Cc. i dpoints in Hazard ification Process

Toxicology endpoint selection is based on the NOELs and LOELs established in the Data Evaluation
Records (DERs) prepared for each study. Examples of appropriate endpoints used for establishing
the NOELs/LOELs may include the following:

1. Acute Neur: ‘otoxicity Battery.
> Mortality

> Clinical signs indicative of neurotoxicity including cholinergic signs either in the presence or
absence of cholinesterase inhibition :

» Cholinesterase inhibition

» FOB and/or motor activity measurements evaluated at the estimated time of peak effect Gi €.,-
within 8 hours of dosing).

> Histopathological findings

> Other non-neurotoxic but biologically significant findings (i.e., systemic and/or biochemical
effects)

2, Developmental Toxicity Studies - The use of developriiental studies in the TES process often .
assumes that toxic effects could result from exposure to a single dose. ‘Consequently, decisions:
conceming the appropriateness of endpoints for acute hazard identification from these studies

must Be baséd on professional judgement,

» Matemal toxicity, characterized as deaths, clinical: signs (e.g., cholinesterase inhibition,
neurotgxic/cholinergic clinical signs) are appropriate if the possibility that these effects
occurred after a single dose can not be discounted. -

» Developmental toxicity, characterized as deaths (embryonic/ fetal resorptions, fotal/ pup ©
deaths, post implantation loss), fetal/pup body weight decrements, and permanent alterations
(malformations or visceral and skeletal variations), are appropriate if the positility that these

. effects occurred after a single dose can not be discounted. .

Other factors considered in the selection of developmental toxicity endpoints include:

> Developmental toxicity observed at maternally toxic or excessive doses generally lessens
concem that effects could result from a single dose

> Developmental toxicity observed in the absence of maternal toxicity Beneraly increases
_ * concer that effects could result from asingle dose e

> Slope of the dose-response curve ~ : =

«
a

16



c 1 Dev. ental Toxi L

These studies are relevant ONLY when:
(1) Dermal toxicity studies are not available to ascertain toxicity via this route;

(2) No sygtemic or dermal toxicity is seen in the 2lor 90-day dermal toxicity studies but
developmental toxicity studies indicate'a concem for developmental toxicity in the
absence of matemal toxicity (since developmental parameters are not examined in the
dermal studies); :

(3) The nature and severity of the developmental toxicity observed across species ate of
concem or multiple observations of developmental toxicity (which constitute a
syndrome) were observed in a single or multiple species; and/or

(4) Using the NOEL ‘rom the developmental toxicity studies would increase the
_ protection against potential adverse effects on the developing fetuses as well as the’
general population.

d, The 2-Generation Reproduction Study (dietary):

The period of dosing ( 70 days prior to mating) represents exposure of intermediate duration;
the route of exposure, however, is oral. Therefore, this study should be used only when the,
areal (syniemc) repreacive or eal tricity any hg minor concer and ate the cst e
appropriate cndpoint for inermedietpterm hazard identification. we

» ¢ Lons-Térm Studies (ora.

When a relevant study’ sats appropriate for the intermediate term exposure periods
‘unavailable, then the interim data from the long-tenm studies may be used. However,thé:
data should be included as a part of the overall evaluation of subchronic effects when .
-the wed -of-the-evidénce evaluation is condubted.‘These data may provide a broader date ’.” :
"base fix valnation OF appropriate endpols nd hosted Ven ation for insect tem :

In identifying hazards for Intermediate-Term risk assessment, critical endpoints and considerations

: are similar to those that are currently used in establishing e NOEL/LOEL in any toxicity study.
Generally, a weight-of-the-evidence approach should be used in which appropriate endpoints from -
all available 90-day studies are considered together. Considerations would include the similarity of ~ -
effects among species, time course of development of effects (if this can be determined from the
studies), and similarity or differences in effect levels among species. The dose identified for . ~

_ intermediate-term risk assessment should not be higher than the dose selected for short-term risk
assessment. If the dose identified i is from an oral study, then a dermal absorption factor (estimated, :)
not known) must be used.

em

10°:





1, BACKGROUND

The Office of Pesticide Programs (QPP), has historically, focused on comprehensive risk assessment for
chronic dietary [Reference Dose (R{D)] exposure, or for endpoints based on cancer, developmental or
reproductive hazards. During the re-registration process, it became apparent that there were pesticide
uses and exposures other than dietary which needed to be addressed. Therefore, the decision was made
to perform comprehensive risk assessments for acute dietary as well as occupational and residential -
exposures. In order to accomplish this, based on the use pattern, several exposure scenarios have been.
developed and the toxicology data base is systematically evaluated for hazard identification for the
various exposure scenariog. For hazard identification, the toxicology endpoint selection (TES)] entails.
identification of doses and endpoints from appropriate toxicological studies that most closely matched
the route and duration of exposure for which a risk assessment is required. Hazard identification is
accomplished at the Health Effects Division's Hazard Identification Assessment Review Committee
(HIARC) meetings.

Exposure scenarios evaluated by the HIARC are divided into dietary and non-dietary, the latter of which
is then subdivided by duration and route of exposure. Acute Dietary refers to a one day or 24 hour -
dietary exposure and Chronic Dietary refers to life-time dietary exposure. Non-dietary exposures ~
include Occupational or Residential Exposures via the dermal and inhalation routes that are divided
into three time periods: a Short-Term exposure period of 1 to 7 days; an Intermediate-Term exposure

. period with a duration of 7-days to several months; and a Long-Term exposure period covering a
substantial portion of the life time (i.e., several months to life-time).

