462 µg/L (n=120) or 54 µg/L (n=51).
Urinary iodine was 1,236 µg I/g creatinine in the high iodine group and
428 µg I/g creatinine in the low iodine group. Assuming a body weight
of 40 kg and lean body mass of 85% of body weight, the above urinary
iodine/creatinine ratios are approximately equivalent to iodine
excretion rates, or steady state ingestion rates of 1,150 (29
µg/kg/day) and 400 µg/day (10 µg/kg/day) in the high and low iodide
groups, respectively.  Although the subjects were all euthyroid with
normal values for serum thyroid hormones and TSH concentrations, TSH
concentrations were significantly higher (33%) in the high iodine group.
The high iodide group had a 65% prevalence of goiter and a 15%
prevalence of Grade 2 goiter compared to 15% for goiter and 0% for Grade
2 goiter in the low iodine group.

A review of the available data has shown iodine to be negative for
carcinogenicity in studies conducted up to the testing limit doses
established by the Agency; therefore, no carcinogenic analysis is
required.

	Mutagenicity		

The Agency has granted waiver requests for a mutagenicity battery
conducted with iodine for oral exposures to this chemical (Memorandum:
from S. Diwan to J. Smith and M. Rice, 12/96) 

	Dermal Absorption

The data for dermal absorption of iodine show a low percentage of
absorption (1%; ATSDR, 2004).  Considering the published data on the
toxicity of iodine, and the estimated worst-case exposures from dermal
uses of iodine in antimicrobial pesticide formulations, it was concluded
that a quantitative assessment of dermal exposures was also not needed
for iodine and iodine complexes.  Therefore, potential dermal exposures
from antimicrobial uses of formulations containing iodine and iodine
complexes present no risk of concern.  

	Metabolism and Excretion

Iodine is an essential dietary component and is required for synthesis
of thyroid hormones thyroxine (T4) and triiodothronine (T3) by the
thyroid gland.  These hormones are essential for life and regulate many
key biochemical reactions, especially protein synthesis and enzymatic
activity in the developing brain, muscle, heart, pituitary, and kidney. 
The synthesis and secretion of T3 and T4 is under the control of the
thyroid-stimulating hormone (TSH) form the anterior lobe of the
pituitary gland.  TSH excretion increases when circulating thyroid
hormone decreases and vice versa as a negative feedback mechanism.  TSH
stimulates iodide transport from the blood into thyroid cells, oxidation
of iodide to iodine, and iodine binding to tyrosine, the essential amino
acid of T3 and T4.  Iodine comprises 65% of T4 and 59% of T3 by weight. 
To ensure an adequate supply of thyroid hormones, the thyroid must trap
about 0.060 mg of iodine per day.  Hypothyroidism, hyperthyroidism,
iodermia, and thyroiditis are four disorders affected by iodine intake.

The iodide salts, sodium and potassium iodide, are soluble in water and
oral doses are generally considered to have 100% gastrointestinal
absorption.  Under normal dietary iodine intake levels, the human body
contains approximately 10-15 mg of iodine, of which approximately 70-90%
is in the thyroid gland.  During inhalation exposure to iodine, humans
cleared iodine vapor from the respiratory tract with a half-time of
approximately 10 minutes, with much of the iodine being transferred to
the gastrointestinal tract (ATSDR, 2004).  

	Developmental and Reproductive Toxicity tc \l2 "Dermal AbsorptionNo
studies have been reported dealing with the skin absorption of iodine
and iodophor complexes.  Although it is possible that, under conditions
of very severe prolonged exposures to this chemical,  absorption through
the skin, it is doubtful any appreciable systemic/dermal injury would
occur because iodine and iodophor complexes has (1) a low order of
dermal irritancy, (2) is not a skin sensitizer, and (3) showed  no
evidence of dermal or systemic toxicity following repeated dermal
applications of 2ml (approximately 600 mg/kg) iodine and iodophor
complexes applied to the skin of rabbits in a 21-day dermal toxicity
study.  Metabolism and ExcretionThe fate of 14C-labeled iodine and
iodophor complexes in rats and of unlabeled material in rabbits was
recently studied.  Following oral dosing, the rat and rabbit excreted
most of the iodine and iodophor complexes in both unchanged and/or
oxidized forms (mono- and dicarboxylic acid derivatives of iodine and
iodophor complexes).  In rabbits dosed with 200 or 2000 mg/kg iodine and
iodophor complexes respectively excreted 34.3% or 28%, of the
administered dose in the urine as unchanged iodine and iodophor
complexes and 35.2% as a hydroxyacid form of this chemical.  In the
studies with rats, little if any C14-oxalate or C14-iodine and iodophor
complexes in conjugated form was found in the urine.  Trace amounts of
orally administered 14C iodine and iodophor complexes were excreted in
expired air as carbon dioxide (<1%) and in detectable amounts in feces
(2 to 5 %).  The total elimination of radioactivity (urine, feces and
CO2) during the five day period following an oral dose of labeled
compound (22.5 mg) ranged from 91 to 98%.  The majority of the
radioactivity appeared in the urine. 26Developmental and Reproductive
Toxicity 

