UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM

Date: March 15, 2012 OFFICE OF CHEMJCAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Prometon: Human Health Assessment Seeping Document in Support of Registration Review
DP Barcode: D405084 Registration No.: NA PC Code: 080804 Decision No.: NA Petition No.: NA Risk Assessment Type: NA TXRNo.:NA MRIDNo.:NA Regulatory Action: Registration Review Seeping Case No.: 2545

FROM:

THRU: CAS No.: 1610-18-0 40CFR: NA

William Irwin, PhD, DABT , Toxicologist/Risk As Wade Bri tto n, MPH, Industrial Hygien Q t William Donovan, PhD, Chemist Risk Assessment Branch V (RAB V) ' Health Effects Division (7509P) Office of Pesticid e Programs

Michael Metzger

# /J~**j)~** Acting Branch Chief, RAB V Health Effects Division (7509P J. ' 

## a . ' Office of Pesticide Programs V 

# b

TO: Steven Snyderman/ Kaitlin Keller Risk Management and Implementation Branch III (RMIB III) Pesticide Re-Evaluation Division (7508P) Office of Pesticide ProgramsPrometon Human Health Scoping D ocument 0405084

Executive Summary
The HED Prometon Registration Review Team has eval uated the most recent human health assessments and database for the herbicide prometon to determine the scope of work necessary to support registration review for the chemical. The main non-occupational exposu re is through drinking water. Registered u ses of prometon are limited to non-agricultural areas including rights-of-way, military installations, recreational areas, airports, highway medians, lumber and industrial yards, railroads , guard rails, firebreaks , and pipelines.
Prometon is a non-selective "bare-ground " herbicide labeled for pre- and post-emergence applications to manage annual and perennial grasses and broadleaf weeds in parking lots, roadsides and und er pavement. Following use, all vegetation is typically killed resulting in a bare-ground patch where the herb i cide was applied. Prometon is a photosynthetic inh i bitor which acts by disruptin g 

### C02 fixation and production of intermediary ene rgy components- ATP and NADPH. The most efficacious weed control method is through direct soil applications, which with sufficie nt water from rainfall or irrigation , allows prometon to readily move to the root systems.
The exposure database for prometon has been reviewed and determined to be complete. Because prometon is a non-food / non-feed chemical, any potential dietary exposure is attributed only to drinking water sources. The most recent dietary assessment (drinking water only) conducted to su pport the 2008 Reregistration Eligibi li ty Deci sion (RED) concluded that risks were below the level of concern. HED does not expect that a new dietary risk assessment will be needed for Registration R eview.
All occupational exposure scenarios previously assessed for workers applying prometon are not of concern at some level of personal protection. Occupational exposures to workers re-entering prometon treated areas are not anticipated because the chemical is used in non-agricultural areas , and there are no post-application activities required so that re-entry is unnecessary. No occupat ional expos ure data gaps were identified during the Registration Review scoping proce ss for prometon. Any changes in exposure assumptions, or update in prometon endpoint selection may require a revi sion of occupatio nal exposures/risks.
Residential exposure scenarios were evaluated previously, and 2 of the 7 residential handler scenarios assessed were determined to be o f concern. Based on the risks of concern , the product registrant(s) agreed to voluntary cancellation of all residential uses of prometon. Th i s agreement is detailed in the Prometon Reregistration Eligibility Decision (RED). On January 2 , 2012 the Agency published in the Federal Register (FR Vol. 78, No. 1) a notice of receipt of requests for an amendment to delete all re sident ial uses of prometon on registered labels. However, these produ cts continue to be availabl e for residential use. If these uses are not withdrawn, an updated assessment of re sidential handler exposure may be required during registration review using the revised 2012 Residential S tandard Operating Procedures (SOPs).
The only data requirement is a 28 -d ay inhalation toxicity study.

Page 2 of 17Promet on Human Health Scoping Document 0405084

In accordance with t he Agency's 1986 Guideline for Carcinogen Risk Assessment, Prometon is classified as a Group D Chemical (Not Classifiable as to Human Carcinogenicity). Prometon was negative in the mutagenicity/ genet i c toxicity studies including a bacterial mutagenicity (Ames test) , rat micronucleus test and an unscheduled DNA synthesis test. Prometon is a di-N-alkyl methoxy triazine herbicide but because it did not demonstrate mammary gland tumors in Sprague -D awley strain rats was not included in the common mechanisms model for the chlorotriazines that included atrazine, simazine and propazine (refer to the document entitled "The Grouping of a Series of Triazine Pesticides Based on a Common Mechanism of Toxicity" prepared by U