Occupational and residential exposure involves three categories of exposed individuals: 1) pesticide
handlers, which includes those who mix, load and apply pesticides in their work; 2) reentry workers,
which includes agricultural workers who reenter treated fields or greenhouses to harvest crops or ” :
undertake.any other work in a treated area; and fon-agricultural workers whose work area is treated with ©
’ pesticides; and 3) individuals who are exposed at home or in the workplace to pesticides applied by :
themselves, family members, or professional applicators. :

This guidance dcouinent describes the procedure ujed in toxicology’ sadpcins selection fx te nid
chronic dietary, as well as occupational and-residential risk assessments:. ‘For each exposure scenario, . ~
guidance is provided for: 1) evaluation of toxicity studies that are relevant for use ({.e., route and =, ~
duration of the study being similar to the exposure duration of interest); 2) selection of appropriate...
endpoints for hazard identification (i.e., doses and, endpoints that best define the potential hazard in“: ~ -
+ association with the exposure scenario); 3) the process for hazard identification (ie, use ofa weight of-
evidence type approach in which all available studies are considered together as opposed to the results of
a single study); 4) the influence of dermal absorption in hazard identification; 5) the criteria for the use
of NOEL, LOEL, and the appropriate endpoints i in the hazard identification Process; and 2) the use of
MOEs i in risk assessments.



» Developmental toxicity observed across species or the effects are clearly dose-related

> Multiple observations of developmental toxicity (which constitute a syndrome) observed in a
single or multiple species

> Developmentalendpoints are not appropriate if equivocal or marginal developmental toxicity
occurted only at the highest dose tested, were seen only in one species and were not
accompanied by any other developmental effects.

3. 21-Day Dermal Toxicity Study

» Mortality

» Decreases in body weight gain and/or food consumption

> Clinical and/or cholinergic signs indicative of neurotoxicity
» Cholinesterase inhibition

» Systemic toxicity

4, 90-D: dies

> Neurotoxicity (e.g., clini¢al/cholinergic ‘ signs, ChEI, FOB, motor ractivity) =

+ Systemic toxicity (e.g., mortality, body weight changes, alterations i in clinical pathology
parameters, changes i in organ weights)

» Gross and/or histopathological lesions

5. 2-Genefation Reproduction Study:

> Reproductive aind fertility parameters of both sexes

» Systemic toxicity (e.g., mortality, clinical signs, body weight and food consumption, and *
organ weight changes) of parental animals of either generation

»  Alternations in reproductive parameters (conception rate, number of corpora lutea etc.)

v

Offspring data (e.g., number of pups born, pup ‘viability, body weight changes, gross
abnormalities)

> Reproductive organ toxicity (e.g., changes in the weights of the testis, prostate, seminal
vesicle and epididymis, and ovaries

v

Histopathological lesions of the testis, prostate, seminal vesicle, vas déferens, epididymis,

17



IX. REFERENCES.

Bames, D.G., and Dourson, M. 1988. Reference Dose (R£D): Description and Use in Health Risk
Assessments. Regulatory Toxicology and Pharmacology 8:471-486. ‘

Engler, R. 1994. Guidance Document and Process Statement for Less Than Lifetime Hazard
Assessment. Memorandum. R. Engler, January 10, 1994.
A ‘

e . :
Makris, S., and Rowe, J. 1994. Acute Risk Assessment Policy For Developmental Effects Observed in
the Presence or Absence of Maternal Toxicity. - Memorandum: S. Makris and J. Rowe, Health Effects
Division, Office of Pesticides Program. November 21, 1994.

U.S.Environmental Protection Agency. 1986. Guidelines for the Health Assessment of Suspected
Developmental Toxicants. Fed. Reg.. 51:34028-34040. . :

U.S. Environmental Protection Agency. 1991 Gudielines for Developmental Toxicity Risk Assessment. .
Fed. Reg. 56:63798-63826. . . _

Whalan, J and Pettigrew, 1998. DRAFT: Inhalation Risk Assessments and the Combining of ‘Margin of

Exposures. John Whalan and Hugh Pettigrew, Health Effects Division, Office of Pesticide Programs,
March 6, 1998. . :

19

ee



‘Step Il: | Combine the converted oral equivalent doses to obtain total exposure via these rout
(inhalation and dermal).” of

Step I: Compare the combined dose to the oral NOELs for the appropriate exposure period (i.e.,
Short-, Intermediate-, or Long-Term).

Vv. THE INFLUENCE OF DERMAL ABSORPTION IN RISK ASSESSMENT.

Dermal absorption is a significant factor in occupational or residential exposure risk assessments since
these exposures occur most frequently via the dermal route. Under the current toxicology data :
requirements, often data are not available to perform the route-specific risk assessment due to’'the lack of
either dermal absorption data or appropriate dermial studies. One of the greatest difficulties encountered
by the Committee is the task of estimating the proportion of the pesticide that is absorbed through the
_ skin: Dermal absorption is critical especially when the hazard identified is from an oral study in which
_the experimental conditions (oral dosing) do not simulate the real-life exposure (dermal) scenario.
‘Therefore, a correction must be made for this differerice in absorption rates (i.c., oral vs. dermal). This’.
can be accomplished by the use of a dermal absorption factor to adjust (correct) oral (systemic)
absorption to potential derma! absorption. This correction should be described as an additional .
uncertainty in the final risk assessment. In determining dermal absorption, the Committee considers the
weight-of-evidence approach including dermal absorption studies as well as comparison of the dermal
and oral studies as discussed below. *

When dermal absorption data are avilable, caution sustbe exercised a to what dermal absorption @
value to use. Some factors that effect percent dermal absorption include; application site; the type:and ” ue
amount of vehicle used; total tie of application; total dose applied; and the disnibution of the: wl

