820K88005
August, 1987
GLYPHOSATE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately tl an another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 1071-83-6
Structural Formula
O 0
11
HO-C-CH9-N-CH?-P-OH
I I
H OH
Glycine, N-(Phosphonomethyl)
Synonyms
Rodeo*; Roundup*.
Uses
0 Herbicide for control of grasses, broad leaved weeds and woody brush
(U.S. EPA, 1986b).
Properties (Meister, 1983)
Chemical Formula C3HgN05P
Molecular Weight 169.07
Physical State (25°C) White crystalline solid
Boiling Point
Melting Point 200°C
Density 1.74
Vapor Pressure —
Water Solubility 10 g/L
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor —
Occurrence
0 Glyphosate has been found in none of the :-:urface water samples and
in only 1 of the ground water samples (in the state of California)
analyzed from 64 samples taken at 61 locations (STORET, 1987).
Environmental Fate
0 14c-Glyphosate (94% glyphosate, 5.9% aminomethylphosphonic acid) and
aminomethylphosphonic acid were stable in sterile buffered water at
pH 3, 6, and 9 during 35 days of incubation in the dark at 5 and 35°C
(Brightwell and Malik, 1978).
0 14c-Glyphosate (94% glyphosate, 5.9% aninomethylphosphonic acid) was
adsorbed to Drummer silty clay loam, Ray silt, Spinks sandy loam,
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Lintonia sandy loam, and Cattail Swamp sediment with Freundlich-K
values of 62, 90, 70, 22, and 175, respectively (Brightwell and
Malik, 1978). For each soil preparation, the maximum percentages
of applied glyphosate desorbed were 5.3, 3.7, 3.6, 11.5, and 0.9%,
respectively. At concentrations ranging from 0.21 to 50.1 ppm,
14c-Glyphosate was highly adsorbed to five soils, with organic matter
contents ranging from 2.40 to 15.50% (Monsanto Company, 1975).
Adsorption of glyphosate ranged from 71 (Soil E, 2.4% organic matter,
pH 7.29) to 99% (Soil C, 15.5% organic matter, pH 5.35).
0 14c-Glyphosate (94% glyphosate, 5.9% aminomethylphosphonic acid)
was slightly mobile to relatively immobile, with less than 7% of the
applied 14C detected in the leachate from 30-cm silt, sand, clay,
sandy clay loam, silty clay loam, and sandy loam soil columns eluted
with 20 inches of water (Brightwell and Malik, 1978). Aged (30 days)
14c-glyphosate residues were relatively immobile in silt, clay and
sandy clay loam soils with less than 2% of the radioactivity detected
in the leachate following elution with 20 inches of water. Both
glyphosate and aminomethylphosphonic acid were detected in the leachate
of aged and un-aged soil columns.
III. PHARMACOKINETICS
Absorption
0 Feeding studies with chickens, cows and swine showed that ingestion
of up to 75 ppm glyphosate resulted in nondetectable glyphosate
residue levels (<0.05 ppm) in muscle tissue and fat (Monsanto Company,
1983). The duration of exposure was not reported in this report.
Glyphosate residue levels were not detectable (<0.025 ppm) in milk
and eggs from cows and chickens on diets containing glyphosate.
Distribution
0 No information on the distribution of glyphosate was found in the
available literature.
Metabolism
0 No information on the metabolism of glyphosate was found in the
available literature.
Excretion
After a single oral or intraperitoneal dose, less than 1% of the
administered dose was retained after 120 hours of treatment (U.S. EPA,
1986b). In rats fed 1, 10 or 100 ppm of 14C-glyphosate for 14 days,
a steady-state equilibrium between intake and excretion of label was
reached within about 8 days. The amount of radioactivity excreted
in the urine decreased rapidly after withdrawal of treatment. Ten
days after withdrawal, radioactivity was detectable in the urine and
feces of rats fed 10 or 100 ppm of the test diet. Minimal residues
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of 0.1 ppm or less remained in the tissues of high-dose rats after
10 days of withdrawal. No single tissue showed a significant
difference in the amount of label retained.
IV. HEALTH EFFECTS
Humans
No information on the health effects of glyphosate in humans was
found in the available literature.
Animals
Short-term Exposure
0 An oral LD5Q of 5,600 mg/kg in the rat is reported for glyphosate
(Monsanto Company, 1982a).