. S

. EPA Office of Pesticide Programs Health E f fects Division. March 2002). The immunotoxicity study did not indicate toxicity to the immune system at the limit dose.
There were no indicat i ons of inc re ased susceptibility to the fetuses or neonatal animals in either the rat or rabbit developmental toxicity studies or the rat mu lti-generation reproduction study

. A quantitative acute dietary risk assessment is not required since there were no acute toxicity endpoints of concern identified in the database, includ i ng the p r e-natal studies in rats and rabbits. A chronic Reference Dose was derived from the NOAEL of 5 mg/kg/day established in the chronic dog study

. The LOAEL of20 mg/kg/day was based on emesis and decreases i n body weight/body weight gain. This dose and endpoint i s supported by comparable findings in the two-year chronic study in rats and the two

- generation reproduction study in rats. The 2 1 -day dermal tox ic i t y study in r abbits was selected for quantification of dermal risk. The LOAEL of 500 mg/kg/day based on decreases in body weight and food consumption was selected as the risk assessment point of departure (POD) because a NOAEL was not estab l ished in that study. The Leve l of Concern (LOC) is a Margin of Exposur e (MOE) of I ,000 which i ncludes the 1 

### OX for inter-species extrapolation, 1 

### OX for intra

- species variation and 1 

### OX UF for extrapolation from the LOAEL to an est i mated NOAEL. An oral POD (NOAEL of 5 mg/kg/day) was selected fo r quantificat i on of inhalation risk. The HASPOC determined that th e use of an oral POD results in unacceptable MOE (190 fo r l oaders and app li cators) and that a sub-chronic inhalation tox i c ity study is requ i red. Therefore the LOC for quantification of inhalation risk is an MOE of I ,000 which includes the I 

### OX for inter-species extrapolation, 

### lOX for intra-species variation I 

### OX uncertainty factor for the lack of a subchronic inh alation t oxicity study (UFos). The PODs, endpoints of concern and the FQPA Safety Factor w ill be re-evaluated upon receipt of a ll studies.
The t oxicity p rofile and endpoints are presented in Tables A.2.1, A.2.2 , and A.2.3 of the Attachments section of th i s document.
Residue Chemistry
Prometon is not currently regis tered as a pest i c i de for uses in food commodities; therefo re, evaluat i on of residues in crops is not needed. Dietary Exposure
Prometon is no t currently registered for food-uses in agricultural commodities. Dietary exposures are limited to the potential presence of prometon in drinking water. The most recent dietary exposure analysis for prometon r eported a maximum exposure leve l of0.016 mg/kg/day

Page 4 of 17Prometon Human Health Scoping Document 0405084
(33% cRfD) for All Infants(< 1 year old), based on a prometon water concentration of236 ppb for ground water (D342903 1 W. Donovan, 9/04/2007). The estimated drinking water concentration (EDWC) of236 ppb was characterized by the Environmental Fate and Effects Division as being a high-end estimate (D335304, J. Hetrick, 7/3112007). As a result, HED does not expec t to update the dietary exposure analysis in regis tration review, unless a new EDWC significantly higher than 236 ppb is provided.
Residentia l Exposure
Residential handler exposures were considered in the most recent residential risk assessment (0349797, W. Britton, 3/ 2008). Combined handler dermal and inhalation residential risk estimates were calculated using the Aggregate Risk Index (ARI). The ARI approach was required to combine the dermal and inhala tion routes of exposure because of the different target levels of concern (LOCs). The majority of handler exposures assessed were not of concern to HED (i.e., ARls are**~1) .**  However, 2 of the 7 residential handler exposure scenarios iden tified were of concern and, as a result, the product registrant(s) agreed to voluntary cancellation of all re sidential uses of prometon. As mentioned, the notice of receipt to cancel re sidential use s was published January 2, 2012.
Residential post-application exposure to prometon i s not expected because HED does not anticipate significant dermal exposure from previously treated areas. Residential u se of prometon is lim ited by current labeling to areas where no plant growth
· is desired and dermal contact with these areas is assumed to be limited. Current lab eling recommends that granular and liquid fonnulations of prometon be watered-in to be effective. This practice causes prometon to move into the root zone of the soil, further reducing the potential for postapplication exposure. Conclusion

