Document ID: EPA-HQ-OPP-2007-0604-0010
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-08-27T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDE

                                                                        
                   AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:  19/JUN/2008

SUBJECT:	2,6-Dichlorobenzamide (BAM ); 2,6-Dichlorobenzamide (BAM ) as a
Metabolite/Degradate of Fluopicolide and Dichlobenil.  Human Health Risk
Assessment for Proposed Uses of Rhubarb, Dichlobenil on Caneberries
(Subgroup 13-07A), and Bushberries (Subgroup 13-07B).  

  

PC Code:  027401, 027402, 027412	DP Barcode:  354111

Decision No.: 380110	Registration No.: 400-168

Petition No.: 7E7230	Regulatory Action: Section 3 Registration

Risk Assessment Type:  	Case No.:  NA

TXR No.:  NA	CAS No.: 70852-53-8

MRID No.:  NA	40 CFR:  NA

	         									

FROM:	Debra Rate, Ph.D., Biologist

		Alternative Risk Integration and Assessment (ARIA) Team

		Risk Integration, Minor Use and Emergency Response Branch (RIMUERB)

		Registration Division (RD) (7505P)

		

			AND

Mark Dow, Ph.D., Biologist

		ARIA

RIMUERB/RD (7505P)

THROUGH:	Dana Vogel, Branch Chief

Registration Action Branch I (RAB1)

Health Effects Division (HED)(7509P)

 

TO:		Susan Stanton, Environmental Specialist

		Minor Use Team

RIMUERB/RD (7505P)

In connection with a request for new uses of the active ingredient,
dichlobenil, HED/RD of EPA's Office of Pesticide Programs has evaluated
the toxicity and exposure databases for 2,6-dichlorobenzamide (BAM)
which is a common metabolite/degradate of dichlobenil and fluopicolide. 
This assessment summarizes the human health risks from exposure to BAM
resulting from the existing and proposed uses of dichlobenil and
existing uses of fluopicolide on agricultural commodities, turf, and
ornamentals.  A separate human health risk assessment has been completed
for fluopicolide residues of concern (DP Num: 325091, F. Fort,
05/MAR/2008) and is concurrently being completed for dichlobenil (DP
Num: 341453, D. Rate, 11/JUN/2008).

HED recently completed a Section 3 Human Health risk assessment for BAM
as a result of new uses of fluopicolide on tuberous and corm vegetables
(except potato), leafy vegetables (except Brassica), fruiting
vegetables, cucurbit vegetables, grapes, turf, and ornamentals.  Details
of that assessment are contained in the document entitled
2,6-Dichlorobenzamide (BAM ) as a Metabolite/Degradate of Fluopicolide
and Dichlobenil.  Human Health Risk Assessment for Proposed Uses of
Fluopicolide on Root Vegetables (Subgroup 1A), Leaves of Root and Tuber
Vegetables (Group 2), Bulb Vegetables (Group 3), and Head and Stem
Brassica (Subgroup 5A) (DP Num: 349864, F. Fort, 19/MAR/2008).  This
document is an update to the previous memorandum sited above and changes
only those aspects of the BAM risk assessment which are affected by the
addition of the new uses of dichlobenil on rhubarb, caneberries
(Subgroup 13-07A) and bushberries (Subgroup 13-07B).  

 

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc198947714"  1.0  Summary of
Registered/Proposed Uses	  PAGEREF _Toc198947714 \h  4  

  HYPERLINK \l "_Toc198947715"  2.0  Hazard Characterization	  PAGEREF
_Toc198947715 \h  4  

  HYPERLINK \l "_Toc198947716"  2.1	Hazard Characterization and Endpoint
Selection	  PAGEREF _Toc198947716 \h  4  

  HYPERLINK \l "_Toc198947717"  2.2	DEREK Analyses for BAM,
Fluopicolide, and Dichlobenil	  PAGEREF _Toc198947717 \h  6  

  HYPERLINK \l "_Toc198947718"  3.0  Dietary Exposure Assessment	 
PAGEREF _Toc198947718 \h  7  

  HYPERLINK \l "_Toc198947719"  3.1  Food Residue	  PAGEREF
_Toc198947719 \h  7  

  HYPERLINK \l "_Toc198947720"  3.2  Drinking Water Estimates	  PAGEREF
_Toc198947720 \h  8  

  HYPERLINK \l "_Toc198947721"  3.3  Dietary Exposure (Food and Drinking
Water)	  PAGEREF _Toc198947721 \h  8  

  HYPERLINK \l "_Toc198947722"  4.0  Residential Exposure	  PAGEREF
_Toc198947722 \h  9  

  HYPERLINK \l "_Toc198947723"  5.0  Aggregate Exposure	  PAGEREF
_Toc198947723 \h  11  

  HYPERLINK \l "_Toc198947724"  5.1  Acute Aggregate Risk	  PAGEREF
_Toc198947724 \h  11  

  HYPERLINK \l "_Toc198947725"  5.2  Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc198947725 \h  11  

  HYPERLINK \l "_Toc198947726"  5.3  Long-Term Aggregate Risk	  PAGEREF
_Toc198947726 \h  12  

  HYPERLINK \l "_Toc198947727"  6.0  Cumulative Risk Assessments and
Risk Characterization	  PAGEREF _Toc198947727 \h  12  

  HYPERLINK \l "_Toc198947728"  7.0  Occupational Exposure	  PAGEREF
_Toc198947728 \h  13  

  HYPERLINK \l "_Toc198947729"  7.1 Handler Exposure and Risk	  PAGEREF
_Toc198947729 \h  13  

  HYPERLINK \l "_Toc198947730"  7.2  Postapplication Exposure and Risk	 
PAGEREF _Toc198947730 \h  15  

  HYPERLINK \l "_Toc198947731"  8.0  Data Needs and Label
Recommendations	  PAGEREF _Toc198947731 \h  15  