0 Bababunmi et al. (1978) reported that daily intraperitoneal admini-
stration of 15, 30, 45 or 60 mg/kg to rats for 28 days resulted in
reduced daily body weight gain, decreased blood hemoglobin, decreased
red blood cell count and hematocrit values and elevated levels of
serum glutamic-pyruvic transaminase and leucine-amino peptidase during
the experimental period. The investigators did not specify the dose
levels at which these effects were observed.
Dermal/Ocular Effects
0 A dermal I^g for glyphosate in the rabbit was reported to be
>5,000 mg/kg (Monsanto Company, 1982a).
Long-term Exposure
0 In subchronic studies reported by the Weed Science Society of America
(1983), technical-grade glyphosate was fed to rats at dietary levels
of 20, 60 or 200 mg/kg/day and to dogs at 50, 1 50 or 500 mg/kg/day
for 90 days. Mean body weights, food consumption, behavioral reactions,
mortality, hematology, blood chemistry and urinalysis did not differ
significantly from controls. There were no relevant gross or histo-
patholocical changes. No other details or data were provided.
0 Bio/dynamics, Inc. (1981a) conducted a study in which glyphosate
was administered in the diet to four groups of Sprague-Dawley rats
(50/sex/dose) at dose levels of 0, 3.1, 10.3 or 31.5 mg/kg/day to
males or 0, 3.4, 11.3 or 34.0 mg/kg/day to females. After 26 weeks,
body weight, organ weight, organ-to-body weight ratios and hematological
and clinical chemistry parameters were evaluated. No significant
differences between control and exposed animals were observed at any
dose level.
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Reproductive Effects
0 Bio/dynamics, Inc. (1981b) investigated the reproductive toxicity of
glyphosate in rats. The glyphosate (98.7% purity) was administered
in the diet at dose levels of 0, 3, 10 or 30 mg/kg/day to Charles
River Sprague-Dawley rats for three successive generations. Twelve
males and 24 females (the FQ generation) were administered test diets
for 60 days prior to breeding. Administration was continued through
mating, gestation and lactation for two successive litters (F1a,
Fit,). Twelve males and 24 females from the Fib generation were
retained at weaning for each dose level to serve as parental animals
for the succeeding generation. The following indices of reproductive
function were measured: fetal, pup and adult survival; parental and
pup body weight; food consumption; and mating, fertility or gestation.
Necropsy and histopathologic evaluation were performed as well.
No compound-related changes in these parameters were observed when
compared to controls, although an addendum to the pathological report
for this study reported an increase in unilateral focal tubular
dilation of the kidney in the male F^ pups when compared to concurrent
controls. Based on data from this study, the authors concluded that
the highest dose tested (30 mg/kg/day) did not affect reproduction
in rats under the conditions of the study.
Developmental Effects
0 Glyphosate was also administered to pregnant rabbits (route not
specified) at dose levels of 75, 175 or 350 mg/kg/day on days 6
through 27 of gestation (Monsanto Company, 1982a). No evidence of
fetal toxicity or birth defects in the offspring was observed.
However, at dose levels of 350 mg/kg/day, death, soft stools, diarrhea
and nasal discharge were observed in the animals.
Mutagenicity
0 The Monsanto Company (1982a) reported that glyphosate did not cause
mutation in microbial test systems. A total of eight strains (seven
bacterial and one yeast), including five Salmonella typhimurium strains
and one strain of Bacillus subtilis, Escherichia coli and Saccharomyces
cerevisiae, were tested. No mutagenic effects were observed in any
strain.
0 Njagi and Gopalan (1980) found that glyphosata did not induce reversion
mutations in Salmonella typhimurium histidine auxotrophs.
Carcinogenicity
0 Bio/dynamics, Inc. (1981b) conducted a study to assess the oncogenicity
of glyphosate (98.7% purity). The chemical was given in the diet to
four groups of Sprague-Dawley rats at dose levels of 0, 3.1, 10.3 or
31.5 mg/kg/day to males or 0, 3.4, 11.3 or 34.0 mg/kg/day to females.
After 26 weeks, animals were sacrificed and tissues were examined for
histological lesions. A variety of benign and malignant tumors were
observed in both the treated and control groups, the most common tumor
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occurring in the pituitary of both sexes and in the mammary glands of
females. The total number of rats of both sexes that developed
tumors (benign and malignant) was 72/100 (low dose), 79/100 (mid
dose), 85/100 (high dose) and 87/100 (control). An increased rate of
interstitial cell tumors of the testes was reported in the high-dose
males when compared to concurrent controls (6/50 versus 0/50), but
this was not considered to be related to compound administration.
