Boric A cid / Salts of Boric Acid Draft Risk Assessme nt DP No. 0418384

UNITED STATES ENV IRONMENT AL PROTECT l ON AGENC Y

WASI ll NGT O

. D. C. 20460

OFFICE OF CHEM I CAL SAFETY
AND POLLUTION PREVENTION

MEMORAND U M

D A T E: December l

, 20 1 5

SUBJECT: Boric Acid/Sodium Salt s of Boric Acid. Human H ea lth D raft R i sk Assess m e nt fo r Registration Rev i ew

.

P C Codes: 0 11 001, 0 1 1102

, 011103

, 011104

, 01 1 107

, DP B a r code: 0418384

01 1 110

, 011111

, 011112

, 011002

D ec i s i o n No.: 488334 Re g i stration No .: Multiple Re g i s tration s Regulator y Action: R egistrat i on R ev i ew Case No.: 00 24 Petiti o n No.: N I A
Ri s k A ssess m e nt T y p e: Single C h e mical Aggregate
TXR No.: N I A CAS Nos.: 10043-35-3, 1303-96-4

, 11 30-12-4

, 1 2 179

- 04-3, 1330-43-4

, 1 2008-4 1-2

, 15 293- 77-3

, 130 3-86-2

MRID No.: N I A 40 CFR: 180 .1 1 21, 1 80.920

, 180.940

FR OM: Matt h ew Crow l ey, Bio l og i st/Ris k

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THROUGH: Ri sk Assessme n t Branch 11

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Health Effects Div i sio n (7509 P )

Timothy C. D ole, C IH

, Indu s tr i al H ygie ni st \ ·

# ~~ Ri sk Assess m e nt and Sc i e n ce Suppo rt Bran c h (RASS B)

Antim i crobia l s Di vis ion (75 1 OP)
Office of Pest i c id e Program s

Chr i st i na Swartz

, Branch C h ief

# lf.w~ Risk Assessment Branch II

Chr i stop h er Sc hl osse r , Toxicolog i st/ D esignated R ev i ewer Kelly L owe , E n vironme nt al Scientist/ D esignated

### ev**ewe 7~~** **~** Risk Assessment Rev i ew Committee (RARC)

- ....... - /

H ea l t h Effects Di visio n (7509 P )

Steve Wei ss, B r a n c h C hi e f 

# ?ft.**u/~** Risk Assessment a nd Sc i ence S upp o rt Br a n c h

Ant imi crob i als D ivision (751 OP)
Office of P es ticide P rogramsBoric Acid/Salts of Boric Acid Draft Ri sk Assessment

TO: Moana Appleyard, Chemica l Review Manager
Ri sk Management and Implem e ntation Branch V
Pesticid e Re-evaluation Divi s ion

Sandra O'Nei ll

, Chem i ca l R ev i ew Manager Regulatory Management Bran c h I I

Antimicrobials Di v ision (751 OP)
Office of Pesticide Program s DP No. 0418384

As part of R egistrat i o n R ev iew

, the Pesticide Re-evaluation Divi sio n ( PRO) and the
Antimicrobials Di vision (AD) of the Office of Pe st icide Programs (OPP) ha s requested
evaluation of the ha za rd a nd exposure data and conduct occupationa l a nd r es idential exposure assessments, as n eeded, to esti m ate the risk to human health that will result from the curre ntl y

r eg i s tered uses of p es ticid es. This memorandum se rves as the draft ri s k assessment (ORA) of the dietary, occupationa l and residentia l exposure, and aggregate risk from th e currently registered
conventio nal and antimicrobial uses of bor i c acid and it s sodium salts (sodium tetraborate decahydrate, sod ium t e trab orate pe n tahydrate, sod ium tetraborate anhydrous

, disodium
octaborate tetrahydrate, disodium octaborate anhydrous and sodium m e tab orate).

Since the l ast ri s k assessment, completed for th e To l erance Reregistration E ligibility Decision (TR.ED) proce ss (L. H ansen, 26 Jul y 2006, 0320894)

, th e Health Effect s Divi s i on (HED) and
AD h ave conducted a r e-ev aluation of the toxicological database including s ub mission of
additional toxicity studies and a re-assessm e nt of non-dietary risks

, in cluding updated r esidential
and occupational risk assess ments and a ri sk assessment for exposures v ia spray drift. The risk

assessment was provided by Matthew Crowley (RABII)

, the residue che mi st ry review was provided by Denni s McNeilly (RABIV)

, the occ upati onal/ re siden tial exposure assessment was provided by Matthew Crow le y (RA BII) and Timothy Dole (RASSB / AO)

, and the hazard

c haracteri zat ion was provided by Linnea Han se n (RABil).