  HYPERLINK \l "_Toc198947732"  8.1	Toxicology	  PAGEREF _Toc198947732
\h  15  

  HYPERLINK \l "_Toc198947733"  8.2	Residue Chemistry	  PAGEREF
_Toc198947733 \h  15  

  HYPERLINK \l "_Toc198947734"  8.3	Occupational and Residential
Exposure	  PAGEREF _Toc198947734 \h  15  

  HYPERLINK \l "_Toc198947735"  9.0  References	  PAGEREF _Toc198947735
\h  15  

   HYPERLINK \l "_Toc198947735"  Appendix A:  Toxicity Profile Table	 
PAGEREF _Toc198947735 \h  15  



1.0  Summary of Registered/Proposed Uses  XE "1.0  Summary of
Registered/Proposed Uses"  

In connection with Petition No. 7E7230, dichlobenil is being proposed
for use on rhubarb, caneberries and bushberries.  Dichlobenil,
formulated as the 4% granular product Casoron® 4G (EPA Reg. No.
400-168), is to be applied at a maximum seasonal rate of 2 lb ai/A to
rhubarb, 4 lb ai/A to caneberries, and up to 6 lb ai/A to bushberries. 
The product is applied directly to soil while the target crop is
dormant.  

ARIA is presently recommending for the following tolerances for
dichlobenil (parent):

Caneberries (Subgroup 13-07A)	0.10 ppm

Bushberries (Subgroup 13-07B)	0.15 ppm

Rhubarb	0.06 ppm

BAM is a common metabolite/degradate of both fluopicolide and
dichlobenil.  There are no registered uses for BAM itself. 

2.0  Hazard Characterization  XE "2.0  Hazard Characterization "  

The hazard assessment for BAM has not changed since the previous
assessment; therefore only a brief summary is included in this document.
 

	2.1	Hazard Characterization and Endpoint Selection  XE "2.1	Hazard
Characterization and Endpoint Selection"  

The submitted acute and chronic studies on BAM were sufficient to
evaluate human hazard potential.  BAM demonstrated moderate acute
toxicity (Category III) via the oral route of exposure.  In subchronic
and chronic toxicity studies, the primary oral effects seen in the rat
and dog were body weight changes.  Adverse liver effects were also
observed but at doses of BAM that were higher than those of dichlobenil.
 There is no evidence that BAM is either mutagenic or clastogenic nor is
there evidence of endocrine mediated toxicity.  BAM is considered to be
neurotoxic.  In the absence of carcinogenicity study data for a second
species, HED has assumed that BAM’s carcinogenic potential is similar
to that of dichlobenil, the parent compound having the greatest
carcinogenicity potential.  Dichlobenil is classified as “Group C,
possible human carcinogen.  Quantification of cancer risk is based on
the reference dose (RfD) approach which requires comparison of the
chronic exposure to the RfD.  Using this methodology will adequately
account for all chronic toxic effects, including carcinogenicity, likely
to result from exposure to dichlobenil and therefore to BAM.  An FQPA SF
of 10X for database uncertainty has been retained for the acute and
chronic dietary and incidental oral exposure scenarios for
incompleteness of the database with regard to the systemic neurotoxic
potential of BAM, including olfactory toxicity and also, in the case of
acute dietary exposure, use of a LOAEL to extrapolate to a NOAEL.  For
the dermal and inhalation routes of exposure, the FQPA SF for BAM
toxicity has been reduced to 1X because the effect of concern, olfactory
toxicity, was chosen for these exposure scenarios. 

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment is found in Table
2.0.

Table 2.0.  Summary of Toxicological Doses and Endpoints for
2,6-Dichlorobenzamide (BAM) for Use in Dietary, Residential, and
Occupational Human Health Risk Assessments

Exposure Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary (General population, including infants and children)	LOAEL
= 100 mg/kg/day 

	UFA = 10X

UFH = 10X

FQPA SF4,5 = 10X (includes UFL and UFDB)	aRfD = aPAD = 0.1 mg/kg/day
Dose-range finding assay for in vivo mouse erythrocyte micronucleus
assay LOAEL = 100 mg/kg/day based on lethargy after a single oral dose.

Acute Dietary (Females 13-49 years of age)	NOAEL = 30 mg/kg/day	UFA =
10X

UFH = 10X

FQPA SF4 = 10X

(includes UFDB)	aRfD = aPAD = 0.03 mg/kg/day	Developmental toxicity
(rabbit) Offspring LOAEL = 90 mg/kg/day based on increased incidences of
 late abortion and skeletal (bipartite interparietal bone) and visceral
(postcaval lung lobe agenesis) anomalies.

Chronic Dietary (All populations)	NOAEL = 4.5

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF4 = 10X

(includes UFDB)	cRfD = cPAD = 0.0045 mg/kg/day	Chronic toxicity (dog)
LOAEL = 12.5 mg/kg/day based on decreased body weight and body weight
gain.

Incidental Oral

Short- and Intermediate-Term (1-30 days and 1-6 months)	NOAEL = 14

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF4 = 10X

(includes UFDB)	Residential LOC for MOE = 1000	90-day oral (rat) LOAEL =
49 mg/kg/day based on decreased body weight gain (M) and reduced
skeletal muscle tone (day 4 only in males; days 91 and 92 only in
females).

Dermal

Short-, Intermediate-, and Long-Term (1-30 days, 1-6 months, and >6
months)	NOAEL = 25

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X (residential uses only)	Residential and Occupational LOC
for MOE = 100	5-day dermal using dichlobenil6 (mouse; literature study
1) LOAEL = 50 mg/kg/day based on olfactory epithelial damage.

Inhalation

Short-, Intermediate-, and Long-Term (1-30 days, 1-6 months, and >6
months)	NOAEL = 3.1

mg/kg/day 2	UFA = 10X

UFH = 10X

FQPA SF = 1X (residential uses only)	Residential and Occupational LOC
for MOE = 100	28-day inhalation using dichlobenil6 (rat) LOAEL = 5.5
mg/kg/day3 based on nasal degeneration.