Based on the data from this study, the authors concluded that the
highest dose level tested (31.5 and 34.0 mg/kg/day for males and
females, respectively) was not carcinogenic in rats.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (approximately 7 years) and lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW) = mg/L ( /L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 1 00 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
No information was found in the available literature that was suitable
for determination of the One-day HA value for glyphosate. It is, therefore,
recommended that the Ten-day HA value be used at this time as a conservative
estimate of the One-day HA value.
I'en-day Health Advisory
The teratology study in pregnant rabbits has been selected to serve as
the basis for determination of the Ten-day HA for the 10-kg child. In this
study, pregnant rabbits that received glyphosate at dose levels of 0, 75,
175 or 350 mg/kg/day on days 6 through 27 of gestation showed effects at
350 mg/kg/day; however, no treatment-related effects were reported at lower
dose levels. The No-Observed-Adverse-Effect-Level (NOAEL) identified in
this study is, therefore, 175 mg/kg/day. While a developmental end point may
not be the most appropriate basis for derivation of an HA for a 10-kg child,
use of this study provides an extra margin of safety.
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Using a NOAEL of 175 mg/kg/day, the Ten-day HA for a 10-kg child is
calculated as follows:
Ten-day HA = (175 mg/kg/day) (10 kg) = 17.50 mg/L (17,500 ug/L)
(100) (1 L/day)
where:
175 mg/kg/day = NOAEL, based on absence of altered physical changes
and mortality in rabbits.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Longer-term Health Advisory
No information was found in the available literature that was suitable
for determination of the Longer-term HA value for glyphosate. It is, therefore,
recommended that the adjusted DWEL for a 10-kg child be used at this time as
a conservative estimate of the Longer-term HA value.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2), A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided ky the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised
in assessing the risks associated with lifetime exposure to this chemical.
The study by Bio/dynamics (1981b) has been selected to serve as the
basis for determination of the Lifetime HA value for glyphosate. In this
study, the reproductive toxicity of glyphosate in rats was investigated over
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Glyphosate August, 1987
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three generations. Even though no compound-related changes in the reproductive
indices were observed when compared to controls at a dose level of 30 mg/kg/day,
there were pathological changes of renal focal tubular dilation in male F3b
weanling rats at this level. Therefore, the lower dose level of 10 mg/kg/day
was identified as the NOAEL.
Using a NOAEL of 10 mg/kg/day, the Lifetime HA is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (10 mg/kg/day) = 0>1 mg/kg/day
where:
10 mg/kg/day = NOAEL, based on absence of renal focal tubular
dilation in rats.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.1 mg/kg/day) (70 kg) = 3.5 mg/L (3,500 ug/L)
(2 L/day)
where:
0.1 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (3.5 mg/L) (20%) = 0.70 mg/L (700 ug/L)
where:
3.5 mg/L = DWEL.
201* = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986a), glyphosate may be classified
in Group D: not classified. This category is for substances with
inadequate animal evidence of carcinogenicity.
0 The evidence of carcinogenicity in animals is considered equivocal by
the Science Advisory Board (Pesticides), and has been classified in
Category D [Office of Pesticide Programs has requested the manufacturer
to conduct another study in animals (U.S. EPA, 1986)].
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VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 No other criteria, guidelines or standards were found in the available
literature pertaining to glyphosate.
0 Tolerance of 0.1 ppm has been established for the combined residues
of glyphosate and its metabolite in or on raw agricultural commodities
(U.S. EPA, 1985a).
VII. ANALYTICAL METHODS
0 Analysis of glyphosate is by a high-performance liquid chromatographic
(HPLC) method applicable to the determination of glyphosate in water
samples (U.S. EPA, 1985B). In this method, a known volume of sample
is applied to a Bio-Rad prefilled AG 50W-X8 column. The column
effluent is injected via an auto injector onto a primary column
packed with a cation exchange resin, but used in an anion-exclusion
mode to eliminate interferences. The effluent from this column flows
onto a strong anion-exchange column where the analytical separation
is accomplished. Detection and quantitation are made with a spectro-
photometer at 570 run. The method detection limit for glyphosate is
5 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 No information was found in the available literature on treatment
technologies capable of effectively removing glyphosate from contami-
nated water.
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IX. REFERENCES
Bio/dynamics, Inc.* 1981a. Lifetime feeding study of glyphosate (Roundup
Technical). Project No. 77-2062 for Monsanto Co., St. Louis, MO. EPA
Accession Nos. 246617 and 246621. (Unpublished report)
Bio/dynamics, Inc.* 1981b. A three-generation reproduction study in rats
with glyphosate. Project No. 77-2063 for Monsanto Co., St. Louis, MO.