Pag e 2o f99Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 3 of 99 Table of Contents
1.0 Executive Summary

................................ ................................ ................................ ............... 5
2.0 HED and AD Recommendations

................................ ................................ ........................... 7
2.1 Data Deficiencies/Conditions of Registration

................................ ................................ 8
2.2 Tolerance Considerations

................................ ................................ ............................... 8
2.2.1 Enforcement Analytical Method

................................ ................................ ............... 8

2.2.2 International Harmonization

................................ ................................ ..................... 8

2.2.3 Tolerance Recommendations

................................ ................................ .................... 8

2.3 Label Recommendations

................................ ................................ ................................ 9
3.0 Introduction

................................ ................................ ................................ .......................... 10
3.1 Chemical Identity

................................ ................................ ................................ ......... 11
3.2 Physical/Chemical Characteristics

................................ ................................ ............... 12
3.3 Pesticide Use Pattern

................................ ................................ ................................ .... 12
3. 4 Anticipated Exposure Pathways

................................ ................................ ................... 14
3.5 Consideration of Environmental Justice

................................ ................................ ....... 14
4.0 Hazard Characterization and Dose

- Response Assessment

................................ .................. 14
4.1 Toxicology Studies Available for Analysis

................................ ................................ .. 15
4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

................................ . 16
4.2.1 Dermal Absorption

................................ ................................ ................................ .. 17

4.3 Toxicological Effects

................................ ................................ ................................ ... 18
4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

................................ ..... 20
4.4.1 Completeness of the Toxi cology Database

................................ ................................ 20

4.4.2 Evidence of Neurotoxicity

................................ ................................ ......................... 21

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

............ 21

4.4.4 Residual Uncertainty in the Exposure Database

................................ ........................ 21

4.5 Toxicity Endpoint and Point of Departure Selections

................................ .................. 21
4.5.1 Dose

- Response Assessment

................................ ................................ .................... 21

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

........ 24

4.5.3 Cancer Classification and Risk Assessment Recommendation

.............................. 24

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

................................ ................................ ................................ ............................ 24

4.6 En docrine Disruptor Screening Program

................................ ................................ ............. 26
5.0 Dietary Exposure and Risk Assessment

................................ ................................ .............. 27
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ ...... 29
6.1 Residential Handler Exposure

................................ ................................ ...................... 30
6.2 Residential Post

- application Exposure

................................ ................................ ......... 34
7.0 Non

- Occupational Bystander Post

- Application Inhalation Exposure and Risk Estimates

.. 37
8.0 Non

- Occupational Spray Drift Exposure and Risk Estimates

................................ ............. 37
9.0 Aggregate Exposure/Risk Characterization

................................ ................................ ......... 38
10.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 39
11.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 39
11.1 Occupational Handler Exposure/Risk Estimates

................................ .......................... 39Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 4 of 99 11.2 Occupational Post

- application Exposure/Risk Estimates

................................ ............. 49
11.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

...................... 49

11.2.2 Occupational Post

- application Dermal Exposure/Risk Estimates

.......................... 49

12.0 Public Health and Pesticide Epidemiology Data

................................ ............................... 50
13.0 References

................................ ................................ ................................ .......................... 50
13.1 OPP Mem oranda

................................ ................................ ................................ .......... 50
13.2 MRID Submissions

................................ ................................ ................................ ...... 51
13.3 Published Literature and Other Documents

................................ ................................ . 56 Appendix A: Toxicity Profile and Executive Summaries

................................ ............................ 59
A.1 Toxicology Data Requirements

................................ ................................ .................... 59
A.2 Toxicity Profiles

................................ ................................ ................................ ........... 60
A.3 Hazard Identification and Endpoint Selection

................................ .............................. 66
A.3.1 Acute Reference Dose (aRfD)

– All Populations Including Females Age 13

- 49 and
Children 66

A.3.2 Chronic Reference Dose (cRfD)

– All Populations Including Females Age 13

- 49 and
Children

................................ ................................ ................................ ................................ . 66
A.3.3 Incidental Oral Exposure (Short

- Term, 1

- 30 days and Intermediate

- Term, 1

- 6 month)

................................ ................................ ................................ ................................ ............... 67

A.3.4 Dermal Absorption

................................ ................................ ................................ .. 67

A.3.5 Residential and Occupational Dermal Exposure (Short

- and Intermediate

- Term; 1

- 30 days and 1

- 6 months)

................................ ................................ ................................ ....... 67

A.3.6 Residential and Occupational Inhalation Exposure

................................ ................ 67

A.4 Executive Summaries

................................ ................................ ................................ ... 69
A.4.1 Subchronic Toxicity

................................ ................................ ................................ 69

A. 4.2 Prenatal Developmental Toxicity

................................ ................................ ........... 73

A.4.3 Reproductive Toxicity

................................ ................................ ............................ 77

A.4.4 Chronic Toxicity

................................ ................................ ................................ ..... 80

