### U. **S. EP A Chemical Saf** **ety Advisory Commit te**  **e (CSAC)**

**Meeting** 

## 1 **- Br**  **omopr opane**  **(1 -**  **BP) TSCA W**  **ork Plan Chemical Risk Assessmen**  **t Spr**  **ay Adhesiv**  **es, Dry Cleaning and Degr easing Uses** 

Ma y 24 - 25, 2016 Arlington, V

A

# P **RESENT**

**AT ION**  

# O **UTLINE**



# • Ov er view of Dr aft 1 - BP Assessmen t

• Pe er R eview Char ge

• Ke y Science Issues

**| 2** 

# B **AC KG**  **ROUND**

**S LIDES**  **3 -**  **4 RELA** 

**TE TO**  **C HARGE**  **Q UESTIONS**  **1 -**  **1 THROUGH**  **1 -**  **2** Ph ysical - Chemical Pr operties

− Vo latile , vapor pr essur e 146.3 mmHg @ 20 o C

− Boiling point 20 o C at 760 mmHg

− Slightly soluble in wate r (2.45 g /L at 20 o C)

− Low flammability

− Low en vir onment al per sistence

− Low bioconcentr ation and bioaccumulation pot ential

**| 3**  **Based on ph ysical/**  **chemical pr operties**  **(high volatility)**  **and en**  **vir onmental**  **fate, combined**  **with a low ecological hazard**  **profile, risks**  **associat ed with**  **en vir**  **onmental and**  **dermal e xposures**  **were not assessed.**

# C **ONCEPTU AL**  

# M **ODEL**

**| 4**  **Ef fe**  **cts**

**Ef fe**  **cts** Manufacturing

# O **CCUP**

**AT IONAL**  

# E **XPOSURE** 

# A **SSESSMENT S**  **LIDES 5**  **– 30**  **RELA**

**TE TO**  **C HARGE**  **Q UESTIONS**  **2 -**  **1 THROUGH**  **2 -**  **4** 

### Objectives: • Es timate number of e xposed work er s • Assess inhalation e xposur e concentr ations:

− 50 th (centr al t endency) and 95 th (high - end) per centile v alues

− Es timate ex posur e f or “w ork er s” and “ occupa tional non user s”

− Es timate ex posur es pr e - engineering contr ols or “pr e - EC ” (as a baseline) and pos t - EC to see risk reduction 

### • Calculate:

− acut e concentr at ions (AC)

− chr onic concentr at ions [ Ave ra ge Daily Concentr at ion (ADC) and Lifetime A ve ra ge Daily Concentr at ion (LADC)] **| 5** 

### Method: “ To p - Down” appr oach

1. Identify the NAICS codes f or the indus try sector s 2. Es timate total employment using US Census and Bur eau of Labor Statistics da ta 3. Refine estimate of total by applying a f act or (mark et penetr at ion of 1 - BP f or that use) 

### Re sults:

− Spr ay A dhesiv es: 1,500 to 12,000

− Dry Cleaning and/ or Spot Cleaning: 1,100

− Va por Degr easing: 4,700 to 24,000

− Cold Cleaning: not es timated

− Aer osol Degr easing: 2,500 to 12,000 **| 6**  

# E **ST IMA**  **TING** 

# N **UMBER OF**  

# W **ORKERS**

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** Method: 1. Conduct compr ehensiv e lit er atur e sear ch for monitoring data 2. Pe rform e xposur e modeling t o augment and compar e with e xposur e monitoring data

**| 7** 

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **S PRA**  **Y** 

## A **DHESIVE**

• 1 - BP is used in spr ay adhesiv es for foam cushion manuf acturing ( e.g. , the furnitur e indus try )

• Spr ay guns ar e used t o spr ay - apply an adhesiv e on to fle xible foam surfaces

• T hr ee NIOSH Health Haz ar d E va luations (HHEs) pr ovided monitoring data on 1 - BP e xposur e fr om spr ay adhesiv e use in foam cushion manuf acturing

• Tw o of the thr ee HHEs also compar e e xposur e pr e - and post - engineering con tr ols (pos t - EC ) **| 8** 

## E **ST IMA** 

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **S PRA**  **Y** 

## A **DHE SIVE** 



### • EP A defined the following:

− **Spr ay**  **er s**  manually spr ay apply the 1 - BP adhesiv e

− **Non -**  **spr ay**  **er s**  do not dir ectly perform spr ay ing, but either handle the 1 - BP adhesiv e ( e.g ., assembler s) or work in an ar ea/departmen t wher e spr ay ing occur s

− **Occupational non**  **- user**  **s** do not r egularly perform work in an ar ea of the facility wher e spr ay ing occur s **| 9** **| 10** 



## E **STIMA TING**  

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **S PRA**  **Y** 

## A **DHESIVE** 

## – **M ONIT** **ORING** 

## , **P RE**  

## - **EC**

• Based on Data in NIOSH HHEs8hrTWAConcentration(ppm)

n =85 n=31 n=39 95 th percentile 7 5 th percentile M ean 25 th percentile 5 th percentile 50 th percentile 95 th percentile 7 5 th percentile M ean 5 th percentile 50 th percentile