EPA Accession Nos. 245909 and 247793. (Unpublished report)
Brightwell, B., and J. Malik. 1978. Solubility, volatility, adsorption and
partition coefficients, leaching and aquatic metabolism of MON 0573 and
MON 0101: Report No. MSL-0207.
Meister, R.T., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister
Publishing Company, p. C117.
Monsanto Company. 1975. Residue and metabolism studies in sugarcane and
soils. Montsanto Agricultural Products Company, 800 Lindbergh Blvd.,
St. Louis, MO.
Monsanto Company. 1982a. Material safety data sheet, glyphosate technical.
800 N. Lindbergh Blvd., St. Louis, MO. MSDS No. 107-83-6.
Monsanto Company. 1982b. Rodeo herbicide for aquatic vegetation management.
Technical manual. 800 N. Lindbergh Blvd., St. Louis, MO. 82-L01.
Monsanto Company. 1982c. The health and environmental safety aspects of
Roundup herbicide: An overview. 800 N. Lindbergh Blvd., St. Louis, MO.
Roundup Herbicide Bulletin No. 3.
Monsanto Company. 1983. Rodeo herbicide: Toxicological and environmental
properties. 800 N. Lindbergh Blvd., St. Louis, MO. Rodeo Herbicide
Bulletin No. 1.
NAS. 1977. National Academy of Sciences. Drinking water and health. Vol. I.
Washington, DC: National Academy of Sciences.
NAS. 1980. National Academy of Sciences, National Research Council. Drinking
water and health. Vol. 3. Washington, DC: National Academy Press.
pp. 77-80.
Njagi, G.D.E., and H.N.B. Gopalan. 1980. Mutagenicity testing of some
selected food preservatives, herbicides and insecticides. Bangladesh
J. Bot. 9:141-146. (abstract only)
Olorunsogo, 0.0. 1981. Inhibition of energy-dependent transhydrogenase
reaction by N-(phosphonoznethyl)glycine in isolated rat liver mitochondria.
Toxicol. Lett. 10:91-95.
Olorunsogo, O.O., and E.A. Bababunmi. 1980. Inhibition of succinate-linked
reduction of pyridine nucleotide in rat liver mitochondria "in vivo" by
N-(phosphonomethyl)glycine. Toxicol. Lett. 7:149-152.
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Glyphosate August, 1987
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Olorunsogo, O.O., E.A. Bababunmi and 0. Bassir. 1977. Toxicity of glyphosate.
Proceedings of the 1st International Congress on Toxicology. G.L. Plaa
and W.A.M. Duncan, eds. New York: Academic Press, p. 597. (abstract
only)
Olorunsogo, O.O., E.A. Bababunmi and O. Bassir. 1979a. Effect of glyphosate
on rat liver mitochondria in vivo. Bull. Environ. Contain. Toxicol.
22:357-364.
Olorunsogo, O.O., E.A. Bababunmi and 0. Bassir. 1979b. The inhibitory effect
of N-(phosphonomethyl)glycine in vivo on energy-dependent, phosphate-
induced swelling of isolated rat liver mitochondria. Toxicol. Lett.
4:303-306.
Rueppel, M.L., B.B. Brightwell, J. Schaefer and J.T. Marvel. 1977. Metabolism
and degradation of glyphosate in soil and water. J. Agric. Food Chem.
25:517-528.
Seiler, J.P. 1977. Nitrosation in vitro and in vivo by sodium nitrite, and
mutagenicity of nitrogenous pesticides. Mutat. Res. 48:225-236.
Shoval, S., and S. Yariv. 1981. Infrared study of the fine structures of
glyphosate and Roundup. Agrochimica. 25:377-386.
STORET. 1987.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 180.364. July 1.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. U.S. EPA Method 140
- Revision A - Glyphosate. Fed Reg. 50:40701. October 4, 1985.
U.S. EPA. 1986a. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Fed. Reg. 51(185):33992-34002. September 24.
U.S. EPA. 1986b. U.S. Environmental Protection Agency. Guidance for the
registration of pesticide products containing glyphosate as the active
ingredient. Case No. 0178, June, 1986.
Weed Science Society of America. 1983. Herbicide handbook, 5th ed.
Champaign, IL: Weed Science Society of America, pp. 258-263.
Confidential Business Information submitted to the Office of Pesticide
Programs.
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