A.4.5 Carcinogenicity

................................ ................................ ................................ ....... 85

A.4.6 Mutagenicity

................................ ................................ ................................ ........... 86

A.4.7 Neurotoxicity

................................ ................................ ................................ .......... 87

A.4.8 Me tabolism

................................ ................................ ................................ ............. 88

A.4.9 Immunotoxicity

................................ ................................ ................................ ....... 90
Appendix B: Chemical Identity and Physical/Chemical Properties

................................ ............ 93 Appendix C: Use Pattern Summary

................................ ................................ ............................. 95Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 5 of 99 1.0 Executive Summary

Use Profile

Boric acid and its sodium salts are inorganic compounds with registrations for use as active ingredients in insecticides, acaricides , herbicides, algaecides, fungicides and wood and material preservatives. Products are both liquid and solid formulations ranging from < 1% to 100% active ingredient and used in agricultura l , residential and commercial settings. Boric acid and its
sodium salts are also present as inert ingredients in pesticide products as well as ingredient s in

non

- pesticide consumer products.

Hazard/Toxicology Assessment

The toxicity database for boric acid/sodium salts has been upd ated since previous assessments
and i s considered complete for the purposes of human health risk assessment. The toxicology studies submitted to EPA in support of registration of boric acid/borate salts were conducted on boric acid or sodium tetraborate decahydrate (borax). For purposes of toxicological evaluation, studies on boric acid and borate salt compounds may be compared, and dosing considered equivalent, when they are normalized for exposure to boron (boron equivalents).

Boric acid/borate salts generally show low acute lethality by all routes (Toxicity Categories III or IV). Acute dermal and eye irritation potential vary among the different compounds. For example, sodium tetraborate decahydrate is Category I for eye irritation and IV for skin irritation, while boric acid is Categor y III for both.

Animal toxicity tests indicate that the testis is a target organ, causing atrophy and decreased spermiation , leading to decreased fertility . Other effects were hematological changes and decreased body weight. At high doses, clinical sign s of toxicity were observed. A bsorption is very low across intact skin. Increased pre

- natal susceptibility was observed in the rat, mouse and rabbit: developmental toxicity, including skeletal and visceral variations and malformations and
decreased feta l body weights, were observed in the presence of less severe, or absence of, maternal toxicity. For all exposure scenarios, uncertainty factors (UFs) are 10x for interspecies (UF A ) variation , 10x for intraspecies (UF H ) variation, and 1x for the F ood Quali ty Protection Act (F QPA ) safety factor

. The FQPA factor of 1x is based on an adequate toxicology database, well

characterized and clear no observed adverse effect levels ( NOAELs ) and lowest observed adverse effect levels ( LOAELs ) , dose selection being protective of potential developmental toxicity, and use of conservative inputs and models for exposure assessment. Thus a total UF of 100x applies, with estimation of risk in the form of Margins of Exposure (MOEs) based on a
level o f concern (LOC) of 100.

Boric acid/borate salts are classified as “not likely to be carcinogenic to humans” under the Agency ’s revised 2005 Cancer Guidelines. Genotoxicity studies did not indicate mutagenic or clastogenic potential. Epidemiological da ta do not indicate any boron exposure

- related cancers
in humans.

Dietary (Food and Water) Exposure and RiskBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 6 of 99 Based on data demonstrating that residues of boron in/on treated commodities are indistinguishable from those in/on control samples, and on the ex pectation that the low application rates associated with agricultural uses are not expected to add significantly to background levels in drinking water, a quantitative dietary risk assessment was not conducted

. B oric acid/sodium salts are exempt from the r equirement of tolerances

.

Residential Exposure and Risk

Residential exposure is possible via consumer pesticide use of products containing boric
acid/sodium salts applied as both liquid sprays/solutions and as solids (dusts , powders, or granules) in indoor and outdoor residential settings. Dermal and inhalation exposures are possible during application

, and dermal, inhalation, and incidental oral exposures (e.g., children’s hand

- to

- mouth exposures) are possible after applications. P ost

- application i ncidental
oral risk estimates for children were found to be of concern for broadcast spray treatments to carpets (MOEs < 100), primarily due to the relatively high application rates. All other handler and post

- application risk estimates were not of concer n

.

In the 2006 T olerance R eregistration E ligibility D ecision (TRED)

, boric acid/sodium salt

e xposures via non

- pesticide consumer use products (i.e., laundry detergent and general purpose cleaners) as well as its presence as an inert ingredient in pesticid e products

, were also considered
in the residential exposure pathway for purposes of characterizing the aggregate assessment s

. Those assessments, which did not identify any risks of concern, are included for registration
review.

Non

- Occupational Spray Dr ift Exposure and Risk

As n o risks of concern were identified from the direct spray lawn use, and the direct spray use on home lawn s would result in higher dermal and incidental oral exposures than would occur from spray drift onto residential areas resu lting from agricultural uses

, t here are no risks of concern for exposures resulting from spray drift

.