Cancer	Classification: Formally unclassified; parent herbicide
dichlobenil classified as “Group C, possible human carcinogen” with
RfD approach utilized for quantification of human risk

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal
to human (interspecies), UFH = potential variation in sensitivity among
members of the human population (intraspecies), FQPA SF = FQPA Safety
Factor, UFL = use of a LOAEL to extrapolate a NOAEL, UFDB = to account
for the absence of key data, NOAEL = no observed adverse effect level,
LOAEL = lowest observed adverse effect level, RfD = reference dose (a =
acute, c = chronic), PAD = population adjusted dose, MOE = margin of
exposure, LOC = level of concern, N/A = Not Applicable

1   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Deamer+NJ%22%5BAuthor%5D"  Deamer NJ ,  
HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22O%27Callaghan+JP%22%5BAuthor%5D"  O'Callaghan
JP ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Genter+MB%22%5BAuthor%5D"  Genter MB . (1994).
Olfactory toxicity resulting from dermal application of
2,6-dichlorobenzonitrile (dichlobenil) in the C57Bl mouse.
Neurotoxicology 15(2):287-93

2 Calculated as follows: [(NOAEL) x (m3 / 1000 L) x (10.26 L / hr) x 6
hr/day x (1 / 0.236 kg)], where NOAEL= 12 mg/m3 from 28-day inhalation
toxicity study (Sprague Dawley rat)

3 Calculated as follows: [(LOAEL) x (m3 / 1000 L) x (10.26 L / hr) x 6
hr/day x (1 / 0.236 kg)], where LOAEL= 21 mg/m3 from 28-day inhalation
toxicity study (Sprague Dawley rat)

4 The FQPA SF has been retained in the form of a UFDB for the lack of
neurotoxicity data, including olfactory toxicity data.

5 The FQPA SF has been retained in the form of a UFL and UFDB for the
use of a LOAEL to extrapolate a NOAEL and for the lack of olfactory
toxicity data.

6 In the absence of route-specific data, endpoints for all dermal and
inhalation exposure scenarios were identical to those for dichlobenil
(parent), since olfactory toxicity has been observed following i.p.
administration of BAM in mice [  HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Brittebo+EB%22%5BAuthor%5D"  Brittebo EB ,  
HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Eriksson+C%22%5BAuthor%5D"  Eriksson C ,  
HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Feil+V%22%5BAuthor%5D"  Feil V ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Bakke+J%22%5BAuthor%5D"  Bakke J ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Brandt+I%22%5BAuthor%5D"  Brandt I . (1991).
Toxicity of 2,6-dichlorothiobenzamide (chlorthiamid) and
2,6-dichlorobenzamide in the olfactory nasal mucosa of mice.   HYPERLINK
"javascript:AL_get(this,%20'jour',%20'Fundam%20Appl%20Toxicol.');" 
Fundam Appl Toxicol  17(1):92-102].

DEREK Analyses for BAM, Fluopicolide, and Dichlobenil  XE "DEREK
Analyses for BAM, Fluopicolide, and Dichlobenil"  

Comparative Toxicity using Derek analysis for Dichlobenil, Fluopicolide
and BAM, DP Num: 352656, M. Manibusan, 12/MAY/2008.

Brittebo EB, Erkisson C, Feil V, Bakke J, Brandt I. 1991. Toxicidty of
2,6-dichlorothiobenzamide and 2,6-dichlorobenzamide in the olfactory
nasal mucosa of mice. Fundam Appl Toxicol. 17(1):92-102.

Carlsson C., Harju M, Bahrami F, Cantillana T, Tysklind M, Brandt I.
2004. Olfactory mucosal toxicity screening and multivariate QSAR
modeling for chlorinated benzene derivatives. Arch Toxicol.
78(12):706-15.

Dichlobenil and fluopicolide are pesticides that share a common
metabolite and/or environmental degradate, BAM.  Based on rat metabolism
studies, BAM is not formed in vivo (<0.09% of the total administered
dose in rats) therefore, it has been assumed that neither toxicological
profiles for dichlobenil or fluopicolide would be reflective of the
toxicity specific for BAM.  Derek analysis focuses on structural
similarities of BAM and parent chemicals (dichlobenil and fluopicolide)
to determine whether relative toxicity predictions would be different
based on structural alerts.

Comparative Toxicity

Overall, Derek is confirmatory of the animal data for fluopicolide and
dichlobenil, which forms the bases for the toxicity prediction for BAM. 
Based on the available animal data and Derek analyses, BAM does not
appear to cause different organ specific toxicities compared to
fluopicolide and dichlobenil.  The kidney and liver toxicities are
common to all three compounds.  With respect to relative toxicity,
conclusions from the evaluation of the animal studies appear to confirm
that both fluopicolide and dichlobenil appear to be more or equally
toxic compared to BAM.  Based on the Derek evaluation, Derek did not
appear to distinguish fluopicolide toxicity compared to BAM based on
alerts issued only for the benzamide (BAM) portion of the structure,
indicating that the remaining pyridine structure would not contribute
significant biological activity.  Derek also confirms the liver toxicity
profile and slight to minimal kidney effects evident in the empirical
data for all three compounds.

Olfactory Toxicity

Based on dermal and inhalation exposures to dichlobenil and i.p.
administration of BAM, olfactory toxicity was determined to be a target
organ effect.  The BAM-mediated olfactory toxicity was observed only in
one study collected from open literature (Brittebo et al., 1991) at a
dose (100 mg/kg) eight times higher than that which caused the same
effect using dichlobenil (12 mg/kg i.p.).  No olfactory effects were
reported for Fluopicolide.

All three compounds are structurally similar based on sharing the
2,6-chlorinated benzene structure; the 2,6-positioning of chlorines in
combination with an electron-withdrawing group in the primary position
of the benzene ring is an arrangement that appears to facilitate
olfactory mucosa toxicity (Carlsson et. Al. 2005).  Based on this rule
based reasoning, the nitrile group on the dichlobenil is a better
electron withdrawing group than the amide group on BAM, which is equal
or less than the pyridine group on fluopicolide.  This ranking is
reflective of the potency of olfactory toxicity exhibited in the animal
studies (dichlobenil>BAM>Fluopicolide).