-admitiistered dose'(e,g., quantity in skin wash and.on ‘the protective cover; L
the washed skin, material in selected organs, iftcollected,-and the residue. in the carcass); ‘When dermal *
absorption studies are available, the Committee reviews the data and selects the dermal absonjtion value» - :
(Percent) reported for a 8-10 hour period, the time petiod that reflects an average wore day forthe. pet
pesticide handlers {mmixer/loader/applicator). ; : :

"When dermal absorption data are not avilable, the Commits extirnies dermal dbsdrption by: he
comparing the DEL eased ntsc nd deroal aus nthe sane pects) evaleting (on 8 :
-- ease by case basis) the physical nature of'the pesticide (.e., granular, Powdenetc}; and 3) examining the"

"similarity of the concemed pesticide to other chemicals or classes of chéinical compounds. ‘When ”

neither the appropriate LOELs and/or data on the pesticide nor structurally related chemicals are -
‘available (i.¢., asa default), the Committee will assume 100% dermal absorption (alikely overestimate).

When a dermal absorption factor is estimated by comparing the appropriate LOELs, the Committee
relies on oral and dermal studies conducted in the sane species. When such data are available, the
Committee will compare: 1) the LOEL from a 90- feeding study in rats to that of the LOEL éstablished
in the 90-day dermal study in rats, 2).the maternal or developmental LOEL (as the case may be) from a
developmental study in rabbits to the LOEL in a 21-day or 90-day dermal toxicity study in rabbits, 3) the ©
LOEL from the acute neurotoxicity study in rats to the LOEL in the 21-day or 90-day dermal toxicity
study in rats, or 4) the LOEL from a reproductive study to the LOEL established in the Uday or 90-da:

derma! toxicity study, and so on. ,
¢: -

on 14



Ill. OCCUPATIONAL OR RESIDENTIAL EXPOSURE RISK ASSESSMENTS
A. SHORT-TERM DERMAL RISK ASSESSMENT
1. Objective \

The objective is to identify Short-Term hazard based on the toxic effects observed in studies -
where the treatment conditions in experimental animals are similar to the route (dermal) and
duration (1-7 days) of human-exposure.

a .
2. Relevant Studies for Short-Term Dermal Hazard Identification Process

The guideline study that is most directly applicable to this route (dermal) and exposure period of
concer (1-7days), is the 21-day dermal toxicity study. In the absence ofa 21-daydermal —.
toxicity study or other dermal studies, toxicity studies in which the route of administration is oral _
may be used for short-term hazard identification. If an oral study is used’for dermal exposure risk -
assessment, the magnitude of dermal absorption must be ascertained and a dermal absorption
factor must be identified for route-to-route extrapolation. The procedure for identifying the

dermal absorption factor is discussed in detail in Section V.

In general, a Short- Term dermal exposure risk assessment will not be necessary if no systemic
. toxicity was seen at the Limit-dose (1000 mg/kg/day) i in the 21-day dermal study. However, if.

. the toxicity profile of the pesticide indicates serious concems for toxicological effects not
evaluated in-the 21-day study (e.g,, neurological or developmental effects), then a weight-of-
evidence approach must be used in which all available studies (oral and dermal) are considered
concomitantly: for endpoint selection. _ - oc, . . t )

Studies that are considered tobe mos eutable fo this sk astsoment ere:

a. 21-day Dermal Toxicity Study :

This study infts of rabbits (682-2) is pertinent because 1) the experimental eqntions me
(derma! applications) simulate human dermal exposure ‘Gepending onthe intended pesiie
_ formulgtion’and use scenario, and 2) the treatment period (6 hours/day, 5 days/week for -
weeks), although longer, socs encompass the expose pesiod of conser (2 1-7 days). ©

These studies (§83-30) are considered to be appropriate when:

(1).A 21-day dermal toxicity study i is not available:

(2)Ne systemic toxicity is seen in the availble 21-day study but data from the . :
- deyelopmental toxicity studies indicate a serious concern for developmental effects in the =:

absence of maternal toxicity. Thus, the concer for the developmental effects outiveighs

the lack of adverse effects in the dermal study since the dermal studies do not evaluate

parameters that characterize developmental toxicity endpoints;

chon
a



evaluated: 1) type and degree of neurotoxicological effects.observed; 2) time of occurrence of
these effects; 3) doge-response curves; 4)similarity and/or differences in toxicity between the
Sexes; and 5) the appropriateness of the NOEL/LOEL established,

If the acute endpoint identified is froma developmental toxicity study, (based on either maternal
or developmental effects), a determination is made if these, are in fact potentially manifested
after a single or (at most) after very few doses and when these effects are of the greatest concer.
Also, results of the developmental toxicity studies are compared for any similarity or differences
in the observed toxicity between Pecies. Acute hazards may also be identified by extrapolating
data from subchronic or chronic toxicity studies if the hazard is identified early in the study.

4 rd Identification For V; Population $s

The HED Dietary Risk Evaluation System (RES) contains food consumption data for U.S
Populaiton and 22 subpopulaito and can Provide acute dietary tisk assessments for various
‘subpopulations such as Females 13 + years, pregnant, Nursing infants, Non-nursing infants,
Children 1-6 years old and 7-12 years old, Males, 13-19 years, Males 10 years and older,
Females 13-19 years, and Females 20-years and older... oo .