Volatilization/Residential Bystander

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The A gency has developed a Volatilization Screening Tool and a subsequent Vo latilization Screening Analysis, and d uring Regi stration Review, the Agency will u s e this analysis to determine if data (i.e., flux studies) or further analyse s are required for boric acid/sodium salts

.

Aggregate Exposure and Risk

Because the contribution of background dietary intake of boron is impli citly accounted for in the background dietary intake by the laboratory animals in the toxicology studies, aggregate risk is represented by the non

- dietary risk assessment

. Non

- dietary incidental oral risk estimates for
children following broadcast spray t reatments to carpets were found to be of concern (MOEs <Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 7 of 99 100), primarily due to the relatively high application rates. All other non

- dietary (i.e., residential handler and post

- application ) risk estimates for both pesticide and non

- pesticide uses were not of

concern

.

Occupational Exposure and Risk

Occupational exposure is possible via professional use of p roducts containing boric acid/sodium
salts applied as both liquid sprays/solutions and as solids (dusts , powders, or granules) in agricultural, commercial and residential settings. Dermal and inhalation exposures are possible during and after applications

. I nhalation exposures for some occupational handler scenarios

were the only occupational exposures to have risk estimates of con cern (MOEs < 100), requiring respirator s to mitigate risks . Some labels currently require respirators (and some only under certain conditions like in confined spaces), though most do not. For dust applications to structural building components (e.g., att ics, crawl spaces, soffits, etc.) and agricultural buildings (e.g., poultry houses) standard respirator s (i.e., filtering face

- pieces) do not mitigat e inha lation
risk estimates of concern. All other handler and post

- application risks were not of concern.

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions
to Address Environmental Justice in Minority Populations and Low

- Income Populations.”

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which inc lude studies from
the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Residential SOPs (Lawns/Turf, Indoor Envi ronments); and other registrant

- submitted handler exposure monitoring studies (MRIDs 44339801, 45250702, 45333401, 44439901, 45519601, 45167201, 43600102) and a human dermal absorption study (MRID 48507005) are (1) subject to ethics review pursuant to 40 C FR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board (HSRB) . Descriptions of data sources, as well as guidance o n their use, can be found at the following Agency websites: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risk s/occupational

- pesticide

handler

- exposure

- data

, http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

risks/occupat ional

- pesticide

- post

- application

- exposure , and http://www2.epa.gov/pesticide

science

- and

- assessing

- pesticide

- risks/stand ard

- operating

- procedures

- residential

- pesticide

.

2.0 HED and AD Recommendations

HED and AD ha ve examined all applicable databases for boric acid/sodium salts, and concludes
that t here are no residue chemistry, occupational/residential, or toxicology data deficiencies that would preclude the continuation of all registered uses and tolerance exemptions.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 8 of 99 In terms of human health risk concerns, there are no dietary risks of concern resulting from pesticide uses of boric acid and its sodium salts

. However, in the context of aggregate exposure and continuation of the tolerance exemptions, HED recommend s consider ation of the risk estimates of concern identified for post

- application incidental oral exposures resulting from broadcast spray treatments to carpets

. Additionally, HED and AD recommend reconciling default requirements for personal protective equipment (PPE) and restricted entry intervals (REIs) during any product label updates/revisions, based on consideration of risks of concern
identified for some o ccupational inhalation handler exposures. Finally, modification s to the tolerance exemption expressions to more accurately match the chemical names in this regulatory

case is recommended

.

2.1 Data Deficiencies/Conditions of Registration

There are no dat a deficiencies for boric acid/sodium salts.

2. 2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Boric acid/sodium salts are exempt from the requirement of tolerances without application rate
limitations , therefore an enforcement analytical method is not applicable

.

2.2.2 International Harmonization

W hile boric acid/sodium salts are exempt from the requirement of a tolerance in the U.S. and there is no Codex maximum residue level (MRL), various countries have boric aci d/sodium salts tolerances/MRLs by way of default values specified for those respective countries. For example, Canada has a default MRL of 0.1 ppm while the European Union (EU) has a default MRL of 0.01 ppm. Default MRLs are not considered for the purpos es of international harmonization.

2.2.3 Tolerance Recommendations

In 1971, e xemptions from the requirement of a tolerance were granted for boric acid and sodium metaborate “as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only” (40 CFR 180.1001(d); 36 FR 24216). Sodium tetraborate was later added to 40 CFR 1001(d) in 197 5 (4 0 FR 48681 ). In 2004 this citation was changed to 40 CFR
180.920.

