Document ID: EPA-HQ-OPP-2008-0258-0010
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-03-04T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC  20460

OFFICE OF PREVENTION,

PESTICIDES AND TOXIC SUBSTANCES

MEMORANDUM

Date:		14 January 2009

Subject:	Dimethomorph.  ADDENDUM to the Human Health Risk Assessment for
the Proposed Food/Feed Use of the Fungicide (Associated with Section 3
Registration) on Succulent Lima Beans, Ginseng, Grapes and Turnip Tops. 

um™

From:		William T. Drew, Chemist/Risk Assessor

		Risk Integration Minor Use and Emergency Response Branch (RIMUERB)

		Registration Division (RD), 7505P

	and

		Karlyn J. Middleton, Toxicologist

		Registration Action Branch 2 (RAB2)

		Health Effects Division (HED), 7509P

Through:	Richard A. Loranger, PhD, Senior Scientist

		Christina Swartz, Branch Chief

		RAB2/HED, 7509P

To:		Sidney Jackson and Daniel Rosenblatt, RM Team 5

		RIMUERB/RD, 7505P

SUBJECT ACTION

	This addendum to the 6 November 2008 risk assessment document (RAD) for
dimethomorph (D349253) was created in response to the Office of General
Counsel’s request that HED clarify the rationale for reduction of the
FQPA Safety Factor from 10x to 1x (in light of effects seen in the
developmental toxicity studies in rats and rabbits), and to document a
revision of the subchronic/chronic toxicity profile table (to reflect
the upgrade of the reproductive toxicity study to “acceptable”). 
New text is shown in bold type.  

Developmental Toxicity Studies   TC \l3 "3.3.3	Developmental Toxicity
Studies (Refer to the 6 November 2008 RAD, Section 3.3.3)

	In a developmental toxicity study in rats, reductions in body weight,
body weight gain, and food consumption were seen in maternal animals at
the LOAEL of 160 mg/kg/day (NOAEL = 60 mg/kg/day).  Increased
post-implantation loss was also seen at 160 mg/kg/day.  In a
developmental toxicity study in rabbits, increased incidence of abortion
was observed at the LOAEL of 650 mg/kg/day (NOAEL = 300 mg/kg/day).  No
effects were observed in pups at doses of up to 650 mg/kg/day.  Although
post-implantation loss was reported in the offspring LOAEL (rats), and
abortions were reported in the maternal LOAEL (rabbits), it is difficult
to distinguish whether the observed effects are a result of maternal
toxicity or offspring toxicity.  As a result, it is assumed that the
effects could potentially be a result of toxicity to either dams or
fetuses.  Therefore, there is no evidence of increased qualitative
sensitivity in the developmental studies.  

Reproductive Toxicity Study   TC \l3 "3.3.3	Developmental Toxicity
Studies (Refer to the 6 November 2008 RAD, Section 3.3.4)  TC \l3 "3.3.4
Reproductive Toxicity Study 

	In a multi-generation reproductive toxicity study, the P generation
animals were mated in a one-to-one ratio, and given the test material
for 15 weeks before they were mated.  Selection of the parents for the
F1 generation was made shortly after weaning on day 21 post-partum.  The
P1 animals were mated when they were approximately 21 weeks of age,
while the F1 generation was mated at about 15 weeks of age.  

	No clinical signs or necropsy findings which could be associated with
administration of the test material were noted at any dose level in
parental animals.  At 1000 ppm, P generation females weighed
consistently less than controls throughout the 15 week pre-mating period
(p<0.05).  Statistically significant reductions in food consumption were
also noted in 1000 ppm females during the pre-mating period.  In F1
females, body weights were slightly lower in all the dose groups but
differences were not statistically significant.  At the 1000 ppm level,
during several intervals of the pre-mating period, female weight gain
was reduced (p<0.05).  No effects were apparent in males of the P or F1
generations.  For parental systemic toxicity, the NOAEL was 300 ppm, and
the LOAEL was 1000 ppm, based upon decreased body weights and body
weight gains.  

