UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 11/10/06

							

MEMORANDUM

SUBJECT:	Formetanate Hydrochloride: Response to Registrant’s Comments
on EPA’s Interim Reregistration Eligibility Decision for Formetanate
HCl.  PC Code 097301, Case #: 2450, DP # 332275. 

			

								

FROM:	Danette Drew, Senior Scientist

		John Doherty, Toxicologist

		Reregistration Branch 3

		Health Effects Division (HED) (7509P)					

		

THROUGH:	Catherine Eiden, Branch Chief

		Reregistration Branch 3

		Health Effects Division (HED) (7509P)

TO:		James Parker, Chemical Review Manager

		Reregistration Branch I

		Special Review and Reregistration Division (7508P)

As per SRRD request, the HED has prepared responses to the
registrant’s comments on the March 2006 “Interim Reregistration
Eligibility Decision for Formetanate Hydrochloride”. Excerpted
comments and HED’s response to those comments are presented in this
memorandum. See Gowan Company’s letter (dated 8/28/2006; Docket ID:
OPP-2004-0032) for specific science and policy considerations in support
of Gowan’s comments.

Gowan Comment: 

“the IRED occupational assessments employed an inhalation hazard
endpoint 

(cholinesterase NOAEL) derived from an acceptable acute oral
neurotoxicity study in rats (MRID 45314201, 2000). In this study, the
no-effect level for cholinesterase inhibition was 0.1 mg/kg, and the
LOAEL was 1 mg/kg. This allows for the conclusion that the true NOAEL
may be greater than 0.1 mg/kg.”

“We further note and agree with EPA’s own position in this case that
BMD data are preferable to NOAEL/LOAEL data.”

“we believe that the most appropriate inhalation hazard endpoint for
the relevant occupational assessments is the most sensitive BMDL10 value
for adults from the acute comparative cholinesterase study. We note
further that the IRED correctly describes [at Page 21] the use of an
oral endpoint with the assumption of 100% inhalation 

absorption as “a high end default value”.”

“EPA calculated BMDL10 values of 0.18 mg/kg (adult males) and 0.31
mg/kg (adult females). The lowest value (0.18 mg/kg) is the appropriate
hazard input for the inhalation assessments. As a result, Margins of
Exposure (MOE) are 1.8x greater than those presented in the IRED, which
utilized the endpoint of 0.1 mg/kg.”

HED Response:

HED appreciates Gowan’s comment that BMD modeling is an appropriate
method for deriving points of departure in risk assessment.  HED agrees
that the BMD approach for determining the point of departure (PoD) for
inhalation risk assessment may have been appropriate in the
occupational/inhalation risk assessment. HED cannot conclude at this
time, however, that the most appropriate point of departure is the
BMDL10 of 0.18 mg/kg (adult males) calculated from the registrant’s
comparative cholinesterase (CCA) study (MRID 46618901). As described in
the Preliminary Cumulative Risk Assessment of the N-methyl Carbamates
(2005), a study in rats performed by EPA’s National Health and
Environmental Effects Research Laboratory (NHEERL) provides a BMDL10 of
0.05 mg/kg in adult, male brain cholinesterase inhibition suggesting
that a PoD lower than 0.1 mg/kg or 0.18 mg/kg may be more appropriate
for use in formetanate risk assessments.  Prior to the release of the
Revised Cumulative Risk Assessment of the N-methyl carbamates, the
Agency will perform an analysis where a BMD10 and BMDL10 can be
estimated using data from both the Gowan CCA study and the EPA study. 

[Note that the requirement for a 28 day inhalation toxicity study
remains outstanding.]  

Gowan Comment: 

“Two dermal cholinesterase studies are available. MRID 44948501 (1999)
examined whole blood, plasma and brain cholinesterase inhibition in
rats, as well as FOB and motor activity endpoints one hour following the
last dose in a 21 day dosing regime. EPA concluded that the NOAEL for
cholinesterase inhibition in all compartments was 20 mg/kg/day, but
classified the study as supplemental because time-course data were not
available to confirm the time-of-peak effect, and because information on
the time of assays relative to blood sample collection was not reported
in the study. The NOAEL of 20 mg/kg/day determined in this study was not
used in the IRED assessments.

As discussed below, a subsequent and acceptable time-of-peak effect
dermal study (MRID 453119901, 2000) successfully addressed EPA’s first
concern. As stated in the December 22, 2005 revised Toxicology Chapter
for formetanate hydrochloride: 

The time to peak effect was demonstrated to be from 0.5 hours to 3 hours
after removal. 

Since the previous 21-day dermal study (MRID No. 44948501) assessed for
cholinesterase one hour post exposure, the assessment time is
appropriate for that study. 