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **D RY**  

## C **LE ANING** 

• 1 - BP is a solv en t used in dry cleaning machines • Wo rk er s ar e e xposed when:

- Spot cleaning at dry cleaner s

- Adding solv ent to machines

- R emoving loads fr om the machines

- Finishing and pr essing



### • Monitoring data a va ilable fr om NIOSH HHE of 1 - BP use in four New Jer sey commer cial dry cleaning fa cilities

− **Wo rk**  **er s**  ar e oper ators of dry cleaning machines

− **Occupa tional**  **non -**  **user s**  ar e w ork er s who do not spot clean or oper ate the machine **| 11** 

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **D RY**  

## C **LE ANING**  

## – **M ONIT** **ORING** 

## , **P RE**  

## - **EC**

**| 12** 8hrTWAConcentration(ppm)

n=5 n=11 

### • Based on Data in NIOSH HHE

95 th percentile 7 5 th percentile Mean and 50 th percentile 25 th percentile 5 th percentile

## E **ST IMA** 

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **D RY**  

## C **LE ANING**  

## - **M ODELING** 

**| 13**  

### • A multi - zo ne modeling appr oach • EP A/OPPT performed a Mon te Carlo simulation

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **D RY**  

## C **LE ANING**  

## – **M ODELING**  

## , **P RE**  

## - **EC**

**| 14** 8hrTWAConcentration(ppm)

Model – Spot Cleaning Model – Machine W ashing and Finishing Model – O. N.U . 95 th percentile Mean & 50 th percentile 5 th percentile 95 th percentile 5 th percentile 7 5 th percentile 50 th percentile 25 th percentile

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **V APOR**  

## D **EG RE**  **ASING**
• EP A obtained ex posur e monitoring data fr om sev er al sour ces ( e.g. , journal articles, NIOSH HHEs, OSHA IMIS Database, EP

A SNAP data) • Most data we re for batch open - top v apor degr easer s • EP A cate goriz ed these data into pr e - EC and pos t - EC scenarios:

− **Wo rk**  **er s**  oper ate or perform maintenance tasks on the degr easer

, such as dr aining, cleaning and char ging the degr easer bath tank

− **O ccupational non**  **- user**  **s** do not r egularly handle 1 - BP or oper ate the degr easer but perform work in the ar ea ar ound the degr easer **| 15** 

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **V APOR**  

## D **EG RE**  **ASING** 

## – **M ONIT** **ORING** 

## , **P RE**  

## - **EC**

**| 16** 8hrTWAConcentration(ppm)

n=167 n=7 95 th percentile x 50 th percentile

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **V APOR**  

## D **EG RE**  **ASING** 

## - **M ODELING** 
• Near - field / far - field model applied to v apor degr easing • EP A/OPPT performed a Mon te Carlo simulation

**| 17** 

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **V APOR**  

## D **EG RE**  **ASING** 

## – **M ODELING**  

## , **P RE**  

## - **EC**

**| 18** 8hrTWAConcentration(ppm)

95 th percentile Mean and 50 th percentile 95 th percentile

50 th percentile M ean

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **C OLD**  

## C **LE ANING**  

## D **EG RE**  **ASING**

• Cold cleaner s ar e non - boiling solv en t degr easing units • Ty pes:

− Ba tc h - loaded , maintenance cold cleaner

− Dip ta nk

• Emission sour ces:

− E va por ation of the solv en t fr om the solv en t - to - air in te rface

− “Carry out ” of e xc ess solv en t on cleaned parts

− E va por ative losses of the solv en t during filling and dr aining of the machine
**| 19** 

## E **ST IMA** 

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **C OLD**  

## C **LE ANING**  

## D **EG REASING**  

## – **M ONIT**  **ORING DA**  **TA**



### • EP A/OPPT obtained OSHA IMIS data f or two fa cilities:

− The fir st facility manuf actur es decor ative, ar chit ectur al and chur ch lighting , and uses 1 - BP to clean parts in an immer sion pr ocess in an ar ea with gener al ve nt ilation

− The second f acility manuf actur es parts for the aer ospace indus try and uses 1 - BP in a degr easing ta nk equipped with a spr ay no zzle

**| 20** 

## E **ST IMA** 

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **C OLD**  

## C **LE ANING**  

## D **EG RE**  **ASING** 

## – **M ONIT**  **ORING** 

## , P **RE** 

## - **EC**

**| 21**  n=10 n=18hrTWAConcentration(ppm)

## E **ST IMA** 

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **C OLD**  

## C **LE ANING**  

## D **EG REASING**  

## - **M ODELING** 



### • Near - field/f ar - field modeling used

• Model appr oach and input par ameter s for cold cleaning ar e similar to v apor degr easing

• EP A/OPPT performed a Mon te Carlo simulation

**| 22** 

## E **ST IMA** 

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **C OLD**  

## C **LE ANING**  

## D **EG RE**  **ASING** 

## – **M ODELING**  

## , P **RE** 

## - **EC**

**| 23** 8hrTWAConcentration(ppm)

95 th percentile 50 th percentile M ean

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **A ER**  **OSOL** 

## D **EG RE**  **ASING** 

## - **M ONIT** **ORING**

• In volves use of an aer osoliz ed solv en t spr ay fr om a pr essuriz ed can

• Liter atur e sear ch iden tified monit oring data fr om two studies designed to simulate aer osol degr easing

