DATE: 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

8 JANUARY 2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

SUBJECT: D-mannose; Human Health Risk Assessment and Ecological Effects Assessment to 

Support a Proposed Exemption from the Requirement of a Tolerance When Used as 

an Inert Ingredient in Pesticide Formulations. 

FROM: 

TO: 

PC CODE: 700023; CASRN: 3458-28-4; 

. Petition No.: 1E7903; gulatory Action: 40 CFR 180.920 

Mark I. Dow, Ph.D. vJfl &flJ 

Senior Biologist f /}Jt 

Inert Ingredient Assessment Branch (IIAB) 

Registration Division (7505P)A A _ 

11

Jr.-. 

P.V. Shah, Ph.D. ~-'6\J'-Y Chief, Inert Ingredient Assessment Branch (IIAB) 

Registration Division (7505P) 

EXECUTIVE SUMMARY 

This is the Decision Document for D-mannose; Pesticide Petition 01E7903; CASRN 3458-28-4; 

PC Code: 700023. The ISK BIOSCIENCES Corporation, (7470 Auburn Road, Suite A, 

Concord, OH 44077) a wholly owned subsidiary of Ishihara Sangyo Kaisha, Ltd., has submitted 

a petition requesting an exemption from the requirements of a tolerance for the compound Dmannose (CASRN 3458-28-4; PC Code: 700023). Specifically, the request is to use D-mannose 

as an inert ingredient which acts as a sequestrant/binder/filler in pesticide formulations applied 

pre-harvest to all raw agricultural commodities under 40 CFR § 180.920. 

D-Mannose is a simple, six carbon sugar (molecular formula C6-Hl2-06) which occurs 

naturally in mammalian metabolic systems. 
2

The metabolism of D-Mannose is well documented. D-Mannose is involved in an extensive 

series of metabolic transformations being ultimately incorporated into glycoproteins and 

glycolipids or is formed into the sugar fucose which is then incorporated in glycoproteins. The 

glycoproteins and glycolipids are essential to the maintenance of cellular integrity and to cell 

generation. 

Mannose occurs as the free sugar in peaches, apples and oranges. D-Mannose has been 

extensively evaluated for clinical use in the treatment of RUTIs (recurrent urinary tract 

infections). It is approved as a dietary supplement and as such marketed widely. 

In addition to oral exposure from ingestion via natural occurrence in some fruits and vegetables, 

individuals may experience oral exposure and dermal exposure to residues on treated crop sites. 

Since no toxicological endpoint of concern (oral, dermal or inhalation) has been identified and 

since D-Mannose is known to be essential to mammalian metabolic systems, it is not necessary 

to quantify exposures. No adverse effects have been identified which are attributable to 

exposures to D-Mannose. No adverse effects have been identified in the public literature.

The toxicity database is considered complete. There is no evidence of toxicity found in health 

and toxicological internet databases. On the contrary, there is ample evidence that D-mannose is 

integral to mammalian metabolic systems in the formation of glycoproteins. There is no 

evidence of neurotoxicity as a result of exposure to D-mannose. There is no evidence of 

increased susceptibility to infants or children. There are no residual uncertainties identified in 

the exposure databases. Since no toxicological endpoints can be identified, a quantitative risk 

assessment is not necessary. 

D-mannose occurs naturally in a number of agricultural food items. It occurs in all mammalian 

systems evaluated. The Agency does not expect adverse ecological or environmental effects as a 

result of the proposed agricultural use of D-mannose in pesticide products. 

In view of the plethora of documentation regarding the metabolic pathways of D-mannose; the 

biological significance of its contribution to glycoprotein and glycolipid syntheses in mammalian 

systems; its natural occurrence in such fruits as peaches, apples and oranges; its ‘clinical’ use to 

treat urinary tract infections and possible periodontal conditions, its widespread marketing and 

use as a dietary supplement and upon the lack of adverse risk or toxicological information, the 

Agency approves of the use of D-mannose (CASRN 3458-28-4; PC Code: 700023) as an inert 

ingredient which serves as a sequestrant/binder/filler in pesticide formulations applied preharvest to all raw agricultural commodities. The approval is for exemption from the 

requirements of a tolerance under 40 CFR § 180.920 (preharvest application to raw agricultural 

commodities). 