. ‘identification (i¢., endpoints selection} » therefore, must be Pertinent to these population
" subgroups in establishing the acute RID.. ee :

When the endpoint selected is from an acite neutotoxicity study (e.g., cholinergic signs,“ .-". . .
. cholinesterase inhibition, behavioral alterations and/or neuropathology), or from subchronic or

chronic toxicity studies (¢.g.,; toxicity attributable eatly expsoure), it is appropriate for all’:
- Population subgroups (i.e, Females 13+ as well as the General Population which includes ‘infants

On the other hand, when a developmental endpoint is selected from one of the developmental
toxicity studies (rats/rabbits), it is appropriate only for Females 13+ because: 1) the.
developmental effects are in utero effects (i.e., occurs only during Pregnancy) and thus .
applicable only to females of childbearing age; 2) developmental effects are not relevant for adult
" males; and 3) the effects can not Ocour postnatally and therefore not applicable to infants and
children. The acute R£D established ona developmental endpoint should be used for acute
dietary risk assessment only for females of child bearing age (i.e, Females 13 +

Aen



Il. DIETARY RISK ASSESSMENT o.
A. ACUTE REFERENCE DOSE (ACUTE RFD)

1. Objective

The objective is to identify acute hazard (dose and endpoint) based on the toxic effects observed
in a study following a single oral exposure (dose) of the pesticide to establish ani Acute Reference

Dose (Acute RD).
2. Relevant Studi ies for Acut 1. Hazard Identification

-a, Acute Neurotoxicity Study in Rats

This study (§81-8) is pertinent because: 1) animals receive a single oral dose and therefore all
toxicological effects can be attributed to that one dose and 2) the use of three dose levels
yields a NOEL that can be used in risk assessments. This study, however, is not-available in
the existing database for most of the pesticides. :

b. Prenatal Developmental Toxicity Studies

‘ _ The use of the prenatal developmental toxicity studies (§83-3a,b) for acute hazard
identification process presumes that the developmental effects could result from exposure to’
a single dose (US EPA, 1986b, 1991). The cells, tissues and organ systems are part of an
ever-changing environment in a developing animal. An adverse effect is likely to occur when. -
an exposure of sufficient magnitude occurrs during a critical period of fetal development. ®
- and/or of a particular organ system: The nature of the critical period to a'large extent defines
the exposure-conditions such as the dose, duration and frequency, necessary. to result in an ‘:
. valtered development. Consequently, decisions concerning the appropriateniess of endpoints *
-from these studies must be based on professional judgement. The prenatal developmental ”
toxicity studies) are relevant because: 1) the treatment route is oral; 2) a single dose ofa’.
. Substance, administered at a critical point in the development of the organism, can elicit .
developmental effects and 3) frequcaly tis possible to ascertain the relationship between the
day of gosing and the manifestation of the maternal or developmental effects. It is noted, *”:
a Ca ccna aernal Pend consists of repented dosing (2 days for ets and 1 for ‘
Tabbits) to pregnant animals. yy :

©. Other Studies

-The subchronic, chronic, or reproductive janie or carcinogenicity studies | (conducted via
the oral route) ma Us ; a

- during the first few days of the treatment and therefore are appropriate for extrapolation. ~

° Human data when there is information on the exposure levels associated with an appropriate
endpojnt.. The human data, when available, are given first priority, with the animal toxicity
studies serving to complement them. : .



When oral and dermal studies are not available in the same species (i.e., appropriate LOELs), the
Committee will make a comparison of the acute oral and dermal LD,, values to gain some "knowledge"
on dermal absorption. This comparison, however, is less reliable because of the ambiguous nature of the
measurement. If an attempt is made to use the LD,, values, the nature of toxic response (other than .
death) must be evaluated, and more than one dose level should be available. In other words, single dose
studies or Limit-Dose studiés are not used in such comparisons.

When data are available on the physical-chemical properties of the pesticide or on structurally related
compounds, the Committee will use these data in estimating dermal absorption. For example, for one of"
the pyrethroids, the Committee estimated a dermal absorption value of 50% based on the physical and”
chemical nature as well as the similarity of the dermal absorption data for this class of chemical
compounds.

The Committee, in estimating a dermal absorption factor, will routinely use the weight-of-evidence
approach which considers all of the options discussed above. However, the Committee will assume
100% dermal absorption as a default when: 1) there is a concern for high occupational or residential
dermal exposure; 2) an oral study was used for hazard identification; and 3) there is low confidence in
the studies as well as the data available for estimating a dermal absorption factor or in the estimation
itself. Although the 100% default is in most cases an overestimation of exposure, no better default has
been identified. .

VI. THE USE OF NOELs, LOELs AND ENDPOINTS IN TES PROCESS.

The dose identified for calculating the Margins of Exposure (MOE) for the-various s bxposue scénarios is
usually the NOEL (sometime LOEL) established in the appropriate study. Identification of the dose is “~~

based, not on the restilts of a single isolated study, but upon the entire data base using a weight-of-the-
evidence approach. The criteria for use of the NOEL or the LOEL are discussed below.

A. No Observed Effect Level (NOEL) ~

A dos€ should not be selected routinely by default simply because it is the NOEL. The entire dose
response curve should be reviewed to determine how the NOEL relates to the dose at which effects’

actually begin to appear (i.c., the LOEL), Similarly, the toxicology endpoint with the lowest NOEL

should not be automatically selected because that endpoint may not be relevant to the exposure
scenario under consideration.'In some cases, data from two studies may be considered-together to
determine the most appropriate NOEL.

B. Lowest Observed Effect Level (LOEL)

The LOEL is not routinely used in risk assessments because it is identified as the lowest dose in the

study where treatment related effects actually begin to appear. However, a LOEL may be used ifa

NOEL is not established in the critical study, when severity of the effects observed at this dose is of

negligible concern for human risk, or when there is a data gap. Therefore, when a LOEL is

identified for risk assessment, additional modifying factors (range of 3 to 10) may be used in

addition to the total Uncertainty Factor of 100 (i.c., 10 for intra- and 10 for inter-species variation).
& .