. No residential exposure data gaps were identified during the Registration Review process for prometon. While the product registrant(s) agreed to voluntary cancellation of all residential uses of prometon and a notice of receipt of requests for an amendment to delete all residential uses of prome ton on registered labels was published in the Federal Register, th ese products continue to be available for residential use. If these uses are not withdrawn, an updated assessment of re sidentia l handler exposure may be required during registration review using the revised 2012 Residential Standard Operating Procedures (SOPs). Drinking Water Assessment
The previous assessment recommended a conservative chronic EDWC of236 ppb (J. Hetrick , 0335304, 7/3 1 /2007). Shou ld a higher value be recommended during registration revi ew, then HED will re-e valuate t he dietary assessment (water only) based on this information. Aggregate Risk Assessment Assuming a ll residential uses are cancelled , no acute, short-, or intermediate-term exposure scenarios exist for prometon ; the only non-occupational exposure scenar io is the chronic dietary exposure from drinking water , which comprises the aggregate exposure for this chemical. As

Page 5 of 17Prometon Human Health Scoping Document 0405084
previously discussed, there are no risk concerns for chronic drinking wa t er exposure; therefore , there are no aggregate risk concerns. Occupat i ona l Exposure
Due to the manner in which prometon is used, occupational exposures are anticipated for those involved in the application process (i.e., mixers/ loaders, applicators, and mixer / loader / applicators). Occupational exposures to workers re-entering prometon treated areas are not anticipated because the chemical is used in non-agricultural areas, and there are no postapplication activities required so that re-entry is unnecessary.
Prometon containing products are formulated as emulsifiable concentrates, flowable concentrates, granulars, and ready-to-use. Applications of prometon can be made by ground using ground boom , rights-of-way, tractor drawn spreader, and hand-held spray equipment. Product application rates range from 8 to 18 lbs ai/ A, or 0.41 lb ai/1 , 000 

# e. Based upon the use pattern of prometon, HED anticipates both short- (1 to 30 days) and intermediate-term (1 to 6 months) occupational exposures. Long-term handler exposures (greater than 6 months) are no t expected to occur. Occupational handler exposures for all formulations were considered in the most recent occupational risk assessment (D349797 , W. Britton, 3/2008). All handler exposure scenarios assessed (dermal and inhalation combined) resulted in margins ARis 

### 2:. 1 at some level of personal protection and, therefore, were not of concern. Conclusions. No occupational exposure data gaps were identified during the Registration Review seeping process for prometon. Further, there are no significant changes identified which would require an update of the occupational exposure risk assessment. A task force e ffort by the Agricultural Handlers Exposure Task Force (AHETF) may provide improved exposure data relative to that in the Pesticide Handlers Exposure Database (PHED) and the Outdoor Residential Exposure Task Force (ORETF) , which were used previously to assess occupational risks. Any impact to exposure data, or update in prometon endpoint selection may require a revision of the prior assessments to reflect these changes.
Pub l ic Health and Pesticide E pidemiology Data
For the Main IDS (higher severity human outcomes), from January 1 , 2007 to September 13 , 2012, there were 26 incidents reported for prometon for single chemical only in the database and 3 additional incidents reported involving more than one chemical. One incident was classified as major severity which involved a worker entering a greenhouse 2 days after it was treated and developing anaphylactic shock requiring treatment in an emergency room; the other incidents were classified as moderate severity. Overall, there are few incidents involving promet on reported to IDS. In Aggregate IDS (less severe human incidents), from January l, 2007 to September 13, 2012 , there were 106 reported incidents involving prometon.
In SENSOR-Pesticides from 1998 t o 2008 1 40 cases (from 34 events) involving prometon exposure were identified. Prometon is listed as the sole active ingredient in 25 of the 40 cases.

Page 6 of 17Prometon Human Health Scoping Document D405084

T wenty cases are classified as work-related

. A review of case narratives identifies pesticide handling (mix i ng, loading or app l ying) as the activity at the time of case exposure in 22 (of 40) cases. Of the 22 work

-related cases, 12 were due to handling activities and ten non work-related cases were applying the herbicide residentially. Of the 40 cases, six cases are moderate in severity ' and 34 are l ow in severity. Symptoms for the six moderate severity cases varied wide ly and included altered taste, wheezing, pneumonia, and headache. Two moderate severity cases reported major respiratory symptoms

. One case reported "pneumonia, cough and shortness of breath." The second moderate severity case with respiratory symptoms went to the ER and his case report stated 

### " Patient is cyanotic looking around lips, 0 2 

### of92%. Wheezing throughout lungs, c/o chest pain. " Respiratory symptoms are the most commonly reported health effect, followed by symptoms related to the nervous system, gastro i ntestinal , eye and dermal effects