The Agency is has relied on the published scientific literature to
assess the potential developmental and reproductive toxicity of iodine. 
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 iodide.  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. 

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. A second 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.  A third study of
73 infants and children born to 70 patients who received 131I for
ablative treatment of thyroid cancer 2–10 years (mean, 5.3 years)
prior to pregnancy found no thyroid gland disorders (Casara et al.
1993). The maternal 131I exposures ranged from 1.85 to 16.55 GBq
(50–450 mCi); the mean exposure was 4.40 GBq (120 mCi).

A limited number of scientific studies evaluating the potential
developmental toxicity of iodine in rats are available (Arrington et
al., 1965; Lee and Satow). 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 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 Antimicrobials Division’s Toxicity Endpoint Selection Committee
(ADTC) concluded that there is no concern for increased susceptibility
of infants and children to the exposures from antimicrobial uses of
iodine and iodine complexes. Therefore, the FQPA Safety Factor has been
removed (i.e., reduced to 1X) for iodine and iodophor complexes. This
determination is based upon the following observations: (1) the
available hazard data show no evidence of increased susceptibility to
developing offspring, (2) 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
Academy of Sciences recommended dietary allowance of 0.0021 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, and (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.

	Neurotoxicity

In sensitive subpopulations (including fetuses, newborn infants, and
individuals who have thyroiditis or a history of Graves’ disease, 
hypothyroidism occurring in the fetus or newborn infant has the greatest
potential for producing neurological effects.  An iodine-induced
hypothyroid state can result in delayed or deficient brain and
neuromuscular development of the newborn (Boyages 2000b), as thyroid
hormones are essential to the development of the neuromuscular system
and brain. Iodine induced hypothyroidism in an older child or adult
would be expected to have little or no deleterious effects on the
neuromuscular system. Hypothyroidism may be associated with impairment
in neurological development of the fetus or growth retardation (Boyages
2000a, 2000b; Snyder 2000a).  Martin and Rento (1962) reported two cases
of goiter and severe transient hypothyroidism, without neurological
sequellae in infants born to mothers who ingested potassium iodide
during pregnancy; the approximate dosages were 920 and 1,530 mg I/day
(13 and 22 mg/kg/day). Growth acceleration may occur in childhood
hyperthyroidism, which is thought to be related to accelerated pituitary
growth hormone turnover or a direct effect of thyroid hormone on bone
maturation and growth (Snyder 2000b).

Oral exposure to excess stable iodine can also produce hyperthyroidism
in sensitive individuals   These include people who are initially iodine
deficient, those who have thyroid disease, including nodular goiter,
Graves’ disease, those who have been previously treated with
antithyroid drugs, , and those who have developed thyrotoxicosis from
amiodarone or interferon alpha treatments (Roti and Uberti 2001).
Patients who develop thyrotoxicosis may experience neuromuscular
disorders, including myopathy, periodic paralysis, myasthenia gravis,
peripheral neuropathy, tremor, and chorea (Boyages 2000a); however,
these are not likely to occur in iodine-induced hyperthyroidism, except
in sensitive groups, already at risk for neurological problems.

In contrast to oral exposure, dermal exposure to excess iodine may
produce mild transient hypothyroidism and hyperthyroidism  which could
give rise to neurological manifestations of thyroid gland dysfunction
including impairments in neurological development and myopathies
(Boyages 2000a, 2000b). However, based on the mild effects that have
been observed in association with dermal exposures, such severe
neurological sequellae are not likely. 