15



- evaluated fr the following: , andop
Monitoring data; 3) sufficiently long period of exposure to or health effects observed: 4)

adequate control for confounding factors; and 5) appropriateness of Statistical tests used. -
Once the critical study demonstrating the toxic effect of concem has ‘been: identified, the selection
of the endpoint and dose (usually the NOEL but some times LOEL) results from an objective

one



HAZARD IDENTIFICATION -

TOXICOLOGY ENDPOINT SELECTION PROCESS

'” AGUIDANCE DOCUMENT

’ ” Prepared By: _

Jess Rowland
- - Executive Secretary
.« Hazard Identification Assessment Review Committee
: Health Effects Division
Office of Pesticide Programs
August 11, 1998



When a 21-day dermal toxicity study is available and an appropriate endpoint is identified fropae.
this study, then a determination is made on the: 1) type and degree of toxicity observed; 2) { )
relationship between the day of dosing and the manifestation of toxic effects during the first

week of the study; 3) dose-and time-response curves; 4) toxicity between the sexes; 5) ~
relationship between dermal and systemic toxicity; 6) significance of dermal absorption; and 7)
the appropriateness of the NOEL/LOEL established.

When a 21-day atrmal toxicity study is available and: 1) no systemic toxicity is seen; or 2) the
effects seen are not appropriate for this exposure period (1-7 days)of concem (i.e., body weigh
gain depression, alterations in hematological or clinical chemistry parameters measured only at
termination, and/or histopathological lesions, etc.) and 3) the endpoint is not appropriate for

. making regulatory decisions (.g., piloerection, etc), then this study should not be used in hazard
identification.

When a 21-day. dermal toxicity study is available but the toxicity profile of the pesticide indicates
a. potential for neurotoxicity concems via the oral route, then the dermal study should be -
examined to determine wheather neurotoxicity parameters were evaluated. If they were not
evaluated, then this. study must be considered concomitantly with the acute neurotoxicity study.
The toxicity observed in both these studies (oral and dermal) will be evaluated to ascertain the
influence of dermal absorption as well as the relevancy of the effects based on the routes = (oral vs.
dermal) of administrations.

When a 21-day dermal study is available but 1) either no systemic toxicity is seen, of 2) the
systemic toxicity seen does not reflect the toxicity profile of the pesticide (such as potential for @
developmental effects of concem), or 3) a developmental endpoint was used for establishing an
acute R£D, then this study may not be appropriate for this risk assessment. Under these * :
conditions, the:21-day dermial study is not appropriate for this risk assessment because: 4) of the

_ concer for the fetal effects seen;.2) developmental effects are considered to be appropriate for
this exposure period of concem; 3) fetal pardmeters are not evaluated in the dermal toxicity study
(not a Guideline requirement) and these adverse effects can not be determined for the dermal |

: Foun of pour ad 4) the'cudpoint wil provide edequate protein for regnatt workers.

” Under conditions, the developmental endpoint should be selected for this (dermal) risk
assessment along with a dermal absorption factor for route-to-route extrapolation. . “ *

When a21-day dermal toxicity study is not dvaiabl, endpoint selection is dependent on oral 2
toxicity-(prenatal developmental and/or acute neurotoxicity) studies. Under certain * : >
_ circumstances extrapolation from range-finding, subchronic, or chronic studies are acceptable if
the treatment related effects appear early in the study (i.e. 1-7.days). Barly expression of effects
would include, but are not limited to, -cage side observations and interim clinical pathology data.
Endpoints observed during the early part of the study are also appropriate for extrapolation to’.
Short-Term exposures. However, late appearing effects are not sppropriae for extrapolation to
short-term exposures. :

es



(3) The relationship between the day of dosing and the manifestation of systemic toxicity
can be ascertained in these studies since clinical observations are made throughout dosing

period (9 days in rats and 15 in rabbits) making toxicity data available and comparable
for the 1-7 day period;

(4) The nature and severity of the developmental effects observed across species are of
concern or multiple observations of developmental toxicity (which constitute a
syndromte) were observed in a single or multiple species; and/or

(5) Using the NOEL from the developmental toxicity study would increase the protection
against potential adverse effects on the developing fetuses as well as the general
population.

c. Acute Neurotoxicity Battery (oral)
This study (§81-8) is suitable when:
(1) There i is a concem for neurotoxicological effects and/or

(2) The NOEL for acute neurotoxicity or other endpoints i is lower than that for.
developmental toxicity or any other Short-Term endpoint

a. Other Studies" . ;

Range-finding Gf available), subchroaie (oral or dermal), chronic and/or reproductive toxicity -
(oral) studies may be used if treatment-related toxic effects appear early and are mast : ‘
‘ appropriate to extrapolate for short-term exposures: Endpoints that can be used from these
‘Studies include effects that appear to occur-early in the study (i.¢., within 1-7 days). This -
extrapolation from. long-term studies for'short-term hazard identification is valid only if the ~:
"endpoints are established early in the study aid aré thus most appropriate to extrapolate to .
Sect te ea Early indications of effects in subchronic studies might include, but
are not'limited to, cage-side observations, hematology (¢.g,, anemia), clinical: chemistry

(indicate development of abnormal pathology) and histopathology {pre-tieoplastic lesions). °
data. ‘Body weight data from dietary Studies are not appropriate due to palatability problems.- :
Rody weight data from oral (gavage), dermal and inhalation studies aré appropriate as an.
indicators of early animal stress. Therefore, extrapolation from subchronic studies as.-
opposed to chronic studies may yield a higher confidence in selecting an endpoint for this —
exposure period. On the other hand, cases iri which effects appear late (i, €., after several
months) are not appropriate for hazard identification for’ short. term tisk assessment.