I. BACKGROUND

This is the Decision Document for D-mannose; Pesticide Petition 01E7903; CASRN 3458-28-4; 

PC Code: 700023. The ISK BIOSCIENCES Corporation, (7470 Auburn Road, Suite A, 

Concord, OH 44077) a wholly owned subsidiary of Ishihara Sangyo Kaisha, Ltd., has submitted 

a petition requesting an exemption from the requirements of a tolerance for the compound D-
3

mannose (CASRN 3458-28-4; PC Code: 700023). Specifically, the request is to use D-mannose

as an inert ingredient which acts as a sequestrant/binder/filler in pesticide formulations applied 

pre-harvest to all raw agricultural commodities under 40 CFR § 180.920. 

II. Inert Ingredient Profile

A. Summary of Uses

The request is to use D-mannose as a sequestrant, binder or filler in pesticide formulations 

applied pre-harvest to all raw agricultural commodities. In mammalian systems, the primary 

source of D-mannose is the sugar glucose. D-mannose undergoes extensive metabolic 

transformation by being incorporated into glycoproteins and glycolipids. Or, it is formed into the 

sugar fructose that is then incorporated into glycoproteins. D-mannose occurs as the free sugar 

in peaches, apples and oranges. It is absorbed from the gastrointestinal tract of rats at only 12 % 

the rate of glucose. 

B. Physical Chemical Properties

The chemical structure and physical/chemical properties of D-mannose follow: (adopted from 

MSDS – Sciencelab.com, Inc. 11/01/2010).

Physical state/appearance: Solid (solid crystalline powder)

Odor: Odorless

Taste: Sweet

Molecular Weight: 180.16 g/mole

Color: Colorless to light yellow

pH (1% soln/water) not available

Boiling pt. not available

Melting pt. Decomposes. (132o C or 169.6o F).

Critical temperature: not available

Specific gravity: 1.539 (Water = 1)

Vapor pressure: not applicable

Vapor density: not available

Solubility: soluble in cold water

(MSDS – Sciencelab.com, Inc. 11/01/2010

O

OH

HO

OH

HO

OH
4

III. Hazard ASSESSMENT

A. Summary of Toxicity Data.

D-mannose is a naturally occurring compound and is a normal constituent of the human diet. Dmannose is a ubiquitous component of mammalian sera. Searches of the internet reveal not data 

or information indicating adverse effects from exposure to this chemical.

B. Toxicity Profile

Acute Toxicity

No information or evidence has been found to suggest that there is any acute toxicity, 

subchronic toxicity, chronic toxicity, neurotoxicity, mutagenicity, developmental or reproductive 

toxicity or carcinogenicity from exposure to D-mannose. 

Gheyas et al. (1996) studied the dietary fiber composition of ‘Starkspur Supreme Delicious’ 

apple fruit. They discovered differences in the relative amount of monosaccharide residues in 

apple fiber depending upon root stock. The monosacharides they found were rhamnose, 

fructose, arabinose, xylose, D-mannose, galactose and glucose. This paper helps document the

“natural” existence of D-mannose from dietary sources. 

Metabolism and Pharmacokinetics

D-Mannose is a simple, six carbon sugar (molecular formula C6-H12-O6) which occurs 

naturally in mammalian metabolic systems. Alton et al. (1997) found D-Mannose to be essential 

to the metabolism of 33 species of animals including primates, marsupials, rodents, lagomorphs, 

canine carnivores (bears, foxes, dogs), feline carnivores, artiodactyls (including cows and 

Bactrian camels), perissodactyls (rhino) and proboscids (elephants).