Regarding the Agency’s second concern, although a specific time
interval for the time of blood assays relative to collection was not
specified in the 21-day study, the report did specify that all blood
samples were kept on ice until assaying; and there is no mention in the
study of any atypical holding times for the samples. In summary, the
assays were conducted at the time-of peak-effect, and samples were
appropriately maintained on ice prior to assaying. We believe that with
these two concerns addressed, EPA can upgrade MRID 44948501 to
acceptable status and can utilize the NOAEL of 20 mg/kg/day as the
dermal hazard input for the occupational assessments. 

EPA is currently using a dermal endpoint of 10 mg/kg/day from MRID
45311901 for the 

occupational assessments. We reiterate our previously expressed concern
that this endpoint is inappropriate since it is derived from data which
the Agency itself describes as not statistically significant. As
detailed in our earlier submission, the only treatment-related effects
seen in this study are associated with the 500 mg/kg dose. The remainder
of the data reflect only random, baseline variation in cholinesterase
activity. In our view, use of statistically non-significant data is an
inappropriate basis for requiring risk mitigation. The data clearly
support a dermal hazard NOAEL of 20 mg/kg/day.”

HED Response:

The issue of the NOAEL and LOAEL for ChE inhibition by formetanate
following dermal exposure has been reevaluated by HED.  There are two
dermal toxicity studies with formetanate:  an original 21-day study
(1999, MRID No.: 44948501) with dose levels of 0, 10, 15 and 20
mg/kg/day that was determined to have problems related to optimal time
for assessment of ChE activity as well as problems with the assessment
of motor activity and FOB.  In response to HED’s concerns for
deficiencies in this study, a second study (2000, MRID No.: 45311901)
designed to determine the time to peak effect for ChE inhibition
following dermal applications of 0, 10, 20 or 500 mg/kg of formetanate
was submitted. In the 21-day repeat dose study, it was noted that there
was 6.9% (p<0.05) apparent inhibition at 20 mg/kg/day in males based on
the assessment made one hour after removal of the dermal application of
the test material.   The special time to peak effect study verified that
the optimal time for assessment of ChE inhibition was between 0.5 and 3
hours after removal of the dermal application of the test material.  The
time to peak effect study demonstrated that there was 12 to 18% lower
activity (although not statistically significant) at 1, 2 and 3 hours
after removal of the test material in the 20 mg/kg dose group males.  
The activity of ChE for this group was essentially similar to the
control group prior to the optimal time for assessment of inhibition and
returned to the control level after the 3 hour assessment time to
indicate recovery.   Inhibition at 500 mg/kg occurred at the 1, 2 and 3
hour assessment times and also returned to control levels at 19 hours
indicating there was a dose response for inhibition including the 20
mg/kg dose group. The 10 mg/kg dose group was essentially similar to the
control group.  At 500 mg/kg, females were less (maximum 36%) inhibited
than males (maximum 56%) and at 20 mg/kg females did not demonstrate a
consistent lower activity at the critical times for inhibition.  Since
maximum inhibition at 500 mg/kg in males was higher than in females,
further support that the lower activity noted at the critical times in
males at 20 mg/kg is inhibition is evident.  Overall, both the 21 day
repeat dose study and the special time to peak affect study show
evidence of inhibition at 20 mg/kg/day or 20 mg/kg.  Thus, HED concludes
that 20 mg/kg is a LOAEL for a threshold effect on ChE inhibition
following dermal application.   

HED considers that 20 mg/kg is a threshold effect and recognizes that
assigning this level as the LOEAL is a conservative call made in the
best interest of protecting the public from potential exposure and
inhibition of ChE by formetanate.  HED recognizes that assessment of
blood ChE by carbamates is problematic and subject to underestimation to
further justify the selection of 20 mg/kg as a LOAEL for potential
inhibition.  

Since the registrant provided the special time to peak effect for
inhibition of ChE following dermal application and established that the
one hour interval that was used for sampling the blood in the 21-day
dermal toxicity study was within the time to peak effect, the ChE
aspects of the 21-day study can be upgraded to ACCEPTABLE. This assumes
that the conditions of sampling with regard to storage, dilution and
other factors related to the actual assessment of ChE were similar in
both studies.  However, since the registrant did not provide information
on the timing of the FOB and motor activity or positive control data
with a carbamate on FOB and motor activity following dermal exposure,
the FOB and motor activity aspects of this study cannot be upgraded. 
Since carbamates are quick acting the window for detecting the effects
on motor activity and FOB is narrow and the study lacks details as to
how all of the animals were assessed at the critical times for observing
FOB and motor activity.  

The dose levels for the 21-day repeat dose study were 0, 10, 15 and 20
mg/kg/day and the dose levels for the special time to peak effect study
were 0, 10, 20 and 500 mg/kg and both studies support the conclusion
that 20 mg/kg is a threshold LOAEL, a NOAEL of 15 mg/kg/day for
inhibition of ChE is supported.   