• One tested an ex posur e scenario wher e the aer osol degr easing occurr ed inside a non - ve nte d booth, with monitoring also conducted post - EC ( e.g., using a v en te d booth)
**| 24** 

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **A ER**  **OSOL** 

## D **EG RE**  **ASING** 

## – **M ONIT** **ORING** 

## , **P RE**  

## - **EC**

**| 25** 8hrTWAConcentration(ppm)

n=7

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **A ER**  **OSOL** 

## D **EG RE**  **ASING** 

## - **M ODELING**  • Near - field/F ar - field modeling appr oach used • EP A/OPPT performed a Mon te Carlo simulation

**| 26** 

## E **STIMA**

**TING** 

## I **NHALA**

**TION** 

## C **ONCENTRA**

**TIONS** 

## – **A ER**  **OSOL** 

## D **EG RE**  **ASING** 

## – **M ODELING**  

## , **P RE**  

## - **EC**

**| 27** 8hrTWAConcentration(ppm)

95 th percentile 5 th percentile M ean 95 th percentile 5 th percentile M ean 7 5 th percentile

## S **UMMAR Y**  

## :

**O CCUP**  **AT IONAL**  

## E **XPOSURE** 

## E **STIMA TES**  

## , P **RE** 

## - **EC**

**| 28** 

## S **UMMAR Y**  

## :

**O CCUP**  **AT IONAL**  

## E **XPOSURE** 

## E **STIMA TES**  

## , P **RE** 

## - **EC**

**| 29**  **Occupational Use**  **Scenario Air**  **Concentr ation**  **(ppm) Centr**  **al Te**  **ndency (50**  **th per**  **centile) High**  **End**

**( 95**  **th per**  **centile) Wo**  **rk er**  **ONU Wo**  **rk er**  **ONU Spr**  **ay Adhesive**  131 (sprayer) 3 253 (sprayer) 129 **Dry Cleaning** 29.4 12.1 50.2 20.6 **Va por**  **Degr easing**  8.20 0.44 47.7 4.90 **Cold Cleaning**  13.7 2.6 (what if ) 46.9 2.6 (what if ) **Aer osol Degr**  **easing** 16.1 N/D 31.6 N/D

**Estimated 1 -**  **BP Air Concentr ations**  **(8 -**  **hr TW**  **A )**  **Based on Occupational**  **Uses, Monitoring**  **Data**

**Notes:** N/D = no data “what if ” is based on a single data point

# A **CUTE** 

# E **XPOSURE** 

# C **AL CULA**  **TION** Acut e ex posur es for work er s are estimated as follows:

= × 

### wher e: AC = acut e concentr ation (8 - hr TWA) C = contaminant concentr ation in air ( 8 - hr TWA) ED = ex posur e dur ation (8 - hr/da y ) AT = a ve ra ging time (8 - hr/da y) (Acut e ex posur es for consumer s ar e es timated assuming a 24 hr ave ra ging time) **| 30** 

### = × × ×



### Where: ADC = a ve ra ge daily concentr at ion (8 - hr TWA) used f or chr onic

non - cancer risk calculations LADC = lifetime ave ra ge daily concentr at ion (8 - hr TWA) used fo r

chr onic cancer risk calculations C = contaminant concentr at ion in air (8 - hr TWA) ED = ex posur e dur at ion (8 hr /da y) EF = ex posur e fr equency (260 da ys/yr) WY = wo rking year s per lifetime (40 yr) AT = ave ra ging time (lifetime × 260 da ys/yr × 8 hr s /da y)

(lifetime is a 40 yr wo rking lifetime fo r non - cancer risks; and a 70 yr lifetime fo r cancer risks ) 

# C **HRONIC** 

# E **XPOSURE** 

# C **AL CULA**  **TIONS**

**| 31** 

# C **ONSUMER** 

# E **XPOSURE** 

# A **SSESSMENT**

**S LIDES**  **32 -**  **35 RELA** 

**TE TO**  **C HARGE**  **Q UESTIONS**  **3 -**  **1 THROUGH**  **3 -**  **2** 

### Objectives: • Iden tify Consumer Uses

− Aer osol Spr ay A dhesiv es

− Aer osol Spot R emover

− Aer osol Cleaner and Degr easer


### • Es timate exposur e lev els

− 50 th (centr al t endency) and 90 th (high - end) per centile v alues

− No consumer monitoring data a va ilable ther efore modeling wa s used



### • Calculate acute concentr ation using a 24 - hr TWA **| 32** 

# C **ONSUMER** 

# E **XPOSURE** 

# M **ODELING**

**| 33** 



### • Model: Consumer Exposur e Model module within EP A’ s Exposur e and F ate Assessmen t Scr eening T ool (E - FA ST)

− Tw o z one r epr esentation of a house • Zo ne 1: ar ea wher e pr oduct is being used • Zo ne 2: r emainder of the house 

### • Default v alues used wher e applicable • Exposur e fact or s fr om EP A’ s EFH 2011 • Consumer beha vior inputs fr om 1987 Household Solv en t Pr oduct Use Sur vey