While the olfactory effects are relevant for i.p., inhalation and
dermal, these effects may not be directly relevant for the oral route. 
No oral studies, to date, have reported olfactory toxicity for these
compounds.  For example, a chronic dietary dog study on dichlobenil that
assayed for olfactory histopathology did not observe effects on the
nasal epithelium from long term exposure.  Therefore, based on the
different routes of exposure and the negative long term oral study in
the dog, these data indicate that olfactory effects may only occur when
by-passing the liver metabolism.  

Neurotoxicity

Evidence of potential neurotoxicity in reduced muscle tone were reported
in the 90 day rat study at day 4 in males and days 91 and 92 in females
at a dose of 49 mg BAM /kg/day and this was used to establish the
incidental oral  short and intermediate term endpoint.  Lethargy and
ataxia were observed in a dose-range finding pilot study in mice, but
effects were resolved after 24 hours.  In addition, a two week dietary
study reported clinical signs of neurotoxicity in mice at 375 mg/kg/day,
a dose much higher than that established in the 90 day rat study. 
Furthermore, fluopicolide was tested in both acute and subchronic
neurotoxicity studies and no neurotoxicity findings were reported.    

Based on the totality of the data supporting the potential olfactory and
potential neurotoxic effects for BAM,  the composite uncertainty factor
appears to be more than adequate.

3.0  Dietary Exposure Assessment  XE "3.0  Dietary Exposure Assessment" 

Dichlobenil.  Use on Caneberry (Subgroup 13-07A), Bushberry (Subgroup
13-07B).  Summary of Analytical Chemistry and Residue Data.  PP#7E7230,
DP Num: 349398, D. Rate, 12/MAR/2008.

	3.1  Food Residue  XE "3.1  Food Residue"  

Maximum residues of BAM from dichlobenil field trials on rhubarb,
caneberry and bushberry commodities were included in the dietary
assessments.  BAM residues found in the previously submitted and
reviewed field trial studies are shown in Table 2.1 and 2.2. 

Magnitude of BAM Residues in Plants from Use of Dichlobenil

Residues of BAM in crops from dichlobenil field trials are reported in
the table below.  

Table 3.1  Proposed Uses: BAM Residues in/on Rhubarb, Blueberries, and
Blackberries from Field Trials with Dichlobenil.

Commodity	Total Applic. Rate

 (lb ai/A)	PHI (days)	Residue Levels  (ppm)

	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

Rhubarb	0.355-0.366	64-83	3	<0.01	<0.01	<0.01	NA	NA	NA

Blueberries3

(42304201)	0.355-0.361	94	3	0.04	0.06	0.014	0.011	0.012	0.002

Blackberries4

(42452803)	0.353-0.364	94	3	<0.01	<0.01	<0.01	NA	NA	NA

Raspberries

No BAM data were submitted on raspberries.  Blackberry data used to set
tolerances.

3 DP #179079, C. Olinger, 09/FEB/1993.

4 DP #182600, C. Olinger, 05/MAR/1993.

For the caneberry and bushberry crop groups, residue data on the
representative crops (blackberries and blueberries) was translated to
the respective individual crops in each crop group without additional
data (HED SOP 200.1:  Guidance for Translation of Field Trial Data from
Representative Commodities in the Crop Group Regulation to Other
Commodities in Each Crop Group/Subgroup, HED Standard Operating
Procedure (12/SEP/2000)).  

	3.2  Drinking Water Estimates  XE "3.2  Drinking Water Estimates"  

Drinking Water Assessment for the BAM (2,6-Dichlorobenzamide) Degradate
of Dichlobenil, DP Num:340773, J. Angier, Ph.D., 29/AUG/2007.

Since all of the proposed new uses are either equal to or less than all
the application rates used in the previous drinking water assessments
for dichlobenil and BAM, a new drinking water assessment was not
conducted and remains unchanged from the previous assessment.  The
estimated environmental concentrations used in the dietary exposure was
56.2 ppb from SciGrow modeling of BAM residues from dichlobenil use on
nutsedge at 10 lb ai/A.  This BAM residue level is higher than estimated
residues in surface water.

	3.3  Dietary Exposure (Food and Drinking Water)

2,6-Dichlorobenzamide (BAM) as a Metabolite of Fluopicolide and
Dichlobenil.  Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for the Section 3 Registration
Actions for Fluopicolide on Root Vegetables (Subgroup 1A), Leaves of
Root and Tuber Vegetables (Group 2), Bulb Vegetables (Group 3), and Head
and Stem Brassica (Subgroup 5A) and Section 3 Registration Actions for
Dichlobenil on Rhubarb, Caneberries (Subgroup 13A), Bushberries
(Subgroup 13B) and Associated Berry Commodities, DP Number 439722, S.
Piper and D. Rate, 10/MAR/2008.

All of the proposed new uses on dichlobenil were incorporated into the
most recent dietary assessment listed above.  The results of the
analyses are briefly described below:

Conservative acute and chronic (food and drinking water) exposure
assessments were conducted.  Maximum residues of BAM from fluopicolide
and dichlobenil field trials on food commodities with
established/pending tolerances were included in the assessment.  The
assessments used 100% crop treated except for apples, blueberries,
cherries, cranberries, peaches, pears, and raspberries.  No livestock
tolerances are established or proposed for either fluopicolide or
dichlobenil.  The acute dietary (food and drinking water) exposure to
BAM from fluopicolide and dichlobenil on established and proposed uses
is below the Agency’s level of concern for the general U.S. population
and all population subgroups.  The acute dietary exposure estimates at
the 99.9th percentile of the exposure distribution are 11% of the acute
Population Adjusted Dose (aPAD) for the general U.S. population and 28%
aPAD for all infants (<1 year old), the most highly exposed group.

