Document ID: EPA-HQ-OPP-2008-0276-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-12-22T05:00Z

MEMORANDUM

DATE:	4/4/00

SUBJECT:	PP#5F4469.  Prosulfuron in or on Cereal Grains (Except Rice)
and Animal Commodities.  Submissions Dated 12/22/97 Addressing Residue
Chemistry Deficiencies in Establishing Permanent Tolerances.

MRID#s 444492-04 thru -07.

DP Barcode: D242049.

Trade Name: EXCEED Herbicide (Reg.# 100-774)

PEAK Herbicide (Reg.# 100-763)

Class: Herbicide

Chemical: 129031.

Case: 014396.

40 CFR: 180.481.

TO:		James Stone/Jim Tompkins, P.M. Team 25

Herbicide Branch

Registration Division (7505C)

FROM:	G. Jeffrey Herndon, Chemist

RAB2/HED (7509C)

THRU:	Richard Loranger, Branch Senior Scientist

RAB2/HED (7509C)

BACKGROUND

Ciba-Geigy (now Novartis) had previously submitted an application for
tolerances for prosulfuron
(1-(4-methoxy-6-methyl-triazin-2-yl)-3-[2-(3,3,3-trifluoropropyl)-phenyl
sulfonyl]-urea) and registration for Peak Herbicide on cereal grains
(except rice).  In PP#5F04469, the petitioner proposed the following
tolerances (expressed as parent only): 

Cereal grains (except rice)         --  0.01 ppm

Cereal grains (except rice) forage  --  0.10 ppm

Cereal grains (except rice) fodder  --  0.01 ppm

Cereal grains (except rice) straw   --  0.02 ppm

Cereal grains (except rice) hay     --  0.20 ppm

Prior to PP#5F4469, in PP#4F04336, the petitioner proposed the following
tolerances (also expressed as parent only): 

Corn, Forage   --   0.01 ppm  |  Corn, Fodder   --   0.01 ppm

Corn, Grain    --   0.01 ppm  |  Corn, K+CWHR   --   0.01 ppm

Milk           --   0.01 ppm  |

Meat, Fat, Kidney, Liver & Meat By-Products*    --    0.05 ppm

*of cattle, goats, horses, hogs and sheep

These tolerances were established on a time-limited  basis under 40 CFR
§ 180.481 pending resolution of the deficiencies outlined in the G.
Kramer review of 10/29/96.

RECOMMENDATIONS

For the purposes of this Section 3 registration of prosulfuron on cereal
grains, the residue chemistry requirements have been met.  The
tolerances proposed under PP#5F4469 by the registrant for parent
prosulfuron are appropriate.  The tolerances proposed under PP#4F4336
(corn and the animal commodity tolerances) should NOT be reestablished -
the corn tolerances are covered by the cereal grain tolerances and
animal commodity tolerances were determined to be unnecessary
[180.6(a)(3)].

 

Any risk issues will be addressed in the human health risk assessment,
which will be the subject of a forthcoming memo by HED.

	DETAILED CONSIDERATIONS

The following Deficiencies/Conclusions were cited by CBTS in the memo of
G.F. Kramer dated 10/29/96, concerning PP#4F4336 and 5F4469.