. There was one i ncident class i fied as major severity (further described i n Table 1 in the inc iden ts report, D406960). However; it is not clear that this incident is related to prometon or the implicated product (Ground Clear Triox Total Vegetation Killer). The individual developed anaphylactic shock five hours fo ll owing exposure in a greenhouse that had been treated 2 days prior, suggesting that the incident was not related to the product. In addition, the implicated product , Ground Clear Triox Total Vegetation Killer, is intended for outdoor use as a total vegetation killer, and not likely used in a greenhouse (i.e. not a registered use site). Also it is very like l y that multiple pesticide products were used in the greenhouse. It is important to note that, reports submitted t o the IDS are un-substantiated; they represent anecdotal reports or a ll egations only.
Based on the low frequency and severity of incident cases reported for prometon in both IDS and NIOSH SENSOR, there does not appear to be a concern at this time that would warrant further investigation. The Agency w ill continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.
To l erance Assessment and International Harmonization
Tolerances are not established for prometon since no registered pesticide uses in food commodities exist at this time. No Codex maximum residue limits (MRLs) have been established for prometon. Therefore , there are no international harmonization issues

. Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance w i th U.S. Executive Order 12898, "Federal Actions to Add ress Environmental Justice in Minority Populations and Low-Income Populations," http://www.epa.gov/compliance/resources/policies/ej/exec order 12898.pdf. The Office of Pesticide Programs (OPP) typ i cally considers the highest potential exposures from the l egal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, and the variability of diets within the U.S

.. Should these highest exposures indicate potentia l risks of concern, OPP

Page 7 of 17Prometon H uma n He a lt h Scoping D ocument

further refines the risk assessments to ensure that the risk estimates are based on the best available informa ti on
. Cumulative 

### 0405084

Prometon has not been identified as a member of a common mechanism group. Although prometon is a triazine chemical, i t is specifically a methoxy triazine and not included in the common mechanism group or cumulative ass essment group for the chloro-triazines

. A common mechanism of toxic it y has not been demonstrated fo r prometon w i th the other tr i azine compounds. Furthermore , prometon does not produce the DACT (diaminochlorotriazine) metabolite common to the members of t he chloro-tria zine cumulative assessment group.
Human Studies
Prometon risk assessments rely in part on exposure data (i

. e., PHED and ORETF) from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These stud ies have been determined to require a review of their ethi cal conduct , and have received that rev iew
. Endocrine Disruption
As req uired by FIFRA and FF DCA, EPA reviews numerous s tudie s to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxici ty, deve l opmental, reproductive , and general or systemic toxicity. These studies include endpoints which may be suscep t ib l e to endoc r ine influence , i ncluding effects on endocrine target organ histopathology, organ weights, estrus cyclicity , sexual maturation, fertili ty, preg n ancy rates, reproductive l oss, and sex ratios in offspr i ng. For ecological hazard assessments , EPA e valuates acute tests and chronic studies t hat assess growth , developmental and reproduct i ve effects i n different taxonom i c g roups. As part of it s most recent regis tration dec i sion, EPA reviewed these data and se l ecte d the most sensitive endpoints fo r relevan t risk assessment scenarios from the existing hazard databa se. However, as required b y FFDCA section 408(p), prometo n is subject t o the endocr in e screening part of the Endoc rine D i sruptor Screening Program (EDSP)

. EP A has deve lop ed the EDSP to determine wheth er certain substances ( includ in g pesticide active and other ingredien ts) may have an effect in h umans or wild li fe similar to an effect produced by a " naturally occurring estrogen, or other such endocrine effects as the Administrato r may designate." The EDSP employs a two-tiered approach to making the s tatutorily required determinations. Tier 1 cons i sts of a battery of 11 screening assays t o identify the potentia l of a chemical substance to interac t with the estrogen , androgen, or thy roid (E , A, or T) hormonal syste m s
. Chemicals that go through Ti er 1 screeni n g and are found to have the potential to interact with E, A , or T hormonal systems will proceed t o the next s tag e of the E DSP where EPA will determ i ne which, if any, o f the Tie r 2 tests are necessary based on the availab l e data. Tier 2 testing is designed to id entify any adverse endocri ne-related effect s caused by the substance, and estab li s h a dose -r esponse relationship between the dose and the E, A, or T e ffect.