A petition for an exemption from the requirement of a tolerance as an active ingredient on all raw agricultural commodities was submitted in June 1992

. In February 1993 HED’s Metabolism Committee considered and approved this petition and HED included this decision in its section
for the 1993 R eregistration Eligibility Decision (R ED ) . The tolerance exemption was formalized on August 20, 1993 in the Federal Register (58 FR 44282) and discussed in the 1993 RED. Additionally, in 2004 EPA issued a final rule that incorporated existing tolerances exemptions (21 CFR 178.101 0) by the Food and Drug Administration (FDA) thereby establishing under 40
CFR 180.940 an exemption from the requirement for a tolerance for residues of “ boric acid,Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 9 of 99 sodium salt ” as an active and inert ingredient in antimicrobial formulations (food

- contact su rface sanitizing solutions). In its chapter for the 2008 TRED HED recommended that all of these tolerance exemptions be maintained.

HED continues to recommend the tolerance exemptions in 40 CFR 180.1121

, 40 CFR 180.920,
and 40 CFR 180.940

. However

, t he CFR should

, rather than using synonyms or other names, b e modified to more accurately match the standard chemical names , PC codes, and CAS #’s in this regulatory case. The exemptions and comments/recommendations are summarized in Table
2.2.3.a below.

Table 2.2.3. a . Tolerance Summary for Boric acid and its Sodium Salts

C itation Established Exemption Comments /Recommendations

40 CFR §180. 1121 An exemption from the requirement of a tolerance is

established for residues of the pesticidal chemical boric acid and its salts, borax (sodium borate decahydrate), disodium octaborate tetrahydrate, boric oxide (boric anhydride), sodium borate and sodium m etaborate, in or on raw agricultural commodities when used as an active ingredient in insecticides, herbicides, or fungicides preharvest or postharvest in accordance with good agricultural practices

. I t is unclear which active ingredient is meant by “sodium borate”. It is often used as another name for borax (sodium borate decahydrate). If that is the case, “sodium
borate” should be deleted from the tolerance

exe mpt ion so it is not listed twice.

40 CFR §180. 920 “ The following materials are exempted from the

requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to

growing crops only :

Boric acid ( sequestrant )
S odium metaborate ( sequestrant )
S o dium tetraborate ( buffering agent ; corrosion

inhibitor) ” The exemption should be more specific in its
use of “sodium tetraborate” . It is unclear
whether it includes “s odium tetraborate pentahydrate ”, “sodium tetraborate decahydrate” and “sodium tetraborate anhydrous ”, or just a single one of those
chemicals

.

40 CFR §180. 940 (c) “ Residues of the following chemical substances are

exempted from the requirement of a tolerance when used in accordance with good manufacturing practice

as ingredients in an antimicrobial pesticide formulation, provided that the substance is applied on a semi

permanent or permanent food

- contact surface (other than being applied on food packaging) with adequate draining before contact with food

, (c) The follow ing chemical substances when used as ingredients in an antimicrobial pesticide formulation may be applied to:
Food

- processing equipment and utensils :

B oric acid, sodium salt ” It is unclear what active ingredient(s) is/are intended via use of “Boric acid, sodium salt”
in the exemption

.

However, the CAS# listed in 180.940(c) corresponds to sodium metaborate only.
Thus

, if it was intended to only represent sodium metaborate, “boric acid, sodium salt” should be replaced with “sodium
metaborate”

.

2. 3 Label Recommendations

Boric acid/sodium salts product labels vary considerably with respect to requirements for work attire and PPE. For example, some labels do not specify any requirements for work attire and/or
PPE , while others require respirators and cove ralls over long

- sleeve shirt and long pants.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 10 of 99 Similarly, restricted entry intervals (REIs) also vary considerably across labels (e.g., 4 hours versus 48 hours).

Thus, label corrections/revisions during registration review should be consistently made to
de fault to end

- use product and/or technical grade active ingredient acute (ocular, dermal, oral, and inhalation) toxicity requirements. These requirements may vary since each borate sodium salt might have a different acute toxicity profile, in addition to t he potential presence of other active ingredients in a product. In particular, 4 hour REIs should be evaluated in the context of Pesticide Registration (PR) Notice 95

- 3

. The 4 hour REI would not be appropriate for this active ingredient class as sodium t etraborate decahydrate is classified as an acute toxicity category I eye
irrita nt

– a category that typically triggers a 48 hour REI

.

Additional PPE label requirements beyond end

- use product acute toxicity requirements , such as respiratory protection, sho uld be considered as described in the context of any handler risks of
concern identified in this assessment.

3.0 Introduction

Boron is ubiquitous in the environment as a result of natural (e.g., weathering of rocks, geothermal activity, etc.) and anthropo genic (e.g., industrial emissions and wastes) sources (US EPA, 2008). It is normally found combined with oxygen as borates, including boric acid and its sodium salts, which in water a nd under normal physiological aqueous conditions exist a s undissociated boric acid . It is an essential nutrient for plants, and t here is some evidence suggesting that it may be a required micronutrient in mammals based on studies suggesting it is involved in the regulation of metabolism of minerals such as calcium; however, t his has not been definitively established (Naghii and Samman, 1993)

.