Deficiency 2a through f

The following deficiencies must be resolved before the nature of the
residue in corn can be considered to be understood: a) Storage
Stability- As the actual dates of sample extraction and analysis were
not provided for the field-grown samples, the sample storage interval
and state (i.e., homogenates or extracts) could not be determined. 
Analysis of greenhouse-grown samples within 4 months of harvest
demonstrated substantial differences when compared to the
field-grown-samples.  These differences could be explained by
degradation of prosulfuron, CGA-300408 and hydroxylation of CGA-159902
to CGA-304060.  In order to resolve this issue, the registrant should
provide the dates of sample extraction and analysis.  The
greenhouse-grown samples (homogenates or extracts, as appropriate)
should then be reanalyzed after storage for an interval equal to or
greater than that which the field-grown samples were stored.  b)
Bridge-intact metabolites A-13 and O-6 comprised >10% of the TRR in
forage and silage.  The maximum amounts of these metabolites was below
the 0.05 ppm trigger for metabolite identification (0.013 ppm for A-13
and 0.012 ppm for O-6).  However, as these studies were performed at 1X
rather than at an exaggerated rate as required by Agency guidelines,
CBTS is requiring that the registrant identify these metabolites.  c)
During characterization of the bound residues of the field-grown stalk
samples, >10% of the TRR was released into the cellulase and NaOH
supernatants.  However, no metabolite identification of these fractions
was reported.  CBTS requests that the registrant provide the results of
analysis of these samples (i.e., HPLC and 2-D TLC).  d) The
chromatographic data for the analysis of several fractions released from
bound residues were provided.  CBTS requests that the registrant provide
a quantitative analysis of this data.  e) Metabolites CGA-188838 and
G-28533 coeluted on HPLC so that the quantitative data was reported for
a combined total of both compounds.  CBTS requests that the registrant
provide data for these metabolites individually either by quantitative
analysis of existing 2-D TLC chromatograms in which separation was
achieved or by reanalysis of the samples using HPLC methods capable off
achieving separation.  f) The phenyl-specific metabolite CGA-304060
(both free and glucose-conjugated) was found in the triazine-labelled
samples of the field study.  The registrant should provide an
explanation for this result.

Registrant's Response to Deficiency 2

Novartis Submitted the following studies to address these deficiencies:

“Uptake and Metabolism of CGA-152005 in Field Grown Corn After Spray
Treatment with Phenyl-14C-CGA-152005 and Triazine-14C-CGA-152005,
Amendment 1", R. Rezaaiyan, 5/21/97, MRID# 444492-04.

and

“Stability of CGA-152005 Metabolites in Greenhouse Grown Corn After
Spray Treatment with Phenyl-14C-CGA-152005 and Triazine-14C-CGA-152005,
Amendment 2", R. Rezaaiyan, 5/21/97, MRID# 444492-05.

Storage Stability

Novartis provided actual dates for the sample extraction and analysis of
field grown 30-day corn forage, corn silage, and corn stalks.  The
samples were stored in a freezer between 6 and  12 months before they
were analyzed.  To address the potential degradation of the stored
samples, Novartis conducted 2 studies.

The first study (MRID# 444492-05) was a new greenhouse-conducted study
in which resulting homogenates were extracted and analyzed immediately
after harvest and again after 14 months of storage in the freezer
(-20oC), an interval greater than that which the field grown samples
were stored.

Subsamples of 45-day silage stage corn were extracted 13 and 398 days
after harvest.  The amount extractable was 87.5% and 83.1%,
respectively.  A second set of subsamples of 45-day silage stage corn
were extracted 13 and 397 days after harvest.  The amount extractable
was 84.9% and 87.6%, respectively.  Each extract was partitioned with
ethyl acetate.  The organic and aqueous fractions from the extracts were
analyzed by HPLC.  HPLC recoveries ranged from 70% to 95%.  HPLC
profiles of the organic and aqueous fractions were qualitatively and
quantitatively similar, indicating CGA-152005 and its metabolites are
stable in frozen silage stage corn homogenates for a period of about 13
months.

Subsamples of mature corn stalks were extracted 9 and 406 days after
harvest.  The amount extractable was 79.3% and 77.4%, respectively.  A
second set of subsamples of mature corn stalks were extracted 9 and 401
days after harvest.  The amount extractable was 81.6% and 73.3%,
respectively.  Each extract was partitioned with ethyl acetate.  The
organic and aqueous fractions from the extracts were analyzed by HPLC. 
HPLC recoveries ranged from 79% to 99%.  HPLC profiles of the organic
and aqueous fractions were qualitatively and quantitatively similar,
indicating CGA-152005 and its metabolites are stable in frozen mature
corn stalk homogenates for a period of 13+ months.	

In the second study (MRID# 444492-04), several field grown corn samples
were reextracted for identification purposes.  Comparison of HPLC
profiles from these samples were used to show that CGA-152005 and its
metabolites are stable in corn homogenates.