The chronic dietary (food and drinking water) exposure to BAM from
fluopicolide and dichlobenil on established and proposed uses is below
the Agency’s level of concern for the general U.S. population and all
population subgroups.  The chronic dietary exposure estimates are 29%
chronic Population Adjusted Dose (cPAD) for the general U.S. population
and 93% cPAD for all infants (<1 year old), the most highly exposed
group which is of concern to HED.  See Table 3.3. 

Table 3.3.  Summary of Dietary (Food and Drinking Water) Exposure and
Risk for BAM

Population Subgroup	Acute Dietary

(99.9th Percentile)	Chronic Dietary	Cancer

	Dietary Exposure (mg/kg/day)	% aPAD	Dietary Exposure

(mg/kg/day)	% cPAD	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	0.011650	11	0.001317	29	*	*

All Infants (< 1 year old)	0.028470	28	0.004170	93	N/A	N/A

Children 1-2 years old	0.017320	17	0.002284	51

Children 3-5 years old	0.014934	12	0.001985	44

Children 6-12 years old	0.008285	7	0.001297	29

Youth 13-19 years old	0.007207	7	0.000930	21

Adults 20-49 years old	0.008394	8	0.001196	27

Adults 50+ years old	0.006591	7	0.001288	29

Females 13-49 years old	0.008495	28	0.001196	27

4.0  Residential Exposure  XE "4.0  Residential Exposure"  

BAM – Occupational Exposure/Risk Assessment of the Metabolite BAM as
Results from Proposed Uses of Dichlobenil on Rhubarb, Caneberries (Crop
SubGroup 13A) and Bushberries (Crop SubGroup 13B), DP Num: 350517, M.
Dow, 27/MAR/2008.

Occupational and Residential Risk Assessment of Metabolite BAM (to
Support Request for Registration of Fluopicolide on Brassica, Bulb
Vegetables, and Root and Tuber Vegetables),DP Num:347230, K. O’Rourke,
13/DEC/2007.

There are no residential use sites among the proposed new uses of
dichlobenil.  While it is necessary to evaluate residential exposure
from all sources of BAM, the use pattern for dichlobenil is not expected
to result in scenarios with significant residential exposure. 
Dichlobenil products are not intended for use by residential handlers. 
They may be applied by professional pest control operators (PCOs) to
soil/mulch around roses and other woody ornamentals in established
residential plantings, but not to residential lawns or turf.  Dermal and
incidental oral exposures are expected to be negligible from these
sources.  Therefore, BAM exposure estimates are based on fluopicolide
use only.

Exposure to BAM from fluopicolide uses on residential turfgrass and
recreational sites, such as golf courses, has been evaluated in an
earlier assessment (DP Num: 345920, K. O’Rourke, 09/OCT/2007); a
summary of the findings are presented in this document.

Residential handler exposure was not evaluated because the metabolite
BAM is believed to form slowly in plants and soil after the product
containing the parent (fluopicolide) has been applied.

Residential postapplication exposure via the inhalation route is
expected to be negligible; however, dermal exposure is likely for adults
and children entering treated lawns.  Toddlers may also experience
exposure via incidental non-dietary ingestion (i.e., hand-to-mouth,
object-to-mouth (turfgrass), and soil ingestion) during postapplication
activities on treated turf.  The postapplication risk assessment is
based on generic assumptions as specified by the Recommended Revisions
to the Residential SOPs and recommended approaches by HED’s Science
Advisory Council for Exposure (ExpoSAC).  Because turf transferable
residue (TTR) data were not available, turf residues were estimated
using standard assumptions (in addition to BAM surface residue data from
the metabolism studies).  

Exposure and risk estimates for residential exposure scenarios are
typically assessed for the day of application (“Day 0”) because it
is assumed that adults and toddlers could contact the lawn immediately
after application.  However, BAM is a metabolite/degradate which forms
slowly; therefore, these scenarios were assessed assuming that BAM is
present at levels which reflect high-end measurements observed in the
metabolism studies (in which sampling occurred up to 41 and 369 days
after application, for plants and soil, respectively) for “Day 0” in
order to provide a protective assessment.  

As shown in Table 4.0, the short-/intermediate-term dermal MOEs for
adults and children are 10,000 and 6,000, respectively, and the combined
incidental oral MOE for toddlers is 62,000.  These MOEs are greater than
the LOC of 100 for dermal exposure and 1,000 for incidental oral
exposure, on the day of application, and therefore, are not of concern.

Table 4.0.  Aggregate Exposure and Risk Estimates from Residential Lawns

Scenario 

and 

Pathway	

TTR/GR/SR0 (µg/cm2 or g) 1	

PDR0-norm

(mg/kg/day) 2	

Short-/ Int-Term

 MOE 3	

Total MOE 4

Short-/

Int-Term

Adult’s Scenarios

(1) Dermal Postapplication	0.0060	0.0025	10,000	N/A

Children’s Scenarios – All Postapplication

(1) Dermal 	0.0060	0.0042	6,000	N/A

(2) Hand-to-Mouth	0.0060	0.00016	87,000	62,000

(3) Mouthing Grass/Object	0.035	0.000058	240,000

	

(4) Soil Ingestion	0.81	0.0000054	2,600,000

	1 TTR=turf transferable residue on day “0"; GR=grass/object residue
on day “0"; SR0=soil residue on day “0".

2 PDR0norm=potential dose rate on day “0”.

3 MOE = NOAEL/PDR; 

	where Short-/Intermediate-term Dermal NOAEL = 25 mg/kg/day, and
Incidental Oral NOAEL = 14 mg/kg/day.

4 Total Incidental Oral MOE = 1/ [(1/MOEHand-to-Mouth) + (1/MOEGrass) +
(1/MOESoil)]

N/A = not applicable.