In addition to the study by Alton et al., Herman (1971) provides a monographic review of the 

metabolism of D-Mannose. The metabolism of D-Mannose is extremely well documented. DMannose is involved in an extensive series of metabolic transformations being ultimately 

incorporated into glycoproteins and glycolipids or is formed into the sugar fucose which is then 

incorporated in glycoproteins. The glycoproteins and glycolipids are essential to the 

maintenance of cellular integrity and to cell generation. 

Bartlett (1959 and 1968) has shown that human red blood cells contain an unusually high 

concentration of mannose phosphorylation products. Human erythrocytes phosphorylate 

mannose using an enzyme indistinguishable from hexokinase. D-mannose is found in the tissues 

of a number of organs. Research suggests that mammalian systems use mannose transporters to 

deliver mannose to the liver and other organs for glycoprotein biosynthesis (Alton et al. 1997). 
5

Mannose is shown to occur in the heart, spleen, lung, kidney, brain, muscle, liver and liver 

plasma and intestine. Human amniotic fluid has been shown to contain mannose in 

concentrations comparable to the concentration that occurs in the blood.

Mannose occurs as the free sugar in peaches, apples and oranges. As such it is absorbed from 

the gastrointestinal (GI) tract of rats at about 12 % of the absorption rate of glucose. It is thought 

that mannose may be liberated from dietary glycoproteins and glycolipids by the action of 

mannosidase in the GI tract. Gheyas et al. (1996) studied the dietary fiber composition of 

‘Starkspur Supreme Delicious’ apple fruit. They discovered differences in the relative amount of 

monosaccharide residues in apple fiber depending upon root stock. The monosacharides they 

found were rhamnose, fructose, arabinose, xylose, D-mannose, galactose and glucose. This 

paper helps document the “natural” existence of D-mannose from dietary sources. 

D-Mannose has been extensively evaluated for clinical use in the treatment of RUTIs (recurrent 

urinary tract infections). It is approved as a dietary supplement and as such marketed widely. 

Some metabolic mannose is derived from glucose. Glucose intolerance may occur in 

hypersensitive individuals. Very high doses of glucose may cause diarrhea. No implication of 

toxicity to D-mannose has been found.

“D-mannose and fucose are found in a great variety of glycoproteins. The D-mannose and 

fucose content of glycoproteins is reviewed by Eylar (1965).” 

Alton et al. (1987) present a comprehensive discussion of the direct utilization of D-mannose for 

glycoprotein biosynthesis. It was believed that cellular D-mannose was derived entirely from 

glucose. The results of the Alton et al. study indicate that mammals use D-mannose transporters 

to deliver D-mannose from the blood to the liver and other organs for glycoprotein synthesis. 

Alton et al. say “additionally and contrary to expectations, most of the D-mannose for 

glycoprotein biosynthesis in cultured hepatoma cells is derived from D-mannose, not glucose. 

Extracellular D-mannose may also make a significant contribution to glycoprotein biosynthesis 

in the intact organism.” D-mannose is integral to mammalian homeostasis. 

According to the Small Molecule Pathway Database (SMPDB), mannose is not well metabolized 

in humans and it does not significantly enter most carbohydrate metabolism pathways when 

taken orally. Indeed it appears that 90% of mannose ingested is excreted unconverted into the 

urine within 30-60 minutes, with 99% of the remainder being excreted within the following 8 

hours. On the other hand, mannose is present in numerous glycoconjugates including N-linked 

glycosylated proteins. What little mannose that is metabolized appears to be phosphorylated and 

either converted to GDP mannose and sent on to N-glycan biosynthesis or it is isomerized by 

mannose-6-phosphate isomerase into beta-fructose-6-phosphate,which then can be directed into 

the fructose catabolic pathway and ultimately enter the glycolysis pathway to produce energy in 

the form of ATP for the organism.
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C . Toxicity Endpoint Selection

There are no data or other information which indicate any signs of toxicity in normally 

functioning mammalian systems as a result of the presence of D-mannose. In addition, many 

studies described the pharmacological benefits from treatment with D-mannose. A toxicological 

endpoint of concern has not been identified. A quantitative risk assessment is not necessary and 

was not performed.