As pesticidal active ingredients, b oric acid and its sodium salts are regist ered as insecticides,
acaricides , herbicides, algaecides, fungicides and wood and material preservatives. Products are both liquid and solid formulations ranging from < 1% to 100% active ingredient and used in agricultural, residential and commercial settings. Products used in resident ial settings (e.g., dusts in homes, crack and crevice sprays, recreational parks, swimming pools), commercial/industrial areas (e.g., food handling establishments, airport runways, sewers, transport vehicles) and agricultural facilities (e.g., poultry hous es, greenhouses) are applied via hand dispersal, handheld equipment, or by vehicles. Products used on agricultural food/feed crops are applied via handheld sprays or by vehicles; chemigation and aerial applications are prohibited.
Antimicrobial material preservative products are added during the manufacturing of paints, inks/dyes, and coatings, and wood preservation is conducted via brush, trowel, injection, pressure treatment, dip diffusion treatment, or mechanized spraying. Boric acid and its sodium

sa lts are also present as inert ingredients in pesticide products as well as ingredients in non

pesticide consumer products.

The timeline below provides a brief description of its U.S. pesticide r e gulatory h istory

.

1948 Boric acid first registered as a pes ticide.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 11 of 99 1960 Tolerances established for boric acid and its sodium salts (40 CFR 180.271) on cottonseed (30 ppm) and citrus fruits (8 ppm, postharvest). [Year is approximate.]
1971 Exemptions from the requirement of a tolerance are granted for boric acid a nd sodium metaborate “as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only.” (40 CFR 180.1001(d); 36 FR 24216) . Sodium tetraborate was later added in 197 5 (40 FR 48681).
1986 Boric acid and its sodium salts are assessed for an EPA General Registration Standard, requiring producers to submit labels and provide Confidential Statements of Formula (CSF).
1993 EPA removed the previously established tolerances (40 CFR 180.271) and established an exemption from the requirement for a tolerance for residues of boric acid and its sodium salts when used as active ingredients in products applied to all raw agricultural commodities (40 CFR 180.1121). Additionally, in the RED
Document

, EPA concluded that all uses were eli gible for reregistration provided they comply with prevailing labeling requirements.
2004 EPA incorporate d existing tolerances exemptions (21 CFR 178.1010) by the Food and Drug Administration (FDA) thereby establish ing under 40 CFR 180.940 an exemption fro m the requirement for a tolerance for residues of boric acid, sodium salt as an active and inert ingredient in antimicrobial formulations (food

- contact surface sanitizing solutions) an d change d 40 CFR 180.1001(d) to 40 CFR
180.920.
2006 Following passage o f FQPA in 1996 requiring EPA to reassess all pesticide tolerances in the context of aggregate exposure, the boric acid/sodium salts TRED was issued. The tolerance exemptions were maintained as EPA determined there was reasonable certainty of no harm from aggregate exposure. 2009 EPA issue d scoping document in support of Registration R eview, outlining toxicity and residue chemistry data requirements. Boric acid/sodium salts registration review initiated with release of the Registration Review Initial and
F inal Work Plans.

3.1 Chemical Identity

This registration review assessment for boric acid/sodium salts includes the seven (7) compounds
list ed below

. B oric oxide (PC code 011002) is also included in this regulatory case but does not have any active pesticide registrations.

1. Boric acid (PC code 011001 )
2. Sodium tetraborate decahydrate (PC code 011102 )
3. Sodium tetraborate pentahydrate (PC codes 011110 and 011111 )
4. Sodium tetraborate anhydrous (PC code 011112 )
5. Disodium octaborate tetrahydrate (PC code 011107 )
6. Disodium octaborate anhydrous (PC code 011103 )
7. Sodium metaborate (PC code 011104 )

Additional nomenclatures and chemical identity information are in Appendix B

.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 12 of 99 3.2 Physical/Chemical Characteristics

The physical state of boric acid/sodium salts is generally as a white crystalline powder with low vapor pressures ( generally < 10

- 6 mmHg) and low log octanol

- water partition coefficients ( log

K ow ≈

- 1 )

. Under normal physiological aqueous conditions

, boric acid and its sodium salts exist
as undissociated boric acid. There are no known impurities of concern in any of these boron compounds. With the exception of sodium metaborate, which will absorb carbon dioxide to form sodium carbonate and borax, these co mpounds are stable under storage at room
temperature. A more complete description of the physical and chemical properties of boric
acid/sodium borate salts is provided in Appendix B

.