5.0  Aggregate Exposure  XE "5.0  Aggregate Exposure"  

	5.1  Acute Aggregate Risk  XE "5.1  Acute Aggregate Risk"  

In examining acute aggregate risk, ARIA/HED has assumed that the only
pathway of exposure relevant to the acute time frame is dietary exposure
(i.e., any non-dietary exposures are short- and/or intermediate-term in
duration).  Therefore, the acute aggregate risk is composed of exposures
to BAM residues in food and drinking water and is equivalent to the
acute dietary risk shown in Table 3.3.   As noted in that section, the
acute risk estimates are well below the Agency’s level of concern for
the general U.S. population and all population subgroups.

	

	5.2  Short- and Intermediate-Term Aggregate Risk  XE "5.2  Short- and
Intermediate-Term Aggregate Risk"  

No new short- or intermediate-term exposures are expected from the
proposed uses for dichlobenil.  Aggregate risk from previously assessed
exposures is briefly discussed below.

Short-term exposures (1 to 30 days of continuous exposure) may occur as
a result of activities on treated turf.  Incidental oral exposures
related to turf activities have been combined with chronic dietary
exposure estimates to assess short-term aggregate exposure.  Since
aggregate MOEs in Table 5.2 are greater than 1000, they represent risk
estimates that are below Agency’s level of concern.

Table 5.2.  Short-Term and Intermediate-Term Aggregate Risk Calculations

(1/MOE Approach – All LOCs Identical)

Population	Short- or Intermediate-Term Scenario

	NOAEL

mg/kg/day	LOC1 

	Max Allowable

Exposure2

mg/kg/day	Average

Food & Water

Exposure

mg/kg/day	Residential Exposure3

mg/kg/day	Aggregate MOE

(food and

residential)4

General U.S. Population	14	1000	0.014	0.001317	NA	NA

All Infants (<1 year old)	14	1000	0.014	0.004168	0.0002234	3200

Children 1-2 years old	14	1000	0.014	0.002284	0.0002234	5400

Females 13-49 years old	14	1000	0.014	0.001196	NA	NA

1 UFA  = 10x (extrapolation from animal to human (interspecies); UFH =
10x potential variation in sensitivity among members of the human
population (intraspecies); FQPA SFDB = 10x.  10 x 10 x 10 = 1000.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC = 14 mg/kg/day ÷
1000 = 0.014 mg/kg/day.

3 Aggregate MOE = [NOAEL/ (Avg Food & Water Exposure + Residential
Exposure)] 

 	

	5.3  Long-Term Aggregate Risk  XE "5.3  Long-Term Aggregate Risk"    

In examining long-term aggregate risk, ARIA/HED has assumed that the
only pathway of exposure relevant to that time frame is dietary exposure
(i.e., any non-dietary exposures are short- and/or intermediate-term in
duration).  Therefore, the long-term aggregate risk is composed of
exposures to BAM residues in food and drinking water and is equivalent
to the chronic dietary risk shown in Table 3.3.  As shown in Table 3.3,
the chronic risk estimates are below the Agency’s level of concern for
the general U.S. population and all population subgroups.

As noted above, EPA has assumed that BAM’s potential for
carcinogenicity is similar to that of dichlobenil, which is classified
as “Group C, possible human carcinogen”.  ARIA/HED are regulating at
a level that would also be protective of potential carcinogenic effects,
therefore additional quantification of cancer risk is not needed.

6.0  Cumulative Risk Assessments and Risk Characterization  XE "6.0 
Cumulative Risk Assessments and Risk Characterization"  

Unlike pesticides for which EPA has followed a cumulative risk approach
based on a common mechanism of toxicity, EPA has not made a common
mechanism of toxicity finding as to BAM and any other substances. For
the purposes of this tolerance action, therefore, EPA has not assumed
that BAM has 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 the policy statements released by EPA’s Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

7.0  Occupational Exposure  XE "7.0  Occupational Exposure"  

BAM – Occupational Exposure/Risk Assessment of the Metabolite BAM as
Results from Proposed Uses of Dichlobenil on Rhubarb, Caneberries (Crop
SubGroup 13A) and Bushberries (Crop SubGroup 13B), DP Num: 350517, M.
Dow, 27/MAR/2008.

							

	7.1 Handler Exposure and Risk  XE "7.1 Handler Exposure and Risk"  			

Due to the uncertainties regarding the rates and degrees of metabolism
from parent dichlobenil to BAM, this assessment conservatively assumes
all of parent dichlobenil is converted to BAM.  Therefore, the label
rate of application of dichlobenil is assumed to be the equivalent
amount of BAM.  

Based upon the proposed use patterns, i.e., the rates of formulation per
acre, ARIA believes the only method of application will be as a granular
broadcast application to the soil using ground equipment.  As such, the
most highly exposed occupational pesticide handlers are expected to be
loaders performing open-pour loading of granules and applicators using
open-cab tractors pulling broadcast granular spreaders.  

For such ground applications, private (i.e., grower) applicators may
perform all functions, that is, mix, load and apply the material.  The
HED ExpoSAC SOP Number 12 (29 March 2000) directs that although the same
individual may perform all those tasks, they shall be assessed
separately.  The available exposure data for combined
mixer/loader/applicator scenarios are limited in comparison to the
monitoring of these two activities separately.  These exposure scenarios
are outlined in the Pesticide Handler Exposure Database (PHED) Surrogate
Exposure Guide (August 1998).   HED has adopted a methodology to present
the exposure and risk estimates separately for the job functions in some
scenarios and to present them as combined in other cases.  Most exposure
scenarios for hand-held equipment (such as hand wands, backpack
sprayers, and push-type granular spreaders) are assessed as a combined
job function.  With these types of hand held operations, all handling
activities are assumed to be conducted by the same individual.  The
available monitoring data support this and HED presents them in this
way.  Conversely, for equipment types such as fixed-wing aircraft,
groundboom tractors, or air-blast sprayers, the applicator exposures are
assessed and presented separately from those of the mixers and loaders. 
By separating the job functions, HED determines the most appropriate
levels of personal protective equipment (PPE) for each aspect of the job
without requiring an applicator to wear unnecessary PPE that might be
required for a mixer/loader (e.g., chemical resistant gloves may only be
necessary during the pouring of a liquid formulation).  