Toxicology endpoint selection should be made using toxicity data‘generated by the same route as
~ the likely exposure (i.e., dermal). Therefore, in identifying the Short-Term enpdoints, the
‘primary preference should be.the 21-day dermal toxicity study,



Therefore, when a developmental endpoint is selected, another endpoint (ie., a "non-
developmental) MUSTt be selected for the General Population (i.e, adult males, infants and
children). This can be accomplished by evaluating the maternal toxicity observed in the’
developmental toxicity study that was used for Females 13+, or the acute neurotoxicity study, e
and/other oral toxicity studies. For example, if maternal toxicity (e.g., clinical signs, abortions, body
weight loss in early dosing period, etc.) is attributable to a single exposure, it can be used for acute
hazard identification for the General Population. Even though the endpoint identified is maternal
toxicity and occurrs.in pregnant animals, it is appropriate for use for the General Population because
effects are seen in the most sensitive population (i-e., pregnant animals) and thus (the matemal
NOEL) would be protedtive of potential adverse effects on the developing fetuses as well as the
general population. This acute R£D should be used for acute dietary risk assessments for the General
Population including infants and children. |

"When it is not possible to identify a dose and endpoint (i.e., a "non-developmental endpoint")
attributable to a single exposure from any of the available oral toxicity studies, then a determination
is made that no toxicological effects attributable to a single exposure (dose) were observed in oral
toxicity studies. Thus an acute R£D can not be established and ‘an acute dietary risk assessment t will
not be required for the General Population.

B. CHRONIC DIETARY RISK ASSESSMENT (CHRONIC RID)
1, Objective
The objective is to identify chronic hazard (dose and endpoint) based on the toxic effects

observed in a study following repeated oral exposure {Gose) of the pesticide to establish an
Chronic Reference Dose (Chronic R&D). - . &@&

2 Relevant Studies for Chronie Hazard Mdentiiation
"a, Chronic Toxicity Study in Dogs (§ 83-1). -
b. Chronic Toxicity/Carcinogenicity Study in Rats 83-5)
_ Carginogenicity Study in Mice (§83-2)
od. ‘Two-Generation Reproduction Study in Rats (§83-4)

e. Human Data -



vagina, cervix, uterus, fallopian tubes and ovaries as well as the adrenal and pituitary glands,

(both sexes) @

> Other data, such as semen analysis, accessory cell function (testosterone levels secreted by
Leydig cells), and hormonal status [follicle-stimulating hormone (FSH) and luteiriizing
hormone (LH)], when available.

y
6. Long-Term Toxicity Studies

> The selection of appropriate endpoints for long-term hazard identification are essentially
identical to those currently used in establishing the RED such as neurotoxicity (e.g.,
cholinergic signs, ChEI, FOB and motor activity, histopathology), systemic toxicity (e.g.,
changes in body weight and body weight gains, food consumption, clinical pathology
parameters, organ weights, and gross as well as.histopathological lesions), and evidence of -
chronic toxicity or carcinogenicity or other significant toxic effects te. g., target organ
toxicity).

VI. APPLICATION OF THE TOXICOLOGY ENDPOINT SELECTION IN IN RISK
ASSESSMENTS

The dose and endpoints selected in the TES process for the various exposure scenarios are used to

characterize risks. Risk characterization is the discussion of the strengths, weaknesses, uncertainties
assumptions that are part of risk assessment. Risk assessment generally involves the integration of :
on hazard identification, dose response evaluations and exposure assessment to determiné the likelihood © -
that humans will experience any of the various forms of toxicity associated with a, pesticide.: The results
of risk characterization and risk assessment are used by the Agency to support regulatory actions. .

,

he

18





sO talon om derma sn ira nt nse a The urea orisology.

When studies with appropriate duration, species and route are available, selection of dose and
endpoint should include a comparison of results across studies. Points for considerations include,
but are not limited to: 1) whether the effect occurs in multiple species, 2) if the effect is route
specific,.3) time of onset (if it can be determined), and 4) the nature of the dose-response in different
studies. Hazard identification from developmental or reproductive toxicity studies are relevant if the
pesticide has shown the potential to be a developmental or reproductive toxicant and if the dose
identified from these gttdies will increase the protection against potential developmental or

-reproductive effects on the developing fetus as well as the general population. .

Comparison should be made to other subchronic studies or to interim data from long-term studies to
evaluate any potential discrepancy between the various data sets. Interim data should be included as
a part of the overall evaluation of subchronic effects when the weight-of-the-evidence evaluation is
conducted, These data may provide a broader data base for evaluation of the appropriate endpoints.
Increase in severity of a toxic response can be evaluated by comparing the NOELs/LOELs from the
chronic and subchronic studies. If the NOELs/LOELs are similar, greater latitude can be given in
extrapolating from long-term data to intermediate-term situations. Where NOELs/LOELs differ

_ greatly, the effects. may be cumulative in nature,.and direct extrapolation from a long-term study to

an intermediate-term time frame may be an overly Conservative estimate of hazard.
3, LONG-TERM DERMAL RISK ASSESSMENT.
1, Objective
“The objective is to identify tong-term hazard based onthe toxic effects observed in studies where

the treatment conditions in experimental animals are simile to the route. (éermal) and duration -
: (several months to Lfe se) of man expan. :

data requirgments, however, do not contain long-term dermal studies for long-term hazard:
identification and risk assessment.- ‘Long-term studies are usually available by the oral route, in
which the duration of treatment (major portion df the animals life span) cortesponds to the *

exposure period (several months to life time):..Due to this limitation; the Committee must rely on

’ long-term oral studies for long-term hazard identification ‘ and risk assessment tind take détmal:
absorption into account. These studies include the chronic toxicity studies in rodents and noni- -
rodents (§83-1); the carcinogenicity study in mice and rats (883-2); and the 2-generation’ :
reproduction study in rats (§83-4).