Using the NOAEL of 15 mg/kg for dermal exposure, instead of  the 10
mg/kg used in the current risk assessment, results in total (combined)
MOEs above the level of concern for the three scenarios cited in the
comments when utilizing either a PoD of  0.1 mg/kg or 0.05 mg/kg for
inhalation exposure (see Table 1 below). However, if the inhalation PoD
of 0.18 mg/kg were used along with the dermal NOAEL of 15 mg/kg, two of
those scenarios would result in total MOEs of 100 or greater: orchard
airblast application (open cab, WSB, PPE) with an MOE of 120 and aerial
application to alfalfa/high acreage (open cab, WSB, PPE) with an MOE of
100 (note: not a viable scenario as double engineering controls are
assumed). As noted in the previous HED Response (p.2), the Agency will
be evaluating a BMD10 and BMDL10 using data from both the Gowan CCA
study and the EPA NHEERL study.

TABLE 1: Formetanate HCl: Comparison of example total (combined) MOEs 
(first column represents current risk assessment)

SCENARIO	Inhalation 1

0.1	Inhalation 1

0.1	Inhalation 2

0.18	Inhalation 2

0.18	Inhalation 3

0.05	Inhalation 3

0.05

	Dermal 4

10	Dermal 5

15	Dermal 4

10	Dermal 5

15	Dermal 4

10	Dermal 5

15

Applicator: Orchard airblast 

(extra PPE, respirator, hood, WSB)	73	90	91	120	51	59

Mix/Load: Orchard aerial

 (long sleeves/pants, gloves, WSB)	51	57	76	88	30	32

Mix/Load: Alfalfa aerial (high rate)

(extra PPE;WSB)6	57	74	75	100	41	48

1 Inhalation BMDL10 0.10 mg/kg from Gowan CCA (pups; used in current RA)

2 Inhalation BMDL10 0.18 mg/kg from Gowan CCA (adults; proposed by
registrant)

3 Inhalation BMDL10 0.05 mg/kg from EPA CCA (adults; used in NMC
cumulative)

4 Dermal NOAEL 10 mg/kg from dermal study (peak time and 21 day; used in
current RA)

5 Dermal NOAEL 15 mg/kg from dermal study (peak time and 21 day;
proposed new NOAEL)

6 Not a viable scenario; for mixer/loaders, should not use extra PPE
with WSB (2 engineering controls)

Gowan Comment: 

“We note that the reentry assessments are based upon an incorrectly
low dermal toxicity endpoint, which is discussed in the previous
section. If the appropriate dermal endpoint is used, Margins of Exposure
would be double those calculated by the Agency for all scenarios and
reentry intervals would be shorter than those calculated by EPA.”

HED Response: 

(see previous response regarding selection of dermal toxicity dose and
endpoint, pp. 3-4). Reentry activity MOEs were recalculated using the
dermal NOAEL of 15 mg/kg.  Reentry activity MOEs  equal to or over 100
are not achieved until 9 days after the second application of the ai to
citrus fruit trees, 5 days after application to pome and stone fruit
trees, and 4 days after application to alfalfa (see Table 2 below).

TABLE 2: Short-term Post Application Assessment for Formetanate Treated
Agricultural Crops (including ornamentals)

DAT (1)	

Crop Groupings: MOEs for Activity Level (2,3)

	

ALFALFA

Field / row crops, low / medium

 (1 crop) (TC=1500 cm2/hr) (4)	

POME and STONE 

Trees, fruit, deciduous

 (2 crops) (TC=1500 cm2/hr) (5)	

CITRUS

Trees, fruit, evergreen



	

(TC =1500 cm2/hr) (6)	

(TC = 3000 cm2/hr)(7)



0	54	43	43	21



1	65	52	52	26



2	79	62	62	32



3	94	71	71	36



4	107	88	88	43



5	-	100	100	52



6	-	-	-	62



7	-	-	-	75



8	-	-	-	88



9	-	-	-	110

Footnote:-

  1. DAT = Days after treatment; DAT0 = On the day of treatment, after
sprays have dried; assumed approximately 12 hours.

  2. Crop groupings and transfer coefficients from Science Advisory
Council for Exposure: Policy Memo #003.1 'Agricultural Transfer
Coefficients', August 17, 2000.

  3. MOE = Dermal toxicity endpoint (mg/kg-day)/absorbed dermal dose
(mg/kg-d) where the absorbed dose = DFR (ug/cm2) x TC (cm2/hr) x
conversion factor (1 mg/1,000 ug) x exposure time (hrs) x dermal
absorption / body weight (kg).

  4. Medium exposure potential: Irrigation, Scouting, Weeding (hand)

  5. High exposure potential: Harvest (hand), Propping, Pruning (hand),
Training, Tying

  6.  Medium exposure potential: Bagging Fruit, Hand Labor (misc.),
Harvest (hand), Pollination, Staking,                     Topping,
Training, Tying

 7. High exposure potential: Pruning (hand), Thinning

Page   PAGE  6  of   NUMPAGES  6 