	Reproductive indices were not affected by treatment at any dose level
or mating.  The percentage of pups with incisor eruption was noted at
the 1000 ppm dose level in the F1, F2a and F2b generations with
non-significant delays observed at the lower dose levels.  During the
second mating of the F1 generation to produce the F2b generation, a
large number of inseminated females failed to deliver.  This finding
appeared to occur in a dose-related manner at all dose levels but was
not apparent during other matings.  It should be noted that the prostate
gland was apparently affected by the test material in the dog chronic
feeding study, and the organ was not weighed in the chronic rat study. 
No organ weight data were presented for the prostate gland in this
reproduction study but no dose-related histopathology data were apparent
in this study.  For reproductive toxicity, the NOAEL was 300 ppm, and
the LOAEL was 1000 ppm, based upon decreased incisor eruption on day 10
postpartum.  

	This study was originally classified as unacceptable due to several
deficiencies.  However, the petitioner addressed the deficiencies, and
the reproductive toxicity study has been upgraded to acceptable.  

FQPA Safety Factor for Infants and Children   TC \l3 "3.3.3
Developmental Toxicity Studies (Refer to the 6 November 2008 RAD,
Section 3.4)  TC \l2 "3.4	Safety Factor for Infants and Children 

	Previous HED risk assessments cited the lack of environmental fate data
for dimethomorph in consideration of the FQPA Safety Factor.  HED notes
that the required environmental fate data have been received, and have
been incorporated into subsequent risk assessments (including the most
recent).  

	Additionally:  

1. The developmental and reproductive toxicity data did not indicate
increased quantitative or qualitative susceptibility of rats or rabbits
to in utero and/or post-natal exposure to dimethomorph, 

2. there is no evidence of neurotoxicity, 

3. the dietary (food only) exposure assessment did not indicate a
concern for potential risk to infants and children, even though
unrefined field study data are used, resulting in an overestimate of
dietary exposure, and 

4. there are currently no registered residential uses for dimethomorph. 

A.2	Toxicity Profiles TC \l2 "A.2	Toxicity Profiles 

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile for
Dimethomorph.

Guideline Number/ Study Type	MRID(s) [year]/ Classification/Doses
Results

870.3100

90-Day oral toxicity [dog]	42233908 [1991]

Acceptable/guideline

0, 150, 450, 1350 ppm

M: 0, 5, 15, 43 mg/kg/day

F: 0, 6, 15, 44 mg/kg/day	NOAEL = 15 mg/kg/day

LOAEL = 43 mg/kg/day based on decrease in the absolute and relative
weights of the prostate and possible threshold liver effects.

870.3150

90-Day oral toxicity [rat]	42233910 [1991]

Core minimum

0, 40, 200, 1000 ppm

M: 0, 2.9, 14.2, 73 mg/kg/day

F: 0, 3.2, 15.8, 82 mg/kg/day	NOAEL >73/82 [M/F] mg/kg/day

LOAEL was not established in this study, because the highest dose tested
produced no biologically significant effects.  

870.3700a

Prenatal developmental

[rabbit]	42233918 [1989]

Unacceptable/core 

supplemental [Initial rating]

0, 135, 300, 650 mg/kg/day	Maternal NOAEL = 300 mg/kg/day

LOAEL = 650 mg/kg/day based on an increased incidence of abortion
confirmed in a range-finding study.

Developmental NOAEL could not be determined.

LOAEL could not be determined.

870.3700b

Prenatal developmental [rabbit]	44175303

Acceptable

Information supplemental to MRID# 42233918	Maternal NOAEL = 300
mg/kg/day

LOAEL = 650 mg/kg/day based on an increased incidence of abortion
confirmed in a range-finding study.

Developmental NOAEL =650 mg/kg/day [highest dose tested].

LOAEL could not be determined - no effects observed at highest dose
tested.

870.3700c

Prenatal developmental

[rat]	42233919 [1989]

Unacceptable/core 

supplemental [Initial rating]

0, 20, 60, 160 mg/kg/day	Maternal NOAEL = 60 mg/kg/day

LOAEL = 160 mg/kg/day based on reductions in food consumption, mean body
weights and body weight gain.

Developmental NOAEL could not be determined

LOAEL = could not be determined.