# C **ONSUMER** 

# E **XPOSURE** 

# R **ESUL TS** 

**Consumer Use Scenario Air**  **Concentr ation**  **(ppm) Centr**  **al Te**  **ndency (50**  **th per**  **centile) High**  **End**

**(90 th**  **per centile)**  **User Non**  **- User**  **User Non**  **- User**  **Aer osol Spr**  **ay A**  **dhesiv e**  0.5 0.1 6 2 **Aer osol Spot**  **Re mover**  2 0.7 23 6 **Aer osol Spr**  **ay Cleaner**  **s and Degr**  **easer s:**  **Engine Degr**  **easing Use**  16 6 54 20 **Br ak**  **e Cleaning Use**  5 2 22 8 **Electr onics**  **Cleaning Use**  0.5 0.2 7 3 **| 34**  **Estimated 1 -**  **BP Air Concentr ations**  **(24 -**  **hr TW A)**  **Based on R**  **esidential Indoor**  **Uses**

# C **ONSUMER** 

# E **XPOSURE** 

# S **UMMAR Y** 

• Exposur e es timates based on modeling

• Es timated ex posur es for all iden tified use scenarios

• Highes t exposur e potential iden tified for 1 - BP use in aer osol spr ay cleaner s and degr easer s ( e.g. , engine degr easing and br ak e cleaning)

• Insufficient inf ormation to estimate the number of consumer s for the ev aluated uses
**| 35** 

# H **UMAN** 

# H **EA LT**  **H** 

# H **AZARD** 

# I **DENTIFICA TION**  **AND** 

# D **OSE** 

# - **R ESPONSE**  

# A **SSESSMENT S**  **LIDES 36**  **– 42**  **RELA**

**TE TO**  **C HARGE**  **Q UESTIONS**  **4 -**  **1 THROUGH**  **4 -**  **4**

**| 36** **Study Pe**  **rf ormance** 

**Elements Assessment**  **Substance char**  **acterization** Purity > 99%; stability monitor ed **Animal husbandry** Rats (F344/N), mice (B6C3F 1 ); Adequate housing, animal care , and maintenance described **Study design quality** Rats and mice, both se xe s, tr eated via inhalation fo r an exposur e fr equency and dur ation appr opriate and r elevant to determine ex posur e - re lated effect; appr opriate spacing of doses; adequate number of animals/ gr oup **Clinical observations, necr**  **opsy and pathology**  Clinical observations re ported ; all animals necr opsied; all or gans/tissues exa mined for gr oss lesions; histopathological evaluation of all major or gans; adequate description of e xperimental design and pathology pr ocedur es **Data reporting and statistical methods**  Individual animal data provided in tabular f ormat; tumor s (benign/malignant) fr om same or gan appr opriately r eported as combined; historical contr ols ava ilable fo r comparison **Studies inf ormative for**  **cancer assessment**  Ye s, for studies in r ats and in mice No major limitations 

# D **ATA** 

# Q **UA LITY**  

# - **A NIMAL**  

# T**OX ICITY** 

**| 37** 

## C **ONSIDERA**

**TIONS** 

## F **OR** 

## R **EVIEWING** 

## D **ATA** 

## Q **UA LITY**  **IN** 

## E **PIDEMIOL OGICAL**  

## D **ATA Study**  **Po pula**  **tion** Re cruitment Str ategy , inclusion/ exc lusion criteria; Number , time period, age/ se x/ other distribution, geogr aphic ar ea; P articipation ra tes (at each stage), eligibility , comparison gr oup selection, attrition r ate; Follow up; Compar ability (exposed and non - ex posed) **Exposur e**  Specific substance measur ed, analytical methods; T ypes of samples collected (matrix ); Exposur e gr oups defined, methods to assign; Limit of detection or level of quantitation, number of samples above/below; Exposur e distribution (centr al tendency , r ange, etc ); Po tential fo r ex posur e misclassification; Use of TWAs for occupational studies; Empirical , estimated, or modeled ex posur es; Timing of collection; Validation of biomark er s **Statistical Analysis**  Power; Appr opriateness of methods used; R eliable , consistent;

Tr eatment of non - detects or < LO Q; Adjustment of va riables; Explicit pr esentation of re sults; Significance levels clearly defined **Out come**  Novel or va lidated assessment tools, appr opriateness for study

population; Blinding; Explicit , complete pr esentation of re sults; Timing; Confounding; Concor dance of te xt with data r esults in tables; P otential bias **| 38** 

# C **ANCER** 

# H **AZARD** 

# :

**P ROBABLE**  

# M **UT**

**AG ENIC**  

# MO **A**
• NTP R eport on Car cinog ens: “ reasonably anticipat ed to be a carcinogen ”

• Cancer findings include signific an t increases in:

− S kin tumor s in male r ats

− I ntestinal tumor s in female r ats

− Lung tumor s in female mice

• We igh t - of - evidence analysis found sufficient support f or pr obable mut ag enic MOA

• Multiple lines of evidence include in vitro , in vivo and structure activity relationships

• EP A c oncluded “lik

ely human carcinogen” **| 39** 

# C **ANCER** 

# D **OSE** 

# - **R ESPONSE**  

# A **SSESSMENT**

• Appr oach harmoniz ed with NIOSH:

− Benchmark dose modeling (BMD) with BMR 0.1% added risk

− BMC and BMCL e xtr apolated to humans on body weight 3⁄4 scaling and adjus ted fo r e xposur e dur at ion



### • Lung tumor s select ed as basis fo r Inhalation Unit Risk (IUR)

• IUR calculated using linear appr oach: **IUR = BMR**  **÷ BMCL**  = 0.001 ÷ 0.30 ppm = 3 x 10 - 3 

### per ppm (7 x 10 - 7 

### per μ g/ m 3 

### ) **| 40** 

# N **ON** 

# - **C ANCER**  

# D **OSE** 

# - **R ESPONSE**  

# S **UMMAR Y** 

**| 41** 

# H **AZARD** 

# ID **AND** 

# D **OSE** 

# - **R ESPONSE** 



# S **UMMAR Y**  

# :

• PODs identified f or select ed non - cancer and cancer endpoin ts

• Select ed mos t r obus t and sensitiv e HECs fo r each health effect domain

• Non - cancer HECs r ang e fr om 25 - 150 ppm

• Deriv ation of the IUR based on incr eased incidence of lung tumor s in female mice
**| 42** 

# R **ISK** 

# C **HARA CTERIZA**  **TION S**  **LIDES 43**  **– 55**  **RELA**

**TE TO**  **C HARGE**  **Q UESTIONS**  **5 -**  **1 THROUGH**  **5 -**  **4**



### • Risk s ev aluated for acut e/ chr onic inhalation e xposur es to work er s and occupational non - user s
• Risk s ev aluated for acut e inhalation e xposur es to consumer user s and non - user s
• Dev elopmen ta l to xicity select ed as most sensitiv e endpoin t for ev aluating risks associated with 

## acut **e** occupational and consumer ex posur e
• Cancer , dev elopmen ta l to xicity and neur oto xicity select ed as the mos t sensitiv e endpoin ts for ev aluating risks associated with 

## chr **onic** occupational ex posur e **| 43** 

# R **ISK** 

# E **ST IMA**  **TION** 

# : N **ON** 

# - **C ANCER**  

# E **FFE CTS** 

= ( ) Where : MOE = Mar gin of exposure ( unitless) Haz ar d va lue (POD) = select ed HE Cs (ppm ) Human Exposur e = inhalation exposure estimate for each use (ppm ) **MOE estima**  **tes compar**  **ed to**  **benchmark MOEs to determine risk** 

**( i.e**  **., MOE < benchmark MOE indica tes**  **risk)**

**| 44**  

### Risk No Risk

# R **ISK** 

# E **ST IMA**  **TION** 

# : N **ON** 

# - **C ANCER**  

# E **FFE CTS**  **Fo r**  **acut e (non**  **- cancer)**  **ex posur**  **e scenarios (w**  **ork er**  **s and**  **consumer s):** 

• Dev elopmen ta l to xicity: HE C = 31 ppm (8 hour TWA for work er s) HE C = 10 ppm (24 hour TWA for consumer s) **Fo r**  **chr onic**  **(non -**  **cancer) e xposur**  **e scenarios (work er**  **s):**

• Dev elopmen ta l to xicity: HE C = 43 ppm • Neur oto xicity: HE C = 25 ppm
**| 45** 

## N **ON** 

## - **C ANCER**  

## R **ISK** 

## E **STIMA TES**  **FOR** 

## O **CCUP**

**AT IONAL**  

## I **NHALA TION**  

## E **XPOSURES** 

## - **M ONIT** **ORING** 

## D **ATA**

**| 46**  **HE AL**  **TH EFFE CT** 

**, ENDPOINT**  **and STUD**  **Y** 

### Wo **rk er**  **Exposur e**  **95 th**  

### Pe **rc en**  **tile Es**  **timates Benchmark**  **MOE (T**  **otal UF)**  **ACUTE MOE**  **1 CHRONIC**  **MOE 1** 

**OCCUP AT**  **IONAL USES Spr**  **ay Adhesives**  **Dry**

**Cleaning Va**  **por**

**Degreasing Spr**  **ay**

**Adhesives Dry** 

**Cleaning Va**  **por**

**Degreasing Developmental**  **To xicity**  Decreased live lit ter siz e (F 1 ) ( WIL Research, 2001 ) **0.12 0.62**  **0.65 0.17**  **0.86 0.90**  100 **Neuroto xicity**  Decreased traction time ( Honma et al., 2003 ) **N/ A**  **N/ A**  **N/**

**A 0.10**  **0.50 0.50**  1,000 Notes: 1 MOEs (HE C in ppm/ ex posur e estimate in ppm) lower than the Benchmark MOE (T otal UF) indicate potential health risks and ar e denoted in **bold** .