No chemical specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).   For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for “baseline” that is, for
workers wearing a single layer of work clothing consisting of a long
sleeved shirt, long pants, shoes plus socks and no protective gloves as
well as for baseline and the use of protective gloves or other PPE as
might be necessary.   

The toxicological factors used to estimate risk from exposures to BAM
are taken from:  Occupational and Residential Risk Assessment of
Metabolite BAM (to Support Request for Registration of Fluopicolidee on
Brassica, Bulb Vegetables, and Root and Tuber Vegetables, DP Num:
347230, K. O’Rourke, 13/DEC/2007.

The Agency identified dermal toxicological endpoints for short-term
duration (1-30 days), intermediate-term duration (1-6 months) and
long-term duration (> 6 months) exposures.  The No Observable Adverse
Effect Level (NOAEL) is 25.0 mg ai/kg bw/day.  The toxic effect seen was
olfactory epithelial damage and was identified from a 5-day dermal
toxicity study in the mouse.   Since the dermal endpoints were
identified from a dermal study, there is no correction for dermal
absorption in the estimates of exposure.  A body weight of 70 kg is used
to calculate exposure.

The Agency also identified inhalation toxicological endpoints.  The
NOAEL is 3.1 mg ai/kg bw/day which caused nasal degeneration.  The
effects were identified from a 28-day inhalation study in the rat.  HED
and RD assume 100 % absorption via the inhalation route of exposure.   A
70 kg body weight is used to calculate exposure.  

BAM is formally unclassified relative to carcinogenic potential.  
However, the parent compound, dichlobenil, is classified as a “Group
C”, possible human carcinogen with the RfD approach recommended for
quantification of human risk.   Since long-term exposure is not
expected, a cancer risk assessment is not necessary.  

See Table 7.1 for a summary of exposures and risks to occupational
pesticide handlers.  

Table 7.1  Summary of Exposure & Risk for Occupational Handlers Exposed
to BAM as a Result of Applying Dichlobenil

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5	Combined

MOE6

Loader Using Open-pour Loading of Granules

Dermal:

SLNoGlove      0.0084 LC

SLWithGlove   0.0069 MC

Inhal.                0.0017 HC	6.0 lb ai/A	40 A/day	Dermal:

SLNoGlove    0.0288

SLWithGlove 0.024

Inhal.              0.00583	

870

1,040

531	

330

352

Applicator Using Open-cab Broadcast Application of Granules

Dermal:

SLNoGlove       0.0099 LC

SLWithGlove    0.0072 LC

Inhal.                 0.0012 LC	6.0 lb ai/A	40 A/day	Dermal:

SLNoGlove     0.034

SLWithGlove  0.025

Inhal.               0.00411	

735

1,000

754	

371

430

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.   Inhal. = Inhalation.  Units = mg
a.i./pound of active ingredient handled.  Data Confidence: LC = Low
Confidence, MC = Medium Confidence, HC = High Confidence.

2.  Applic. Rate. = Taken from the  IR4 Submission, Section B

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP  No. 9.1.   Science Advisory Council for
Exposure;  Revised 5 July 2000; 

4.  Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units
Treated ( Body Weight (70 kg)  

5.  MOE = Margin of Exposure = No Observable  Adverse Effect Level
(NOAEL)  ( ADD.    NOAEL = No Observable Adverse Effect Level (25 mg
a.i./kg bw/day for  dermal and 3.1 mg ai/kg bw/day for inhalation)

6.  Combined MOE = 1/(1/MOEDermal ) + (1/MOEInhalation)

A MOE of 100 is adequate to protect occupational pesticide handlers from
exposures to BAM.  Since the combined MOEs are all > 100, the proposed
uses do not exceed the Agency’s level of concern.

	7.2  Postapplication Exposure and Risk  XE "7.2  Postapplication
Exposure and Risk"  

For the proposed uses, application of dichlobenil to control perennial
weeds is recommended as a late fall soil treatment, from 15 November to
15 February.  For control of annual weeds, applications are recommended
in early spring, before 1 May.  Applications are either followed by
shallow mechanical incorporation or via "watering-in".  

Due to the recommended timing of application and to the method of
application, ARIA expects any occupational, post-application exposure to
be negligible.  Since it is a granular formulation applied essentially
during "dormant" times, foliar dislodgeable residue exposure is not
expected.  Therefore, a post-application exposure assessment was not
conducted herein.

8.0  Data Needs and Label Recommendations  XE "8.0  Data Needs and Label
Recommendations"  

	8.1	Toxicology  XE "8.1	Toxicology"    XE "8.1	Toxicology"  

None.

	8.2	Residue Chemistry  XE "8.2	Residue Chemistry"  

None

	8.3	Occupational and Residential Exposure  XE "8.3	Occupational and
Residential Exposure"   

None.

9.0  References  XE "9.0  References"  

Amended: Dichlobenil.  Use on Caneberry (Subgroup 13-07A), Bushberry
(Subgroup 13-07B).  Summary of Analytical Chemistry and Residue Data. 
PP#7E7230. DP Num: 349398, D. Rate, 11/JUN/2008.

2,6-Dichlorobenzamide (BAM) as a Metabolite of Fluopicolide and
Dichlobenil.  Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for the Section 3 Registration
Actions for Fluopicolide on Root Vegetables (Subgroup 1A), Leaves of
Root and Tuber Vegetables (Group 2), Bulb Vegetables (Group 3), and Head
and Stem Brassica (Subgroup 5A) and Section 3 Registration Actions for
Dichlobenil on Rhubarb, Caneberries (Subgroup 13A), Bushberries
(Subgroup 13B) and Associated Berry Commodities, DP Num:  439722, S.
Piper and D. Rate, 19/MAR/2008.

Drinking Water Assessment for the BAM (2,6-Dichlorobenzamide) Degradate
of Dichlobenil, DP Num: 340773, J. Angier, Ph.D., 29/AUG/2007.