Page 8 of 17Prometon Human Health Scoping Document D405084

Under FFDCA sect i on 408(p) , the Agency must screen all pesticide chemicals. Between October 2009 and February 2010 , EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients artd 9 inert ingredients. Prometon is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly , as part of registration review, EPA will issue future EDSP orders /data callins, requiring the submission of EDSP screening assays for prometon. For further information on the status ofthe EDSP, the policies and procedures, the list of67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http : //www.epa
. gov/endo/.
Data Requiremen ts
The 28-day inhalation study (870.3465) is required.
References
Author Barcode Date Title
W

. Donovan D349795 3 / 17/2008 Prometon: HED Chapter of the Reregistration Eligibility Decision Document (RED). Phase 4 Revisions. J. Hetrick D335304 7/ 31/2007 Drinking Water Assessment for Uses of Prometon
J

. VanAlstine TXR # I 0 / 25 / 2012 Prometon: Summary of Hazard and Science Policy 0056500 Council (HASPOC) Meeting of October 25, 2012 S. Recore D406960 10/ 15 / 2012 Prometon: Review of Human Incidents Kri s ten Knox NA I 0 / 3 / 2012 Prometon Residential Uses (MANA)

Page 9 o f 17**Pr In** **to u=m=a=n~H~e=a=lt=h~S=co~p~in~g~D==oc=u=m=e=n** **t** ________ __ ____ ______ ____ ________**D~4 05084** 
A tt achments
A
. l Chemical I dentity Table 

### A.l.l Chemical Ide nti ty o f P rometon. H C H3 

# I I H3 C-O"-..**-~:N "**  / N-C H

- C H3 

# r rrStruc ture**~** ,. N 

# T/
References: K. Dockter,

### H/**N· '·** **c~l --** **CH**

# 3 17-JAN-1985 

# I And C H3 The Pesticide Manua l: N2,N 4-diisopropyl-6-methoxy-1 , 3 ,5

- I UPAC Name A World Compend iu m , triazine

- 2 ,4 -di amine 7th ed

. , 1983 , C.R. CAS Name 6-methoxy

- N,N'-bis(l-methylethyl) -1 , 3 , 5- Worthington, ed. The triazine

- 2,4'-diam ine British Crop Protection Common Name Prometon Council, Croydon , Molecular Formula C10H19N50 England , pg
. 695

. Molecular Weight 225 g/mo le CAS Registry Number 1610-18-0 PC Code Number 080804 Physical State Colorless powder Melting Point 91-92°C Solubil i ty (20°C) 620 ppm in water Log Kow (20 ° C) 4.3

Page 10 of 17Prome to n Hum an H ealt h Scoping Document 040508 4



### A.2 Toxicity Profiles and E ndpoints
T able ..\.2 .1 Acute T on city Profile

- Prometon
GUtdehneNo Srudy Type**~fRID(s)** Results Tox.icuy Category 370

. 11 00 A cute oral

- rat 42 132103 LD so= 4 3 4 5 mg'kg 

### m for mal e s and 1 5 1 8 mglkg for f e male <>. 870

. 1 200 Acute dermal

- rab bit 41 609 11 2 >2020 mglkg 

### m 870

. 1 300 Acute inh alation- rat 42132 1 04 L C'sQ 

## = .. > ll 0 .52mgll.

. 870

. 2 400 Acute e y e irrit ation

- rabb it 4 2 144601 Con Ju nctivae 

### m redne ss :md che mo s is and di scha rge regres<.>ing by da y 7 870

. 2500 Acute dermal irrit at io n
- r abb1t 41609113 Aver y s li gh t I\ t eryt h ema cleared b y 2 4 hours 870 2600 Skin s emitiza tion

- guinea pig 41609114 No t a s en si tizer



### --
The acute s tudie s were rt•\
· iewed b y Mari ann e Lewi s . Product**Re gi<.>tr.~tio** **n** Branch_ Specia l Re,
· i ew and**ReR.eg~ tr** **ion** Division (750 9? )

. Refer to memos dated J ul y 18

. 2007 (primary eye and derm.1 l irritation and derll13 1 se nsitization) ; md July 20. 2007 (derm. 1l toxicity)

. The d erma l sensttizatio n stu dy was determined to be unacc eptable but

..based on informa tion f ound in the s tudy and the open literature

. the Agen cy will classify the techmcal as a non**eusuizer.** A new sru d y is not needed

...