For purposes of toxicological evaluation and comparison with expected human exposures, studies on boric acid and borate salt compounds may be compared, and dosing considered equivalent, when they are normalized for exposure to boron (boron equivalents). M olecular weight

- based p ercentages of boron for several boron compounds, used to convert to boron equivalents, are shown below:

Boron Equivalents as Percentage Boron

Chemical Percent boron

Boric acid 17.5%

Sodium tetraborate decahydrate 11.34%

Sodium tetraborate pentahydrate 14.85%

Sodium tetraborate anhydrous 21.49%

Disodium octaborate tetrahydrate 20.96%

Disodium octaborate anhydrous 25.38%

Sodium metaborate 16.5%

e.g., Boric acid (H3BO3) has a molecular weight of 61.83 g/mol. Boron has an atomic weight of 10.8 g/mol.

Therefore, as it contains one boron atom, boric acid is 17.5% boron.

3.3 Pesticide Use Pattern

There are many pesticide products containing boric acid or one of its sodium salts as the active ingredient. These products include insecticides, acaricides, herbicides, algaecides, fungicides
and wood and materials preservatives. A summary of the use pr ofile is provided below.

 Registered formulations include dusts, granules/pellets/baits, wettable or water

- soluble powders/dusts, liquid concentrates, and gels/pastes.

 U se sites include :Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 13 of 99 o Agricultural food/feed crops

 A lfalfa, cane berries, bush berries, coffee, cacao, pome fruit, stone fruit, citrus, herbs, tree nuts, peanuts, strawberry, tobacco, leafy vegetables, bulb vegetables, corn, cucurbi t, fruiting vegetables , legumes, root and tuber vegetables, soybean, cotton, herbs, avocado, kava, banana, guava, papaya, pineapple, watermelon and grasses

o Residential areas (homes, schools, nursing homes, hospitals, etc.):

 Indoor (pet quarters, floors/carpets, attics; cracks/crevices, around appliances, bedding/mattresses);

 Outdo or (lawns, parks, golf courses, building perimeters, patios, driveways, trash areas, wood piles, gardens);

o Pre

- construction wood material /lumber ;

o Wooden structures (utility poles, railroad ties, etc.);

o Structural Building/House Components (wall/cabinet voids, soffits, attic space, crawl spaces)

o Swimming pools;

o Food handling/storage/processing sites;

o Agricultural buildings/facilities (e.g., p oultry houses ) ;

o Industrial areas;

o Sewers/sewage systems;

o Tree stumps;

o Vehicles (ships, buses, etc.);

o Ant mounds ;

o Ma terials (paints, inks, dyes and gypboard coatings)

.

 Depending on the use pattern, the percentage of active ingredient ranges from less than 1% (e.g., liquid concentrate for use on crops) to 100% (e.g., indoor insecticide dusts)

.

 Application types can be broadcast as well as spot or cr ack

- and

- crevice type treatments.

 Applications are made via hand dispersal, handheld equipment (e.g., rotary spreaders, handwand sprayers), or vehicles (e.g., tractor

- drawn spreaders, airblast sprayers). Chemigation and aeria l applications are prohibited. The remedial wood treatment methods include brush, trowel, spray, injection or wrap applications of liquid or paste formulations. The manufacturing facility wood treatment methods include pressure
treatment and mechanized s praying and dipping.

 Application rates vary depending on the use site/target and formulation. For example, in terms of boron equivalents, spray application to crops has a relatively low rate of 0.0018 lb boron/acre, while applications of dusts to poultry houses has a relatively high rate of
448 lb boron/acre.

 The minimum retreatment interval for crop uses is 7 days; non

- crop uses are applied on

an as

- needed basis.

 Work attire and/or personal protective equipment (PPE) is not specified on many labels
while on others, such as the crop use product (EPA Reg. No. 72662

- 3) the label requires protective eyewear/goggles, long

- sleeve shirt, pants, waterproof gloves, shoes and socks. Some labels require use of respiratory protection.

 For many products, such as those not subject to the EPA’s Worker Protection Standard, a restricted entry interval (REI) does not apply. Where applicable, the REI varies from 4
hours on some labels to 48 hours on others.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 14 of 99 A ppendix C provides a more detailed listing of representative regi stered products on which the exposure and risk assessment is based. Application rates are presented in terms of boron equivalents for purposes of comparison with toxicological studies

– conversions from boric acid or a sodium salt are performed using the molecular weight composition of boron in the active ingredient.