 HAZARD PROFILE FOR IODOPHOR COMPLEXES 

The mammalian toxicity database for the iodophor complexes consists of
published literature studies submitted to the Agency by the Iodophor
Joint Venture.  Iodophor carriers are broken down into three groups: 1)
surfactant-iodine complexes with three subgroups: iodine complexed with
propoxyethoxy copolymer carriers [subgroup A]; iodine complexed with
phenoxypolyethoxyethanol carriers [subgroup B]; iodine complexed with
polyvinylpyrrolidone carriers [subgroup C]; 2) amino acid-iodine
complexes (tetraglycine hydroperiodide); 3) iodinated resin complex
(quaternary amine divinylbenzene/styrene copolymer).  The following is a
hazard characterization for the iodophor complexes.

	Surfactant-Iodine Complexes

The primary route of exposure for the surfactant-iodine complex carriers
is via skin contact during the use of the surface disinfectants.  The
propoxyethoxy copolymers are poorly absorbed through intact skin and
show no toxicity following single or repeated dermal applications (no
toxicity has been observed at the highest doses applied ranging from 2
g/kg to > 20 g/kg in acute studies and up to 10 g/kg/day in subchronic
studies).  Similarly, they are of very limited toxicity following oral
dosing.  These chemicals belong to a large family of polyalkylene
glycols (PAGs) and are structurally very similar to chemicals such as
polyethylene glycols (PEGs) that are used extensively in applications
with direct human exposure, including as food additives and in cosmetic
ingredients.  PAGs show no reproductive toxicity at doses below 1
g/kg/day.  In addition, PAGs are not carcinogenic via oral or dermal
routes and show no mutagenic activity.  

The phenoxypolyethoxyethanol (alkylphenol polyethoxylates; APEs) are
poorly absorbed through skin and show no toxicity via skin contact,
although the may result in skin irritation.  These surfactants are of
limited oral toxicity and have no reported toxicity even though there is
extensive human exposure through their use in cleaning and wetting
agents as well as for spermicides.  Nonylphenol (NP), but not
octylphenol (OP), is toxic to the kidney with a NOAEL in rats of
approximately 12 mg/kg/day.  Although NP, but not OP, showed some weak
estrogen-like responses in multigeneration studies (premature vaginal
opening, prolonged estrus cycles) the AP do not result in reproductive
toxicity.  Exposure to APE has resulted in ‘extra rib’ in
developmental toxicity studies with rats at maternally toxic doses but
they are not considered developmental toxicants or teratogens.  

Polyvinylpyrrolidone (povidone) is used in surface disinfection but is
also used extensively in antiseptic preparations of iodine as well as in
drug and other applications leading to direct human contact/intake. 
Animal studies with povidone indicate that the polymer is poorly
absorbed from the g.i. tract (< 0.5%), and is virtually non-toxic with
oral LD50 values of > 40 g/kg.  No toxicity or tumor formation was
observed in studies up to 2 years in duration at very high intake (up to
10% of the diet).  There is extensive human exposure to povidone through
its use in povidone-iodine (e.g. Betadine) antiseptics and in
subcutaneous and parenteral drug administration.  No consistent or toxic
effects in humans have been reported.  

	Amino Acid-Iodine Complexes

Tetraglycine hydroperiodide is a complex of glycine with hydriodic acid
and iodine (ratio 16:4:5).  The complexed portion of tetraglycine
hydroperiodide (glycine) is a required amino acid and is not of
toxicological concern.

	Iodinated Resin Complexes

The iodinated resins are used to impregnate fabric, which provides for
the release of iodine upon contact with microorganisms.  Based on its
use pattern, human exposure to this high molecular weight polymer is
very limited.

Overall, the iodophor carriers are a group of large molecules that have
minimal to no toxicity in mammalian systems.  The use of iodophor
complexes in many products with direct contact to humans indicates that
they are safe under the conditions as described on the registered
product labels.  No additional data requirements were identified for the
sanitizer use of iodophor complexes.

	VI. REFERENCES

Review Documents

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National Academy of Science (NAS), 2001: Dietary Reference Intakes for
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Websites

http://toxnet.nlm.nih.gov

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