Subsamples of 30-day corn forage were extracted 7.4 and 44 months after
harvest.  The amount extractable was 83.1% and 78.8%, respectively.  The
aqueous fractions after ethyl acetate partition were analyzed by HPLC. 
Comparison of HPLC quantitation showed quantitative variances in
composition, particularly of the latest eluting region A-15.  However,
Novartis concluded that the qualitative nature of the CGA-152005
residues was preserved during the freezer storage condition employed in
this study.

Subsamples of corn silage were extracted 10.7 and 44 months after
harvest.  The amount extractable was 79.1% and 70.3%, respectively.  The
aqueous fractions after ethyl acetate partition were analyzed by HPLC. 
The HPLC profiles were qualitatively and quantitatively similar, showing
the stability of CGA-152005 and its metabolites in frozen corn silage
homogenates.

Additional Metabolite Characterization/Identification/Quantitation

Metabolites in regions [A-1], [A-13], and [O-6] were isolated and
purified.  Mass spectral analysis of the metabolites in regions [A-13]
and [O-6] confirmed that [O-6] is the aglycone of [A-13] and region
[A-13] is the glucose conjugate of hydroxy CGA-325030.  Region [A-1] was
separated into 2 peaks by HPLC and identified as G-28533 (10.2% TRR) and
CGA-188838 (12.2% TRR).  These structures are shown in the memo of G.
Kramer dated 2/22/95, concerning PP#4F4336.

Quantitation of Released Radioactivity from Bound Residues

Data were provided which show that all the released metabolites from
bound residue were less than or equal to 0.002 ppm.

RAB2's Comments and Conclusions Concerning Deficiency 2

The additional storage stability data and metabolite
characterization/identification/quantitation data submitted resolves the
questions/deficiencies surrounding the corn metabolism study.  The corn
metabolism study is now complete and acceptable.  Deficiency 2 has been
resolved. 

Deficiency 3a and b

For the ruminant metabolism study, CBTS requests that the registrant :
a) Provide the actual dates of sample extraction and analysis for the
samples; b) If samples were stored longer than 6 months, provide further
evidence of storage stability.  If analysis were not performed within 6
months of collection, then CBTS is willing to consider storage data for
the parent compound in animal RACs, as prosulfuron was the predominant
residue in milk and tissue samples.

Registrant's Response to Deficiency 3

Novartis Submitted the following studies to address this deficiency:

“Response to EPA Review of Prosulfuron: Nature of the Residue in Corn
and Ruminants", 10/23/97, MRID# 444492-06.

and

“Stability of CGA-152005 Fortified into Meat, Milk, and Eggs Under
Freezer Storage Conditions", L. Eudy, 4/30/97, MRID# 444492-07.

Novartis provided actual dates from the goat metabolism study for the
goat sacrifice, extraction of samples, and analysis of samples.  Samples
were held up to 27 months from slaughter to analysis.  Novartis had
previously shown that CGA-152005 and CGA-273437 were stable in goat
liver for 8 months and that CGA-152005, CGA-273437, and CGA-150829 were
stable in milk for 17 months.

In order to address the stability of prosulfuron (CGA-152005) over
longer frozen intervals, Novartis conducted a separate storage stability
study using cold (non-radiolabeled) prosulfuron spiked into samples of
beef muscle, beef liver, milk, and eggs.  The samples were stored frozen
for a period of 25 months (16 months for the egg samples) and analyzed. 
Storage stability recoveries corrected for procedural recoveries
indicated no degradation over the intervals tested (essentially 0%
degradation).  

RAB2 Comments and Conclusions Concerning Deficiency 3

The additional storage stability data submitted resolves the
questions/deficiencies surrounding the goat metabolism study.  The goat
metabolism study is now complete and acceptable.  Deficiency 3 has been
resolved. 