## N **ON** 

## - **C ANCER**  

## R **ISK** 

## E **STIMA TES**  **FOR** 

## C **ONSUMER** 

## I **NHALA TION**  

## E **XPOSURES** 

## - **M ODELING**  

## D **ATA**

**| 47**  **HEAL TH**  **EFFECT ,**  **ENDPOINT and**  **STUD Y**  **Acute**

**HE C**  **(ppm)** ***** 

### Consumer Exposur **e 90 th**  

### Pe **rc en**  **tile Estimat es**  **Benchmark MOE**  **(T otal**  **UF) AEROSOL SPRA** 

**Y ADHESIVE MOE**  **1 AEROSOL SPO**  **T**

**REMO VER MOE**  **1 AEROSOL SPRA**  **Y CLEANERS AND DEGREASERS ENGINE**  **DE GREASER**  **MOE 1**  **BRAKE CLEANER**

**MOE 1**  **ELECTRONICS**

**CLEANER MOE 1**  **User 2**  **Non**   ** User** **3 User**  **2 Non**  ****

**User 3**  **User 2**  **Non**  

** User** **3 User**  **2 Non**  ****

**User 3**  **User 2**  **Non**  

** User** **3 Developmental**  **To xicity**  Decreased live lit ter siz e (F 1 ) ( WIL Research, 2001 ) 10 **1.7 5**  **0.4 1.7**  **0.19 0.5**  **0.45 1.3**  **1.4 3.3**  100 **Not es:**  * The acute consumer H EC s wer e adjusted f or 24 hour e xposur e 1 MOEs (HE C in ppm/ ex posur e estimate in ppm) lower than the Benchmark MOE (T otal UF) indicate potential health risks and ar e denoted in **bold** . 2 MOEs for the use categories can be e xtended to diff er ent age gr oups; however , EP A believed the user s of these pr oducts to be adults. 3 All age categories (< 1 yr s ; 1 - 2 yr s ; 3 - 5 yr s ; 6 - 10 yr s ; 11 - 15 yr s ; 16 - 20 yr s ; and > 21 yr s )

# C **ANCER** 

# R **ISK** 

# E **ST IMA**  **TION**

= × Where: Human e xposur e = Inhalation es timate (LADC in ppm) IUR = Inhalation unit risk (3 x 10 - 3 

### per ppm )

**| 48**  

### Cancer risk es timates wer e calculated for: • Chr onic ( i.e ., occupational) ex posur e scenarios • **N ot f** **or acut**  **e** ( i.e ., consumer) e xposur e scenarios

# C **ANCER** 

# R **ISK** 

# B **ENCHMARK S** 

• 1x10 -6 : 1 chance in 1 million of an individual dev eloping cancer (equiv alent to 1 cancer case in 1 million)

• 1x10 -5 : 1 chance in 100,000 of an individual dev eloping cancer (equiv alent to 10 cancer cases in 1 million)

• 1x10 -4 : 1 chance in 10,000 of an individual dev eloping cancer (equiv alent to 100 cancer cases in 1 million)

**| 49**  = × Where: 95 th per centile cancer risk = 95 th per centile exposur e X IUR Exposed population is the 95 th per centile ( i.e. , 5 per cent of the total number of work er s) Wo rk er s ar e assumed to be exposed 8 hr/da y, 2 60 da y/yr for 40 y ear s

## A **DDED** 

## C **ANCER** 

## R **ISK AT**  **THE** 

## 95 **TH** 

## P **ERCENTILE** 

## F **OR**



## I **NHALA TION**  

## E **XPOSURE S** 



### Incr eased cancer incidence: 5 to 40 work er s **| 50**  

### Occupational **Use of 1 -**  **BP in Spr ay** **Adhesives -**  **Monit oring**  **Data**

## A **DDED** 

## C **ANCER** 

## R **ISK AT**  **THE** 

## 95 **TH** 

## P **ERCENTILE** 

## F **OR**



## I **NHALA TION**  

## E **XPOSURE S** 



### Incr eased cancer incidence: < 1 to 4 work er s **| 51**  

### Occupational Use of 1 **- BP in Dry Cleaning**  **- Monit**  **oring Data**

## A **DDED** 

## C **ANCER** 

## R **ISK AT**  **THE** 

## 95 **TH** 

## P **ERCENTILE** 

## F **OR**



## I **NHALA TION**  

## E **XPOSURE S**  

### Occupational **Use of 1 -**  **BP in V apor**  **Degr easing**  **- Monit**  **oring Data**

**| 52**  

### Incr eased cancer incidence: < 1 to 40 work er s

# C **ANCER** 

# R **ISK** 

# C **ONCL USIONS** 

• Cancer risks to work er s and occupational non - user s ar e significantly incr eased at the occupational ex posur e concentr ations/dur ations assumed for each scenario

• Risk calculations ar e based on conser vat iv e assumptions which ma y pr oduce conser vat iv e cancer risk es timates

**| 53** 

# R **ISK** 

# C **HARA CTERIZA**  **TION** 

# S **UMMAR Y** 

• Non - cancer risks identified for work er s with acute and chr onic e xposur es t o 1 - BP in spr ay adhesiv es, dry cleaning (including use in spot cleaning) and degr easing (v apor , cold cleaning and aer osol)

• Cancer risks identified fo r work er s with chr onic ex posur es t o 1 - BP in spr ay adhesiv es, dry cleaning (including spot cleaning) and degr easing (v apor , cold cleaning and aer osol)

• Non - cancer risks iden tified fo r consumer s with acute ex posur es t o 1 - BP in spr ay adhesiv es, spot re movers and degr easer s