870.3700d

Prenatal developmental

[rat]	44175302

Acceptable

Information supplemental to MRID# 42233919	Maternal NOAEL = 60 mg/kg/day

LOAEL = 160 mg/kg/day based on reductions in food consumption, mean body
weights and body weight gain.

Developmental NOAEL = 60 mg/kg/day

LOAEL = 160 mg/kg/day based on the incidence of post implantation loss

870.3800

Reproduction and fertility effects

[rat]	42233920 [1990]

Unacceptable/core supplemental [Initial rating, subsequently upgraded to
acceptable/ guideline]

0, 100, 300, 1000 ppm	Parental/Systemic NOAEL = 300 ppm

LOAEL = 1000 ppm based on decreased body weights and body weight gains.

Reproductive NOAEL = 300 ppm

LOAEL = 1000 ppm based on decreased incisor eruption on day 10
postpartum.

Offspring NOAEL was not reported

LOAEL was not reported.

870.4100a

Chronic toxicity

[rat]	42233912 [1991]

Acceptable/guideline

0, 150, 450, 1350 ppm

M: 0, 9.4, 36.2, 99.9 mg/kg/day

F: 0, 11.9, 57.7, 157.8 mg/kg/day	NOAEL = 36.2/11.9 [M/F] mg/kg/day

LOAEL = 57.7/99.9 [M/F] mg/kg/day  based on decreased body weight and
increased incidence of arteritis in male rats and  decreased body weight
and significant increased incidence of "ground-glass" foci in the liver
in female rats.

870.4100b

Chronic toxicity [dog]

	42233911 [1991]

Acceptable/guideline

0, 150, 450, 1350 ppm

M: 0, 4.9, 14.7, 44.6 mg/kg/day

F: 0, 5.0, 15.7, 47.0 mg/kg/day	NOAEL = 14.7 mg/kg/day

LOAEL = 44.6mg/kg/day based on decreased prostate weight.

870.4200

Carcinogenicity

[rat]	42233916 [1991]

Acceptable/guideline

0, 200, 750, 20000 ppm

M: 0, 8.8, 33.9, 94.6 mg/kg/day

F: 0, 11.3, 46.3, 132.5 mg/kg/day	NOAEL [systemic] = 33.9/11.3 [M/F]
mg/kg/day

LOAEL [systemic] = 94.6/46.3 [M/F] mg/kg/day based on  decreased body
weight, gross and microscopic lesions in blood vessels, and liver
lesions in males and decreased body weight, gross and microscopic
lesions blood vessels, bone marrow hypercellularity, and liver lesions
in females.

There was no evidence of carcinogenicity

870.4300

Carcinogenicity

[mouse]	42233914 [1991]

Acceptable/guideline

0, 10, 100, 1000 mg/kg/day	NOAEL = 100 mg/kg/day

LOAEL [systemic] = 1000 mg/kg/day based on decreased body weight gain in
males.

There was no evidence of carcinogenicity

Gene Mutation

870.5100a	42233921 [1985]

Acceptable	Negative for inducing reverse gene mutation in either
Salmonella his-mutants or E. coli trp-cells exposed beyond precipitating
concentrations [500 ug/plate], up to the limit dose, 5000 ug/plate,
w/without metabolic activation.

Gene Mutation

870.5100b	42233926 [1989]

Acceptable	Negative for inducing reverse gene mutation in Salmonella TA
strains and E. coli WP2 uvr A exposed, with/without activation, up to
5000 ug/plate.

In vitro mammalian cell gene mutation test

870.5300a	42233923 [1987]

Acceptable	Negative for inducing forward mutation at the
hypoxanthine-guanine phosphoribosyl transferase locus in Chinese hamster
lung [V79] cells treated up to cytotoxic levels [230 ug/mL/-S9; 300
ug/mL/+S9].

In vitro mammalian cell gene mutation test

870.5300b	42233927 [1991]

Acceptable	Negative for inducing forward mutation at the
hypoxanthine-guanine phosphoribosyl transferase [HGPRT] locus in Chinese
hamster lung [V79] exposed, with/without activation, up to cytotoxic
concentrations [180 ug/mL/-S9; 333 ug/mL/+S9].