IV. FQPA Safety Factor considerations

1. In general. Section 408(b)(2)(c) of FFDCA provides that EPA shall apply an additional 

tenfold (10X) margin of safety for infants and children in the case of threshold effects to account 

for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure 

unless EPA determines based on reliable data that a different margin of safety will be safe for 

infants and children. This additional margin of safety is commonly referred to as the FQPA 

safety factor (SF). In applying this provision, EPA either retains the default value of 10X, or uses 

a different additional safety factor when reliable data available to EPA support the choice of a 

different factor.

Given the lack of concern for hazard posed by D-mannose, EPA concludes that there are no 

dietary or aggregate dietary/non-dietary risks of concern as a result of exposure to D-mannose in 

food and water or from residential exposure. Taking into consideration of all available 

information on acetone, EPA concludes that there is a reasonable certainty that no harm will 

result to the general population, or to infants and children from aggregate exposure to acetone 

residues. Based on the weight of evidence presented above, EPA concluded that the FQPA factor 

should be removed.

V. Exposure

Since no toxicological endpoints of concern have been identified, it is not necessary to conduct 

dietary, dermal or inhalation exposure assessments. 

Cancer exposure. 

There is no evidence that D-mannose is carcinogenic. Therefore, a cancer dietary exposure 

assessment is not necessary to assess cancer risk.

Analytical Methodology

Since this request is for an exemption from the requirement of a tolerance, an analytical method 

for enforcement purposes is not required to support this action.

 

Residential (Non-Occupational) Exposure

From non-dietary exposure. The term “residential exposure” is used in this document to refer to 

non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest 

control, termiticides, and flea and tick control on pets). “Residential” use patterns were not 
7

identified in the Registrant’s proposed use of D-mannose. Therefore, “residential” exposure is 

not expected. Further, there are no toxicological endpoints of concern identified with which to 

conduct an exposure and risk assessment. The proposed use does not exceed the Agency’s levels 

of concern. 

VI. Aggregate Risk 

There is no evidence to suggest concern for acute exposures, short-term exposures or 

intermediate-term exposures. No toxicological endpoint(s) have been identified therefore risk 

assessments are not necessary and have not been conducted. . 

VII. Cumulative Exposure

Cumulative effects from substances with a common mechanism of toxicity. Section 

408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or 

revoke a tolerance, the Agency consider “available information” concerning the cumulative 

effects of a particular pesticide's residues and “other substances that have a common mechanism 

of toxicity.”

EPA has not found D-mannose to share a common mechanism of toxicity with any other 

substances, and D-mannose does not appear to produce a toxic metabolite produced by other 

substances. For the purposes of this tolerance action, therefore, EPA has assumed that the Dmannose does not have a common mechanism of toxicity with other substances. For information 

regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity 

and to evaluate the cumulative effects of such chemicals, see EPA's website at 

http://www.epa.gov/pesticides/cumulative.

VIII. Environmental Fate 

In support of the petition, the Registrant characterized the potential environmental fate and 

effects by the use of the predictive model EPISuite®. Based on the EPI Suite calculations of 

physical properties for D-mannose, it is not expected to be of great concern in the environment. 

The log Kow of -2.43 and water solubility of 7.13x105 mg/L suggest that D-mannose is high 

soluble in water. Also based on the vapor pressure of 1.62x10-8 mmHg, D-mannose is not 

expected to be volatile or undergo volatilization. A log Koc of 10.7526 suggests it is a highly 

mobile compound and will not bind readily to soils or sediments.

IX. ECOLOGICAL EFFECTS

Based on the EPI Suite calculations for log BCF of D-mannose, there is little concern for 

the bioconcentration of D-mannose in tissues of organisms. As stated previously in this 

document, D-mannose once ingested is expected to be excreted or metabolized by an organism. 