For most pesticides, a Reference Dose em) i is used for chronic dietary tisk: assessment. - .
_Since long-term.dermal toxicity studies are rarely available, the Committee has to depend o on the

long-term oral studies for identification of long-term hazards. In doing so, the Committee will

evaluate the appropriateness of the dose and hazard identified for establishing the RD in relation

1° . z=.



“D. Hazard Identification Process for Inhalation Exposure Risk Assessment:

-In contrast, if the toxicity observed in that study ‘are clinical signs (such as alopecia and serine, .

inhalation toxicity studies (except for the acute LC,, study) available in the database, the Committee
is left with no option but to resort to the use of an oral NOEL for inhalation risk assessments (i.¢.,
route-to-route extrapolation). While it is generally recognized that route-to-route extrapolations
should be avoided, in the absence of appropriate inhalation toxicity studies, route-to-route
extrapolation overcomes the obstacle of inadequate data by allowing one route to substitute for
another and provides a way to combine risk for multiple routes.

When a subchronic inhalation toxicity study (14, 21 day ora 90-day) i is available, the results should
be carefully evaluated to ascertain if the toxicity.observed is in concordance with the overall toxicity
profile of the pesticide. If the toxicity observed via the inhalation route is similar to those seen in
other studies via the oral route (e.g., cholinesterase inhibition, neurotoxicity, hepatotoxicity, etc.),
then the endpoint can be used for risk assessments. Since this is the only study that is available in
the database, it can be used for risk assessments for any time period (i.e., Short-, Intermediate-, and
Long-Term).

decreases in body weight gain, and/or gross or histopathology of the respiratory tract but the toxicity
profile of the pesticide indicate a concern for developmental, neurotoxicity, or hepatotoxicity, then —_
this study is not appropriate for use in risk assessments since the endpoints observed in that study did
not correspond to the toxicity profile of thepesticide. . Similarly, the endpoints of concem selected for
oral arid dermal exposure risk assessments should be compared with the endpoints observed in the
inhalation study. If the endpoints for oral and/or dermal risk assessments are based on |” -
developmental toxicity, alterations in hematological parameters or neuropathology; then the
inhalation toxicity study is not suitable for risk assessments’ these parameters fic
developmental, hematological.or neurological) are not measure i this s aady. “Unider ‘these ©

conditions, Touté-to-mpue extrapolations should be‘ uted, Bae a ae a

Tn order to conduct route-to-route extrapolations, one must ‘convert exposure levels to mekg/aey
since the oral NOELs are usually reported in mg/kg/day. In-route-to-route extrapolations, “he step:
that allows the conversion from.one route to the other is the dosage expressed in mg/kg/day."In ‘
order to convert the exposure (dermal and inhalation) levels to an otal eqhivalerit dose (i.., us
mg/kg/day, the following. steps are recommended: 1) convert the inhalation exposure (jig/Ib a.i) and: .
the dermal exposure (mg/Ib a.i) to oral equivalent doses (mg/kg/day); 2)-combine the converted oral”
equivalent doses to get a combined dose for total (dermal +: inhalation) exposure;‘and 3) the
combined dose (mg/kg/day) should then be compared with the oral NOEL (mg/kg/day) to calculate
the Margins of Exposure. (The procedure for the “Three C’s” are as follows: ,

Step: Convert the inhalation and dermal exposures to oral equivalent doses (mghkg) as follows:
“a unit inhalation expostire (ug/Ib ai) x absorption rate (100% default) x application rate (Ib ai/acre) x
acres treated x 1 mg/1000 pg/kg + body weight (70 kg or 60 kg for developmental endpoints)

. unit dermal exposure (mg/lb ai) x absorption rate ( % recommended or 100% default) x-application
rate (Ib ai/acre) x acres treated + body weight (70 kg or 60 kg for developmental endpoints) .



gas6

! < .
OCCUPATIONAL OR RESIDENTIAL INHALATION EXPOSURE RISK ASSESSMENT | ;

TABLE OF CONTENTS

BACKGROUND
DIETARY RISK ASSESSMENT ...... 6... occ cece eet e eect eee teen teen ens

A. ACUTE REFERENCE DOSE (ACUTE R£D) .
1. Objective... icc cece cece etree ener nee nee Seve e eee cease
2. Relevant Studies for Acute Dietary Risk Assessment ...... we
3. Hazard |dentification Process for Acute Dietary Risk Assessment . . a
4, Acute Hazard Identification for Various Population Subgroups .................-

B. CHRONIC DIETARY RISK ASSESSMENT (CHRONIC R&D)
L. Objective 0... ccc cence ere e een eee eee n etree ene es
2. Relevant Studies for Chronic Hazard Identification ...........
3. Hazard Identification Process for Chronic Dietary Risk Assessment .. Devens

OCCUPATIONAL OR RESIDENTIAL DERMAL EXPOSURE RISK ASSESSMENT ......

A. SHORT-TERM DERMAL RISK ASSESSMENT
+L Objective 2... cece ence eee ence eet eee e eee e nent teeeees

2. Relevant Studies for Short-Term Dermal Risk Assessment 6°

3. Hazard Identification Process for Short-Term Dermal Risk Assessment sence eee s

B. INTERMEDIATE-TERM DERMAL RISK ASSESSMENT.
1, Objective :
2. Relevant Studies for Intermediate-Term Dermal Risk ‘Assessment :
- 3. Hazard Identification Process for Intermediate-Term Dermal Risk-Assessment , . ..