Page 11 of 17Prometon Human Health Scopi n g Document 0405084

lnblt : \ .:.: '.lubclu**ir~** Clu ouk and Ollm Tollcity P1 ofile for Pa omttou
Cll.ldt.lule Snul:,**T~-pf ~!RID**  :-o.**(yt~rJ** Rt :ulll :"io. Ch-:ifit'ltiou Do:r

s-o J lOO 90- Da y or.ll 00!299S.S (!981 )**~O ~.E** **L** 

### =5**~lt~ dty**  !Oal:C L IY

- rn .ful= LOAEL

.. I.> tDJ1t: dly b.iad Clll ktdluy**"''~** :mG kldney wegbt**rob~** ratw

. 0, 05 .1 5. 5- or 15**c::k~.Uy s~** **~...0** lbr dlt-o::i-t n t :m..ry
. S70.5150 90- D l"'**c.~ l**  ::wH tn cl:ron:c !?edl!:g mJd:y be:!m\
· . tanury ·**~** $70**l~OO 21** **D•:.-~ .t21~2** **l~S7)** NO AEI.**•15a:~~'k."cby** to:ci-city (nbht t ) A«'.,w.bJ. <7t.udotlwe lOAEL = 500**cg 'k~** **da.y** bs:.ed**on~** body**\\-ei~** mcll'= md rood**=~'OI!l** m £ea:.tlu. 0. 2 5 ,**~Oo r**  1 0)0 q\phr 

### a·o**3~so 90-Ihy~** **~o ~l"'dy**  n'Zil:ll:U JJ:Id DOl nqurtel**ta:a.~in-** ( ::;pecte>)
s - o.>-+6.5**ay** uilia!.a.t:cr.**~0 ~hldy** **anJ.lab~~** but woc:!d b

. e**~qu:md** If there \\'eft**~l~C.ml** rnha!atlac**~** to:ID.U.")**(;~> o**  

### roo.\ Plu.u..J 00129983 OOl.;s6C-9 ad**~l 1rtna::t** **i** NO.iUl. "' .)6**=r'lc~Y .w.~** **in 211~90** **9S~ )**  LO

..:..EL = 110 :::1g q 'day ba.:.ed on**~e=•~ ~'a:lOU**  z::,d**·~ ~11n1:::;um**  chrocaoJt=on:bu. D en.lopiJmltal**O. =**  360mgkg:-da:: (H!J.) , LOAE.. 0

. 36. 

### no or J60**oot~ubC::.bt<i r,e:'k~day**  

### s
- orOOb Prauta.l 00Jl99 S4

. 00l-*S609 r.d**~h rerual** **NO =**  3.5 mg'k_g. d;r,•**dn"tl~ in.** **9~** 149'J08 (1 981 LOA.EL., 2 4 5**~''d..wbued Clll~Oody** **.- ~**  1-iliba l;.ll.ulmwn ;;.nd**~** '"C. 5ht mau:.e in**la.c1i::::ati~** and**an=-~** Dt-\"tlop mt11 t'll J.;OAl!l. •24 5 

### me**ks·'~·** (HDT)

. LOAE!.. o

, 0.5 , 35 Ql' 24 5**no ~.tlb~** **~'lc~day** t703SOO F....p1 CIGclloD. mli**~~36151 9**  (l 9S 7) P lln!lll<tl**~~-:.tttait' ~OAEI..**  • 14 .5**~·k(oily** t"L"tlluy effe= G-..Uc!e!me LOAEI... = 3 5

. 00. m;: ikglday**b~** o::t**~body** 

### mrm**~L!in** m DDlt=. m**both~~** ci!Kre.-d f* 0, 20 , 500o r**)C{}~PIP** con::ll:llpti:c.D i:l**::.n.1.le~** in.**:~co:d ~i!llSatl'c::.**  (**~.:;tw::a:ted** 0. l. 45. 3 S.D S Rt-productiH NOAEL ,.. P.<to .ad-1-ene**effKt~** ce Dd {(;3 96tz<J lrr t.bv**~- ~pufovm:;.nc-e]**  fur :u:u!c 3Ild 0

. !.59

.**Off;p~~o.~** 

### = 1..59**~** k g ' d.i;;- (IIJ.l!enW)**3~ l7GJ**  HHS I

..**W.** "' .>9 1" UJW**6v** 'b;.:.4d ® ciw"e

. r.eQ Y'IP**V>llt~ ~'k.g** **dJy <>r~)**  dun::.r**~acunce** penod m**~ond** gt!lel-atlD.Il ill both c:ez:oa-:tngc; · at c. mf,ber O:l:.e

Page 12 of 17Prorneton Human Health Scoping Document 0 4 05084

Tab l t**A.~. 1**  Subd n onic

. C l m:m tc au d Or htr**oxk ~·**  Pro fil e !o r P ro m tto n**G~tid** .lint**'"'~ ~lH** **IKID ~o** **. ~** **•~11 Rt~ul** **J ~o.**  C**~::rfiutio n** **Do :.~-:**  

### s-o
. .uooa Cl:rom c Wlllctly 4()1SS l 02 { l9SS \**~OAfl. 'J.S~** **a US)~'** **k~ cay**  r. n Guidtlme LOA.fl.

.. :l3 3(01**l** 2) q'q d:i)'**b~~edon <l"Ft~:ed**  me.m**body"'~** md**~Ill** Wmi.r.