**- |**  **54**

# A **SSUMPTIONS AND**  

# K **EY** 

# S **OUR CE**  **S OF** 



# U **NCER TA**  **INTY**
• Sit es used for e xposur e monitoring data we re not select ed r andomly
• Exposur e modeling appr oaches employed knowledg e based assumptions
• Risk determinations pr edicated on the pr esumed re lev ance of effects obser ve d in r oden ts to humans
• Dev elopmen ta l effects ma y r esult fr om a single e xposur e during a critical period

• Uncert ain ty re ga rd ing the pr oposed mode of action
• Dermal e xposur es wer e not quan tified **| 55** 

# EP

**A 1 -**  **BP R ISK**  

# A **SSESSMENT** 

# T **EA M** 

Ka therine Anitole St an Bar one Jr

. Chris Brink erhof

f Judith Br own Anjali Lamba Gr eg Macek Pa ul Matthai Albert Monr oe Ginger Moser Alie Muneer Tina Ndoh Nhan Nguyen Shar on Ox endine Andrea Pfahles - Hutchens Justin R oberts Nina Simeonov a Christina Thompson Eva W ong Yin - Ta k W oo

**| 56** 

# Pe er Re view Char ge Ques tions

57

# G **ENERAL** 

# I **SSUES ON**  **THE** 

# R **ISK** 

# A **SSESSMENT**

Question 1 - 1: Please c ommen t on whether the information pr ovided in Section 1 (Backgr ound and Sc ope) is appr opriat e and accur ately char act eriz es the fit for purpose nature of this assessmen t for TSCA r elated uses? Please pr ovide an y specific sugg estions for impr oving the clarity and tr ansparency of the backgr ound information that describes sc ope and limits of the assessmen t .

**58**

# G **ENERAL** 

# I **SSUES ON**  **THE** 

# R **ISK** 

# A **SSESSMENT**

Question 1 - 2: Please c ommen t on the sc ope of the assessmen t, in particular the c onceptual model resulting fr om EP A/OPPT ’s pr oblem formulation. Please pr ovide an y other signific an t lit er ature, reports, or data that wo uld be use ful t o co mplete this char act eriz ation and that ma y support ex pansion or refinement of the sc ope of this assessmen t .

**59**

# O **CCUP**

**AT IONAL**  

# E **XPOSURE** 

# A **SSESSMENT**

Question 2 - 1: Please c ommen t on the appr oaches used, and pr ovide an y specific sugg estions or rec ommendations fo r alt ernative appr oaches, models, or information (references) that c ould be c onsidered by EP A/OPPT for impr oving the wo rkplace e xposure assessmen t, including estimations f or bysta nder/non - user s ( e.g. , w omen of child - bearing ag e).

**60**

# O **CCUP**

**AT IONAL**  

# E **XPOSURE** 

# A **SSESSMENT**

Question 2 - 2: Please c ommen t on whether there are an y additional occupational e xposure scenarios that EP A/OPPT co uld address that ha ve not already been quan tified. Please also pr ovide specific references and/ or data to address such additional ex posures.

**61**

# O **CCUP**

**AT IONAL**  

# E **XPOSURE** 

# A **SSESSMENT**

Question 2 - 3: Fo r the e xposure assessmen ts based on monit oring dat a, are you aware of an y additional sour ces of occupational e xposure monit oring dat a that EP A/OPPT c ould co nsider in its assessmen t? If so , please pr ovide specific lit er ature, reports, or dat a that would help us refine the ex posure assessmen t .

**62**

# O **CCUP**

**AT IONAL**  

# E **XPOSURE** 

# A **SSESSMENT**

Question 2 - 4: Fo r the e xposure assessmen ts based on modeling, ar e you aware of an y additional sour ces of dat a that EP A/OPPT c ould c onsider in deriving the par ameter va lues used in the modeling? If so , please pr ovide relev an t lit er ature, reports, or dat a that would help us refine the par ameter s used in the modeling

**63**

# C **ONSUMER** 

# E **XPOSURE** 

# A **SSESSMENT**

Question 3 - 1: Please c ommen t on the appr oach used and pr ovide an y specific sugg estions or rec ommendations fo r alt ernative appr oaches, models, or use information ( e.g. , information on dur ation, number of user even ts, amoun t used) that c ould be c onsidered by EP A/OPPT in developing and / or ref ining the e xposure assumptions and estimat es fo r spr ay adhesives, aer osol spot remover s and aer osol spr ay cleaner s and degreaser s.

**64**

# C **ONSUMER** 

# E **XPOSURE** 

# A **SSESSMENT**

Question 3 - 2: Exposure estimates were developed fo r three co nsumer uses: spr ay adhesives, aer osol spot r emover s and aer osol spr ay cleaner s and degreaser s. All pr oducts are aer osol spr ays and appear t o be a va ilable for sale and use by co nsumer s in the U .S. There were no current reliable data reg ar ding the c onsumer e xposure scenarios. Please c ommen t on the c onsumer uses select ed for this assessmen t and pr ovide an y specific sugg estions or rec ommendations fo r additional uses (including inf ormation on dur ation, number of user events, amoun t used) that c ould be c onsidered for eva luation.
**65**

# H **AZARD AND**  

# D **OSE** 

# - **R ESPONSE**  

# A **SSESSMENTS**

Question 4 - 1: EP

A/OPPT c oncluded in the risk assessmen t that 1 - BP c ar cinog enesis occur s thr ough a pr obable mut ag enic mode of action based on the t ot ality of the a va ilable data/information and the WOE. Please c ommen t whether the ca ncer haz ar d assessmen t has adequat ely described the WOE reg ar ding the mut ag enic mode of action.