C. LONG-TERM DERMAL! RISK ‘ASSESSMENT :
1. Objective Seow ec ee cece be saccapentisessccccoeces
.2..Relevant Studies for. Long-Term Dermal Risk ‘Assessment.
3. Hazard Identification Process for Intermediate-Term: Dermal Risk Assessment

A. Objective .

C. Relevant Studies for Inhalation Hazard: Identification we . Y
D. Hazard Identification Proces for inhalation Exposure Risk Assessment seeds fedeedlune

THE INFLUENCE OF DERMAL ABSORPTION IN RISK ASSESSMENT. : tenes we eeees
THE USE, OF NOELs, LOELs, AND ENDPOINTS IN TES PROCESS ....... 0.000060 0
APPLICATION OF TES IN RISK ASSESSMENT ......2 0.0 0eeceseeeeeeeee snes leeeas





When an oral NOEL is selected for short-term dermal risk assessment, a dermal absorption factor
should be determined for appropriate route-to-route (oral to dermal) extrapolation. The dermal
absorption factor can be obtained either from 2 dermal absorption study (if available) or
estimated from the oral and dermal toxicity studies (See Section V)..

B. INTERMEDIATE-TERM DERMAL RISK ASSESSMENT.

ry
a

1. Objective

The objective is to identify intermediate-term hazard based on the toxic effects observed in
studies where the treatment conditions in experimental animals are similar to the route (dermal)
and duration (1-week to several months) of human exposure.

2. vant Studi i ei tifica

The current toxicology data requirements contain a number of studies that are relevant for _
intermediate-term hazard identification. In these studies, the duration of treatment corresponds to
the exposure period of concem (one week to several months). However, studies via the dermal
route are limited to the 21-day (§82-2) and the 90-day studies in rats or rabbits (§82-3). Other
studies that may be relevant for intermediate-term hazard identification conducted via the oral

route include: 1) the subchronic neurotoxicity study in rats (§82-6); 2) the subchronic feeding
studies ‘in rats and dogs (§82-1a,b); 3) the prenatal developmental toxicity studies in rats and
rabbits (§83-3a ,b); 4) the 2-genieration reproduction study in rats (§83-4); and 5i interim data
from chronic toxicity (§83-1 a,b) and carcinogenicity: ($832 abystndies, .

a. ictav and 90-Day Dermal Taxi Stes

v. These studies are considered to be directly applicable for the parpose of hazard identification
since the experimental conditions (dermal applications) simulate the real-life exposure
(dermal) depending on the intended pesticide’ formulation and use’ scenario. Also, the:
treatment period (6 hours/day, 5 days/week for 21-or'90-days) encompasses the exposure. :
period ‘Of concern (1 week to.several months). However, for most of the: pesticides, the ae :
day dermal toxicity study.is conducted instead of the 30-day. sty based on the criteria *
specified in the 40 CER: Patt 158. :

. Studies of 90-days duration are conducted in miultiple species (rats and dogs) by the oral
route. In the absence of either a 21-day. or 90-day dermal study, the 90-day oral or :
neurotoxicity studies may be used for intermediate-term hazard identification. However, “”
since multiple species and routes are involved; Selection of.an appropriate dose and exidpoint
should include a comparison of results across these studies and: the intended formulation and ©
use scenario. -



IV. OCCUPATIONAL OR RESIDENTIAL INHALATION EXPOSURE RISK ASSESSMENTS. :
A. Objective : ,

* exposure; 1-7 days for short-term, one week to several months for intermediate-term and several

, In genera, the dermal route of exposure for Sccuptional or residential ies isthe mont sic,
For certain pesticides (and use patterns), such as.the fumigants, the inhalation Toute is the most.

. mitigated or when dermal exposuré has.a very sinall impact (based on extremely low. dermal .:

_as termite treafment and fogging use), 3) the inherent toxicity of the pesticide (ie? Toriety Category =

* toxicity studies. Tey te ely isnot retremended for us nak asscsmats sine this tad is
: conducted primarily to determine the inhalation LC,, values from which a Toxicity Category is

to long-term hazard for occupational or residential exposure requirements. The Committee “oe :
recommend the use of the same dose and endpoint, used for deriving the RfD, for long-term

dermal rrisk assessment. However, if the use pattern and exposure scenario indicates special
concems, if the toxicity of the pesticide warrants a hazard identification different from that of the
R{D, or if the effects seen by the oral route are not expected by the dermal route (i.e., route-
specific effects), then the Committee will identify a dose different from that used for deriving the
RD. Ifan oral NOEL (i.e., the same NOEL used to derive the chronic RfD) are selected for
Long-Term dermal risk assessments, the Committee will select a dermal absorption factor for use
in risk assessments. At times the 21- day or 90-day dermal (when available) study may be used
if the Committee determines that the endpoints observed in this study is appropriate for Long-
Term risk assessments and/or if it believes (based on other studies) that toxicity would not be
expected to increase over time.

The objective is to identify inhalation hazards based on the toxic effects observed in inhalation
studies where the treatment conditions in experimental animals is similar to. the duration of human

months | to life time for long-term.

B. Need for Risk Assessment. ns obs 7 : ee @

significant.: Inhilation exposure is also a concer whes the dermal exposure hasbeen succesfully”

absorption) on the total exposure scenario.’ Therefore,, the need for risk assessment via'this route is
contingent on:/1) the type of pesticide formulation, 2) use-pattern {¢.g., usé in confined spaces such’ -

lesed on LC), anor the degre of expoetre festa (Ls reer Sah 15),

The current toxicology data requirements, are limited to thes acute 2 (§81:3) and sibchronic (§82-4). -

assigned to provide information necessary for determining appropriate language for precautionary ”
labeling. Therefore, the choice of study for this exposure assessmient.is limited to asubchronic
toxicity study of any duration (14; 21 or 90-days).: Also this study then can be used for inhalation
exposure risk assessments for any time period (Short-, Intermediate-, or Long-Term).

When there is a concen for potential inhalation exposure (based on the use pattern) and there are no qm
7 1200 =
s .