Occupational and Residential Risk Assessment of Metabolite BAM (to
Support Request for Registration of Fluopicolide on Brassica, Bulb
Vegetables, and Root and Tuber Vegetables), , DP Num: 347230, K.
O’Rourke, 13/DEC/2007.

BAM – Occupational Exposure/Risk Assessment of the Metabolite BAM as
Results from Proposed Uses of Dichlobenil on Rhubarb, Caneberries (Crop
SubGroup 13A) and Bushberries (Crop SubGroup 13B), DP Num: 350517, M.
Dow, 27/MAR/2008.

Comparative Toxicity using Derek analysis for Dichlobenil, Fluopicolide
and BAM, DP Num: 352656, M. Manibusan, 12/MAY/2008.

Appendix A:  Toxicity Profile Table and Executive Summaries/Published
Abstracts   TC \l1 " Appendix A:  Toxicity Profile Table and Executive
Summaries/Published Abstracts  

Table A.1.  Acute toxicity profile for soil metabolite
2,6-dichlorobenzamide (BAM)a

Guideline No./Study Type	

MRID No.	

Results	Toxicity Category

870.1100/Acute oral toxicity (mouse)	42940201	

1538/1144 mg/kg (M/F)	III

a According to Reregistration Eligibility Decision (1998)

Table A.2.  SUBCHRONIC, CHRONIC, AND GENO- TOXICITY PROFILE FOR
METABOLITE, 2,6-DICHLOROBENZAMIDE (BAM)

Guideline No./

Study Type	

MRID No. (Year)/Doses/ Classification	

Results

870.3100

90-day oral (rat; dietary)

	

00067654 (1967)

0, 50, 180, 600, or 2300 ppm (equal to 0, 4, 14, 49, or 172 mg/kg/day)

Acceptable/Guideline	

NOAEL = 14 mg/kg/day 

LOAEL = 49 mg/kg/day based on decreased body weight gain (M) and reduced
skeletal muscle tone (M&F).

870.3150

90-day oral (dog; dietary)

	

00067655 (1967)

0, 100, 300, or 2000 ppm (equal to 0, 7.5, 22.5, or 150 mg/kg/day)

Unacceptable/Guideline due to parasitic infections (ascariasis) in most
animals	

NOAEL = 22.5 mg/kg/day  

LOAEL = 150 mg/kg/day based on clinical signs (thin appearance, dull
coat, hair loss) and increased liver weight and serum alkaline
phosphatase concentrations (F) and clinical signs (thin appearance, dull
coat, hair loss) (M).

870.4700

Chronic toxicity oral (dogs; dietary)

	

42940203 (1971)

0, 60, 100, 180, or 500 ppm (equal to 0, 1.5, 2.5, 4.5, or 12.5
mg/kg/day) 

Acceptable/Guideline	

NOAEL = 4.5 mg/kg/day 

LOAEL = 12.5 mg/kg/day based on decreased body weight and body weight
gain.

870.4300

Combined Chronic Toxicity/ Carcinogenicity oral (rat; dietary)

	

42940202 (1971), 44043601 (1996), 44052901 (1996)

0, 60, 100, 180, or 500 ppm [equal to 0, 2.2/2.8, 3.6/4.7, 6.5/8.5, or
19/25 mg/kg/day (M/F)]

Acceptable/Guideline	

NOAEL = 6.5 (M) and 4.7 mg/kg/day (F)

LOAEL = 19 mg/kg/day (M) and 8.5 mg/kg/day (F) based on decreased body
weight and body weight gain (≥ week 26) and an increased incidence of
hepatocellular alteration (eosinophilic foci).

Borderline statistically significant (P=0.049) increased incidence of
hepatocellular adenomas at 25 mg/kg/day (F only); dosing considered
adequate (M&F).

870.3700

Developmental toxicity oral (rabbit; gavage)

	

43003601 (1986), 43265201 (1994)

0, 10, 30, or 90 mg/kg/day

Acceptable/Guideline	

Maternal NOAEL= 30 mg/kg/day

Maternal LOAEL= 90 mg/kg/day based on increased incidences of clinical
signs (late abortion, thin appearance) and decreased (severe) body
weight gain and food consumption during dosing.

Developmental NOAEL = 30 mg/kg/day 

Developmental LOAEL = 90 mg/kg/day based on increased 

incidences of late abortion and skeletal (bipartite interparietal 

bone) and visceral (postcaval lung lobe agenesis) anomalies.

870.3800

3-generation reproduction oral (rat; dietary)

	42940204 (1971)

0, 60, 100, or 180 ppm (equivalent 0, 4.5, 7.5, or 13.5 mg/kg/day) 

Unacceptable/Guideline due to lack of individual animal data	Parental
NOAEL = 13.5 mg/kg/day

Parental LOAEL was not observed. 

Reproductive NOAEL = 13.5 mg/kg/day

Reproductive LOAEL was not observed.

Offspring NOAEL = 13.5 mg/kg/day

Offspring LOAEL was not observed.

Non-guideline (literature)

Adult mouse olfactory study (single injection; i.p.)	Brittebo et al.
(1991); no MRID

0, 25, 50, or 100 mg/kg/day (i.p.)

f (PAS) staining of contents of Bowman’s glands (measure of mucus
production) observed at ≥25 mg/kg/day (reversible); degeneration of
olfactory epithelium and necrosis of Bowman’s glands observed at 100
mg/kg/day (sustained).

870.5100

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瑹端a咊

3everse mutation (Ames test)	

43003603 (1992)

At concentrations up to 5000 g/plate (-/+ activation) in S.
typhimurium

Acceptable/Guideline	

Negative with or without activation.

870.5395

In vivo mouse erythrocyte micronucleus assay	

43003602 (1993), 43747101 (1995)

0, 250 mg/kg 

Acceptable/Guideline	

Negative.  

Lethargy observed in dose-range finding (pilot) study at 100 mg/kg/day
(=LOAEL; NOAEL not observed); clinical signs worsened with increasing
dose.

870.5550

 h

	g/ml

Acceptable/Guideline	

Negative.

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