In vitro mammalian chromosome aberration test

870.5375a	42233924 [1986]

Unacceptable	Reportedly positive for chromosome aberrations at the
highest doses tested [160 ug/mL/-S9; 170 ug/mL/+S9].

In vitro mammalian chromosome aberration test

870.5375b	42233925 [1987]

Acceptable	[Confirmatory repeat of Study LMP-180 C, MRID 422339-24]. 
Positive for increased chromosome aberrations at high doses [160
ug/mL/-S9; 170 ug/mL/+S9].

In vitro mammalian chromosome aberration test

870.5375c	42233928 [1991]

Acceptable	Presumptively [weakly] positive, but only in activated
cultures treated at the HDT, in human lymphocyte cultures treated up to
the highly toxic dose, 422 ug/mL; negative in the absence of activation
at all doses.

Mammalian erythrocyte micronucleus test

870.5395a	42233930 [1991]

Acceptable	Negative for inducing micronuclei in bone marrow cells of
mice administered test article i.p.  up to severely toxic levels [200
mg/kg].

Mammalian erythrocyte micronucleus test

870.5395b	42233931 [1989]

Acceptable	Negative for inducing micronuclei in bone marrow cells of
mice treated orally at the limit dose, 5000 mg/kg.

Mutagenicity - DNA damage/repair in vitro

870.5500	42233922 [1986]

Unacceptable	Reportedly negative for inducing unscheduled DNA synthesis
[as measured by liquid scintillation counting] in rat hepatocytes
cultured [for only 3 hours] at doses up to 250 ug/mL, a weakly cytotoxic
level.

Other Effects - Morphologic transformation of cells in culture

870.8800	42233929 [1986]

Acceptable	Negative for transformation in Syrian hamster embryo cells
treated, in the presence and absence of activation,  up to cytotoxic
concentrations [265 ug/mL/+S9; 50 ug/mL/-S9]

870.7485

Metabolism and pharmacokinetics

[rat]	42233932 [1994]

Acceptable

10 mg/kg single dose; 10 mg/kg 14-day repeated dose; 10 mg/kg 7-day
repeated dose; 500 mg/kg single dose	Oral administration of dimethomorph
results in rapid excretion into the urine and feces of rats.  For all
treatment protocols, most [80-90%] of the radiolabel administered was
excreted in the feces.  A considerably smaller amount [6-16%] was
excreted in the urine and only minimal levels [0.1-0.4%] were detected
in the organs and tissues.  Rapid absorption may be inferred by the
rapid excretion of metabolites in the urine and bile.  Saturation of
absorption following single high doses [500 mg/kg] was indicated by
large amounts [(50%] of radioactivity in the feces being associated with
parent compound.  For low- or high-dose treatment, urinary excretion in
female rats tended to be greater [up to 2-fold in low-dose rats] than
that of male rats.  Retention of dimethomorph or
[14C]-dimethomorph-derived radioactivity was generally (1% for most
tissues although the liver exhibited slightly higher levels [1.4%] and
higher levels in the gastrointestinal tract organs was due to
radioactivity in the lumenal contents.  Urinary metabolites resulted
from demethylation of the dimethoxyphenyl ring and oxidation of the
morpholine ring.  Biliary excretion exhibited first-order kinetics with
a low-dose [10 mg/kg] half-life of approximately 3 hours and a high-dose
[500 mg/kg] half-life of 11 hours for males and about 6 hours for
females.  Biliary metabolites accounted for most of the fecal excretion
following low-dose treatment.  The major biliary metabolites were
glucuronides of one and possibly two of the compounds produced by
demethylation of the dimethoxyphenyl ring.  The report provided a
proposed metabolic pathway for dimethomorph.

870.7600

Dermal penetration

[rat]	43917221 [1995]

Acceptable/guideline

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respectively.  Majority of the radioactivity was found in skin swabs and
gauze wash [80.9 to 81.8%].  The percent of the dose in the skin
decreased with dose; at 7.73 mg/kg 17.5% and at 79.62 mg/kg 9.99%

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