. 0. 0 89**.Jor** 71 "'I f ew

= l e :. =d O

. US. 3 1.2 O'l l 01 5 Col**!&!~.We~ ~k** **d:ay.** Sil·H OOb C brouu: taxJClly .;oo9"'90 1 a:;d i:Olt..El..

... 5**~'k~ day**  do;**.;~6581 l**  ( 1 9S6) lOAEl."' :!0 a:; 'k; chy b:t-:ed o n**depr l.'** **~-:i=** cf' bodv Muu_""= \ni.Pl md a cloH**reWed~** :n**~** ID**both~ .**  

### a. 5 , 

### ..: o3Dd 

### so =:'kr
·d.:ty s - J**o~~oo ttm~~** **~SS102** ( 19SS ) Refer to cl:-omc to::acny abo;·e fM 'SOAEI.. and LO

. !,EL and**c:arcno~c:;ty** C"1ll de!me ra t :\o n idf !U' tt of**.u dno** **.ni< it** **.** No..-.-**c;wuw.~** Q

_ 0

. 89

. 2 3.3or 73.7 f OI' .dmoma:..**~arcooe.r.** d fi bra:na:; ';t; l!I e v.'l tb**m.al~** md 0

. ll S , 31:! b. :**ton~alt*ll,,..** Ol' ! 0 .2.5**or~ ~'q** **cby .**  

### s
- o .:JOO c

. .. .. · c:inop-ru.em • -3().;88 HH (!9SS) );OAEL = 7 0**~· 'k** **"&y ~e}** **G-u.i ~**  LOA.EL =**., nm.~'l!'day~** **on ~wn"i\~**  ( mat....)

.**~-~** boCv**'-l"f!i~** pie 6**both~.** OC'll · 0

. ·- 2

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.. T A I535 , TA 15} i ,o rTA t53S s-()5100**~'lth** or**~'lthcut** a:e.ubohc**u1l\~** 0, .2 5 , 100, 500 , 1000 01' 2500**jl~'p!.m Cyto~**  R.JJ**m;.(.TOillUCJ.tu~ -l063~1**  m:i 4 1 9S4J01**~ "~o** **"** om:re= lil«t io!lowq 64$**~** q wd S"'' 5 :!95 td (i9SS)

_ sac:ri:frce at 16

. 24 or**~** hom:;. Attept3llle. (009&02) 648 qltl**hl:ba ~**  do.**t~ ed.** 

- -

Page 1 3 of 17Prometon Human H ea lth Scop ing Document 0 40508 4**T:.tbl~ ~**  :Subd u omc. C lu ou lc 3 nd Othu T

...**~cm** Pt ofilt f ox Pt o mtt o n C.wd' t <.tull T)pt lf'RID :"o () f" f! Rgulll**~-0** Ch7:ifi.-.,non Do:t· Other**Uc.:~dO A**  4363&+33. 4 l9S4303 .=!**~** tnd:.allnn**of=.d :e~u** **le=:** O:tA Tej)m

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### Table A.2.3 Summary of Toxicological Doses and Endpo ints for Prometon for Use in Dietary, Occupational, and Residential Human Health Risk Assessments RfD, Level of Exposure/ Point of Uncenainty Concern for Study and Toxicological Effects Scenario Departure Factors Risk Assessment Acute D ietary (Gen eral Population, includ ing Inf a nts and No re levant toxicity endpoint fo r a sing l e dose exposure was id e ntifi ed. Chi ldren) Acute Dietary (Fema les 13-49 ye ars of age)

Page 14 of 17Prom e t on Human H ea lth Scop ing Document 0405084

Table A.2.3 Summary of Toxicological Doses and E ndp oints for Prometon for Use in Dietary, Occupationa l , and Residential H um a n Health Risk Assessments RID, Level of Ex po sure/ Point of Uncertainty Concern for Study and Toxicological Effects Scena rio Departure Factors Ri sk Assessment Chronic study with dogs: NOAE L = 5 mglkg/ day LOAEL = 20 mg / k g/da y based
on emesis and body weight effects. T h e other co -critical studies w e re th e chronic rat and the two-generation rat reproduction st udies. C hro ni c Rat Study: NOAEL = 0.89 (or 1