**66**

# H **AZARD AND**  

# D **OSE** 

# - **R ESPONSE**  

# A **SSESSMENTS**

Question 4 - 2: EP

A/OPPT iden tified liver t ox icity , kidney t ox icity

, repr oductive/developmental to xicity , and neur ot ox icity in the risk assessmen t as adver se human health e ffects fo r risk char act eriz ation. EP

A/OPPT used these endpoin ts t o c alculate PODs t o assess non - ca ncer risk s associat ed with chr onic inhalation e xposures. As part of the review , please c ommen t on the choice of these endpoin ts as PODs for assessing risk s in humans associat ed with acut e and chr onic inhalation ex posures t o 1 - BP

. Are there other dat a that EP A/OPPT c ould ha ve considered for the haz ar d identification and dose response associat ed with chr onic inhalation e xposures? If so , please pr ovide specific dat a and references. **67**

# H **AZARD AND**  

# D **OSE** 

# - **R ESPONSE**  

# A **SSESSMENTS**

Question 4 - 3: Please c ommen t on the WOE analysis for the choices of non - ca ncer endpoin ts for the acut e and chr onic risk scenarios. Please pr ovide additional data, data interpretation or information that would ha ve informed the W OE analysis and selection of critic al studies for the PODs.

**68**

# H **AZARD AND**  

# D **OSE** 

# - **R ESPONSE**  

# A **SSESSMENTS**

Question 4 - 4: Ty pic ally

, EP A uses the benchmark dose modeling software (BMDS) with a BMR of 10% and the models ar e restricted to multistage models or the br oader suit e of dichot omous models in BMDS and a single best model is chosen for the POD . EP

A/OPPT used an alt ernative appr oach to ca lculate the ca ncer POD ver sus the st andard appr oach of choosing best fit model. Brie fly , EP A/OPPT used a model ave ra ging appr oach c onsidering multiple benchmark dose models t o c alculate the POD at a benchmark response (BMR) level of 0.1%. Please c ommen t on the assumptions, streng ths and weaknesses of the model a ver aging appr oach for determining the POD in the c ancer assessmen t. **69**

# R **ISK** 

# C **HARA CTERIZA**  **TION** Ques tion 5 - 1: EP

A/OPPT interpreted the endpoint of decreases in liv e lit ter siz e f ollowing e xposur e t o 1 - BP bef or e and during gestation, as a surr og ate f or fr ank dev elopmental effects in r elevant to humans per EP

A’ s Guidelines f or Dev elopmental T ox icity Risk Assessment . EP

A/OPPT used this endpoint to calculate a point of departur e (POD) to assess non - cancer risks associated with acute inhalation e xposur es t o 1 - BP . Please comment on the assumptions, st re ng ths and weaknesses of the MOE appr oaches used to es timate the non - cancer risks to work er s and occupa tional non - user s fo llowing acute inhalation e xposur es t o 1 - BP , including the MOEs pr esented in the document. Please comment on the assumptions, st re ng ths and weaknesses of the MOE appr oaches used to es timate risks to consumer s f ollowing acute inhalation e xposur es; including non - user s ( e.g. , bystander s who ma y be childr en, or w omen of childbearing age). Specifically , please comment on the decision to limit the analysis to acute e xposur es without r esidual concerns between events and what data could critically inf orm modifying this appr oach f or consumer s. Please comment on the selection of uncert ainty f act or v alues in deriving the benchmark MOE f or acute inhalation e xposur es. **70**

# R **ISK** 

# C **HARA CTERIZA**  **TION**

Question 5 - 2: Please c ommen t on the assumptions, streng ths and weaknesses of the MOE appr oaches used t o es timate the non - ca ncer risk s t o w ork er s and occupational non - user s fo llowing chr onic inhalation e xposures t o 1 - BP , including the MOEs presen te d in the documen t. Please c ommen t on the selection of uncert ain ty fact or v alues in deriving the benchmark MOE fo r chr onic inhalation ex posures.

**71**

# R **ISK** 

# C **HARA CTERIZA**  **TION**

Question 5 - 3: Please c ommen t on the assumptions, streng ths and weaknesses of the appr oach used t o es timate added lifetime ca ncer risk s t o w ork er s which EP A/OPPT - derived fr om an inhalation unit risk based on lung tumor s in female mice for estimating incremental or added individual lifetime ca ncer risk.

**72**

# R **ISK** 

# C **HARA CTERIZA**  **TION**
Question 5 - 4: Please c ommen t on whether the risk char act eriz ation has adequat ely described the assumptions, uncert ain ties and dat a limit ations in the methodology used t o assess risk s fr om 1 - BP

. Please c ommen t on whether this information and risk c onclusions are presen te d in a logic al, tr ansparent manner and pr ovide sug ge stions that c ould increase clarity in the risk char act eriz ation.

**73**