Most if not all organisms can metabolize D-mannose as part of their routine metabolic pathway 

and therefore there is negligible concern for the ecological effects of D-mannose. According to 

the Food and Agricultural Organization’s (FAO) Aquaculture Development and Coordination 

Programme, mannose is also found in some plant polysaccharides. While mannose is considered 
8

one of the monosaccharides resulting from carbohydrate digestion in land mammals, there are no 

similar studies available for fish http://www.fao.org/docrep/x5738e/x5738e06.htm).

X. DETERMINATION OF SAFETY 

Based on the weight of the evidence, EPA concludes that there is a reasonable certainty 

that no harm will result to the general population, or to infants and children from aggregate 

exposure to residues of the D-mannose when used as an inert ingredient in pesticide formulations 

applied Preharvest to raw agricultural commodities under 40 CFR 180.920.

XI. ENVIRONMENTAL JUSTICE

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

XII. HUMAN STUDIES

This assessment does not rely on any studies in which human subjects were intentionally 

exposed to a pesticide. 

XIII. INTERNATIONAL LIMITS 

There are no international limits established for D-mannose.

IVX. CONCLUSIONS.

D-Mannose is a simple, six carbon sugar that is essential to mammalian metabolic systems. The 

metabolism of D-Mannose is thoroughly understood. D-Mannose occurs naturally in certain 
9

fruit. It is used therapeutically in the treatment of some human pathological conditions. No 

toxicological endpoints of concern have been identified for oral, dermal or inhalation exposures 

to D-Mannose. There are no concerns for acute, short-term, intermediate-term or chronic 

exposures to D-Mannose. Therefore the Agency approves of the use of D-Mannose under 40 

CFR 180.920 as an inert ingredient which serves as a sequestrant, binder or filler applied preharvest to agricultural crops. Approval is without limitation.
10

REFERENCES

Alton, G., Hasilik, M., Niehues, R., Panneerselvam, K., Etchison, J.R., Fana, F. and Freez, H. 

1998. Direct Utilization of D-mannose for Mammalian Glycoprotein 

Biosysthesis. Glycobiology. Vol. 8:3, 285-295.

Alton, G., S. Kjaergaard, J. Etchison, F. Skovby and H. Freeze. 1997. Oral Ingestion of 

Mannose Elevates Blood Mannose Levels: A First Step Toward a Potential 

Therapy for Carbohydrate-Deficient Glycoprotein Syndrome Type I. Biochem. 

Mol. Med. 60:127-133.

Bartlett, G.R. 1959. Human Red Cell Glycointermediates. J. Biol. Chem. 234: 449.

Bartlett, G.R. 1968. Glucose and Mannose Diphosphate In The Red Blood Cell. Biochem. 

Biophys. Acta. 156:231.

Eylar, H. 1965. On the Biological Role of Glycoproteins. J. Theoret. Biol. 10: 89.

Gheyas, F., Young, E., Blankenship, S., McFeeters, R. 1996. Dietary Fiber Composition of 

‘Starkspur Supreme Delicious’ Apple Fruit as Influenced by Rootstock and 

Growing Region. Fruit Varieties J. 50:1, 35-41.

Herman, R. 1971. D-mannose Metabolism. I. Amer. J. Clinical Nutrition. 24: 488-498.

TOXNET. Hazardous Substances Data Bank (HSDB). On-line Scientific Search Engine, 

National Library of Medicine, National Institute of Health. 

http://www.toxnet.nlm.nih.gov.

http://pathman.smpdb.ca/pathways/SMP00064/pathway?level=2

http://www.fao.org/docrep/x5738e/x5738e06.htm

cc:M.Dow(IIAB)

RDI:P.V. Shah, D. Lieu L. Austin

M.I.Dow:S7958:PY1:(703)305-5533:IIAB:7505P