Deficiency 4

CBTS will refer to the Metabolism Committee on the toxicological
significance of metabolites once the deficiencies associated with plant
metabolism have been addressed.  A decision by CBTS concerning which
residues to regulate will then follow.  A tolerance based on the parent
only may not be appropriate; in such an instance a revised Section F and
additional field studies, analytical methodology, animal feeding studies
and storage stability data may be needed.

Registrant’s Response to Deficiency 4

None

RAB2's Comments and Conclusions Concerning Deficiency 4

Prosulfuron has not been presented to the Metabolism Assessment Review
Committee (MARC).  Based in a 1X radiolabeled corn metabolism study, the
TRR of all direct human food items was below the limit of detection (TRR
in corn grain from the phenyl-labeled prosulfuron was < 0.002 ppm, from
the triazine-labeled prosulfuron was < 0.003 ppm).  Therefore, no
metabolites (either singly or in combination) would be expected to be
found in corn grain at levels above 0.003 ppm.

In the animal (goat and hen) metabolism studies, a majority of the
radioactivity was identified as unchanged prosulfuron (60-90% TRR in
tissues/milk of goats and 65-94% TRR in tissues/egg white of hens). 
Based on the cow and chicken feeding studies, meat, milk, poultry, and
egg tolerances were determined to not be required (Category 180.6(a)(3)
- see memo of G. Kramer dated 2/22/95).

RAB2 performed a “worst-case” risk assessment from the use of
prosulfuron on cereal grains.  The assessment was performed using TRR
values from the corn metabolism study, 100% crop treated, and the
toxicological endpoints chosen by Hazard Identification Assessment
Review Committee (report dated 1/24/00) coupled with the FQPA factor (3X
- FQPA Safety Factor Committee, report dated 2/10/00).  The maximum
acute dietary risk was a maximum of 6 % of the aPAD and 2 % of the cPAD
for any population of concern.  The inputs used in these risk
assessments will be outlined in a forthcoming Dietary Exposure memo.

Based on the above information coupled with the regulation of most
sulfonyl-urea herbicides as parent only (9 out of 12), prosulfuron will
be regulated as parent only in cereal grains.  If, in the future, new
uses require the submission of new metabolism data which show detectable
residues on direct human foods, or the livestock dietary burden is
increased enough to remove prosulfuron from category 180.6(a)(3), then
MARC may need to make a call as to the residue to be regulated. 

For the proposed use of prosulfuron on cereal grains, Deficiency 4 has
been resolved.

Deficiency 5 

ACL reports that the prosulfuron standard is not available from the EPA
repository in RTP.  The petitioner should submit standards of
prosulfuron to the EPA repository in RTP along with the MSDS and then
provide CBTS with the Repository ordering codes.  Until the receipt of
the standard and MSDS and ordering codes, the requirements for
analytical enforcement methodology will remain unfulfilled.

Registrant’s Response to Deficiency 5

None

RAB2's Comments and Conclusions Concerning Deficiency 5

A prosulfuron standard is available from the Ft. Meade laboratory
(personal communication between Chuck Stafford and Jeffrey Herndon on
3/15/00).  Deficiency 5 has been resolved.

Deficiency 7

HED notes that the Food Quality Protection Act of 1996 has amended and
strengthened the standard for establishing tolerances under the FFDCA. 
OPP is still assessing the full impact of this change in the law on the
tolerance-setting process and plans to issue guidelines concerning the
establishment of tolerances under the amended statute.  All tolerance
petitions have to meet the requirements of the FFDCA as amended by the
FQPA and OPP may require additional data to determine if the terms of
the amended statute are met.

Registrant’s Response to Deficiency 7

 

None

RAB2's Comments and Conclusions Concerning Deficiency 7

The implementation of FQPA has not affected the residue chemistry
conclusions in PP#4F4336 and PP#5F4469.  However, FQPA considerations
may affect the human health risk assessment (to be completed in the near
future) and therefore, the establishment of the tolerances proposed in
PP#4F4336 and PP#5F4469.  Deficiency 7 has been resolved.

cc:  PP#s 4F04336, PP#5F04469, RAB2 RF, Herndon.



 Of the %TRR in egg yolk, only 23% was identified as prosulfuron.

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