. 18)
m g/kg/day LOAE L = 23.3 (or 31.2) m g/ k g/ day base d on depressed
mean body weight and gains in fema les. Chronic NOAE L =5 UFA = lO x Chronic RfD = Two-General ion R e production Dietary (All mglkg/day U FH=! Ox 0 .0 5 Study: P opu l ations) mglk g/day Pare ntal/ Systemic N OA EL = 1.45 mglkg/day LOAEL = 35.08 mglk g/day based on dec r eased bod y weig h t in males in both g enerations and d ec rea se d food co n s umption in mal es in second generation

. Rep r od u ctive NO A EL = [No adve rse effec ts o n reproductive performance) Offspring NOAEL = 1.59 mg/kg/day (maternal) LOA EL = 39.17 m g/ k gl day based on d ecrease d pup weight durin g lactation period in second ge neration in both ge n e rations at the high e r dose.

Page 15 of 17Prometon Human Health Scoping Doc u ment 0 40 5084

Table A.2
. 3 Summary of Toxicological Doses and Endpoints for Prometon for Use in Dietary, Occupational, and Residential Human Health Risk Assessments RID , L eve l of Exposure/ Point of U n certa in ty Co n cern f or Stud y a nd Tox icolog ical Effects Scenario Depart ure Facto r s Risk Assess me n t Chronic study with dogs : NOAEL=5 mglkg/day LOAEL = 20 mglk g/day based
on emesis and body weight effects. The other co-critical studies were the chronic rat and the two-generation rat reproduction studies

. Chronic Rat Study: NOAEL = 0.89 (or 1.18) mg/kg/day LOA EL = 23

. 3 (or 31.2) mg/kg/day based on depr essed
mean body weight and gains in females. Incidental Oral Short N OAEL=5 UFA = IOx Two-Generation Reproduction and mg/kg/day UFH = 10x 10 0 Study : intermediat e Pare nt a l / S ys temic NOAEL = term 1.45 mg/kglday LOAEL = 35

. 08 mglkg/day b ase d on decreased body weight in males in both generat ion s and decreas e d food consumpt i on in males in second ge nera tion

. Reproductive NOAEL = [N o advers e effects on reproduc t iv e performance] Offspring NOAEL = 1.59 mglkg/ day (maternal) L OA EL = 39.17 mg/kg/day based on decreased pup weight during lac tat ion p e riod in se cond generation in both generations at the higher dose

. D e rmal 21-day dermal tox i c it y study in Sho r t-Term LOA EL= UFA = IOx rabbits with a LOAEL of 500

a nd 500 UFH = IOx 1, 000 mglkg/day based on d e creased intermediate mglkg/day UF L !Ox body weight and food consumption in females.

Page 16 of 17Prometon Human Health Scoping Document 0405084

Table A.2.3 Summary of Toxicological Doses and Endpoints for Prometon for Us e in Dietary , Occupational , and Residential Human Health Risk Assessments RID , Level of Exposure/ Point of Un certainty Co n ce rn for Study and Toxico logical Effects Scenario Departure Factor s R isk Assessment Chronic study with dogs: NOAEL = 5 mg/kglday LOAEL = 20 mglkglday based on emesis and body weight effec t s. The other co
- critical studies were th e chronic rat and the two-ge neration rat reproduction st udi es. Chronic Rat Study: NOAEL = 0.89 (o r 1

. 18) mg/kglday LOAEL = 23.3 (or 31.2) m glkglday based on depressed
mean body weight and gains in female s
.
Inhalation

- NOAEL = 5 UFA= IOx Two-Generation Reproduction all duration s m glkgl day UFw: IOx 1 , 000 Study: UFoa = IOx Parenta l/ S y stemic NOAEL = 1.45 mglk gl day LOAEL = 35

. 08 mglkglday based on decreased body weight in males in both gene rations and decreased food consumption in males in seco nd generation. Reproductive NOAEL = (No adverse effec ts on reproductive pe r formance) Offspring NOAEL = I .59 mg/kglday (mate rn a l ) LOAEL = 39.17 mglkglday based on decreased pup weigh t during l actatio n period in second generation in both generations at the higher dose

. Cancer C las s ification: Group D

--Not Classifiable as to Human Carcinogenicity (oral , d e rmal , inhalation ) UF 

### = un ce rtatnty factor

. UF A = extrapolatiOn from am mal to human ( mtraspec1es). UF B = potennal variation in sensitivity among members of the human population ( inter s pecie s )

. UF L =use of the LOAEL , instead of a NOA E L , for endpoint selection.

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