3.4 Anticipated Exposure Pathways

Based on the registered conventional and antimicrobial uses

, occupational exposures are expected for workers who mix, load, and apply the products, workers who might contact residues in previously treated areas and adults and children via non

- dietary exposure pathways resulting
from residential uses and via spray drift resulting from agricultural uses. For both residential and occupational s cenarios

, short

- and intermediate

- term duration exposure s during and after application are possible; long

- term exposures are not anticipated. Additionally, boric acid/sodium salts are also registered for use in/on numerous food/feed crops that may result in dietary exposure through food or drinking water.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and Lo w

- Income Populations, ” ( http://www.archives.gov/federal

- register/executive

- orders/pdf/12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large v ariety of consumer subgroups according to
well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities i n and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture under the National Health and Nutrition Examination Survey, “ What We E at in America, ” (NHANES/WWEIA). These food consumption patterns are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the co untry. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups

, and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide pro ducts and associated risks for adult applicators and for children , youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development

, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

The toxicology studies submitted in support of registration of boric acid/borate salts were conducted on boric acid or sodium tetraborate decahydrate (borax). Under normal physiological,Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 15 of 99 aqueous conditions, boric acid and the borate salts exist as undisso ciated boric acid. The doses for studies considered in this review have been converted to boron equivalents using the molecular weight

- based percentages shown in Section 3. 2 to permit comparison of the studies

. Boron dietary intakes of the laboratory ani mals from untreated chow and drinking water are considered to be an approximation of human dietary intake (i.e., assumed to mimic human background dietary exposure), thus no adjustment of the doses to account for background boron exposure is needed.

4.1 T oxicology Studies Available for Analysis

The toxicology database for boric acid/sodium borate salts is considered sufficient for hazard characterization. Although many of the submitted studies are older and not conducted according to current guidelines o r G ood Laboratory Practice (G LP ) standards, when taken as a whole the database is considered adequate for assessing risk to humans, and no additional studies are required. These studies have been used to characterize boron hazard by several other reviewin g groups and a gencies, including US EPA Integrated Risk Information System ( IRIS )

, the European Centre for Ecotoxicology and Toxicology of Chemicals ( ECETOC ) , the E uropean C ommission Directorate

- General for Health and Consumers (Scientific Committee on Con sumer Safety), Canadian Pesticide Management Regulatory Agency ( PMRA )

, World Health Organization ( WHO ) and the Agency for Toxic Substances and Disease Registry ( ATSDR )

.

Numerous published studies on boron compounds have also been considered in this asse ssment. These studies provided information regarding human background dietary exposure, general metabolism in the rat, dermal absorption, inhalation toxicity, dose

- response and mechanism of testicular toxicity, and case reports of human poisonings.

The studies available for consideration that were submitted to the Agency are:

 rat, mouse and dog subchronic oral toxicity

 dog chronic, rat chronic/oncogenicity, mouse oncogenicity

 rat, mouse and rabbit developmental toxicity

 rat and mouse multi

- generation reproductive toxicity

 genotoxicity battery

 rat acute neurotoxicity

 mouse immunotoxicity

 in vivo and in vitro human dermal absorption (reviewed and accepted by the Agency for ethical study conduct, memorandum from K. Sherman to C. Swartz dated 1/27/14).

The HED Hazard and Science Policy Council ( HASPOC ) concluded the following toxicology
studies are not required for boric acid/ borate salts (TXR No. 0056768, memo dated 2/5/2014 and
TXR No. 0057245 , dated 12/ 2015 ):

1. Subchronic I nhalation S tudy [Guideline # 870. 3465 ], based on lack of adverse effects in the dog and rat in a published report

, and data supporting physical constraints ( visible dust in the test chamber at higher test concentrations ) that would limit the generation of significantly higher test atm osphere concentrations for a repeated

- exposure studyBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 16 of 99 (Wilding et al. , 1959, MRID 48507002; acute inhalation studies MRIDs 43500104, 43500601, 43500701, 43500801)

. 2. Subchronic N eurotoxicity S tudy [Guideline # 870. 6200b ] based on lack of neurotoxicity
in the acute neurotoxicity screening study and data indicating that neurotoxicity is not likely to be the most sensitive effect.
3. Subchronic ( 21/28 or 90

- day ) D ermal T oxicity S tudy [Guideline # 870. 3200 or
870.3250 ] , based on low absorption (<1%) observed in derma l absorption studies. No toxicity would be expected at the limit dose in this study, based on the very low dermal absorption and results of oral toxicity studies.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

A guideline general metabolism study on boric acid or sodium borate salts was not submitted, but published studies provide information on ADME in rats (Ku et al. , 1991; Vanderpool et al.

, 1994; Chapin et al. , 1997). Boric acid/borate salts are rapidly and well absorbed following oral ingestion. Th is is supported by th e time to maximum plasma concentration ( T max ) , which was within 3 h ou rs of dosing

, absorption of most of the dose by 24 h ou r s , and recovery of >90% of the dose in the urine by 72 h ou rs ( most wa s recovered by 24 h ours)

. Only a small percentage is excreted in feces. Based on the available pharmacokinetic information, plasma half

- life in the rat
has been estimated at 14

- 16 h ou rs. The rate of elimination is largely dependent on renal
clearance.

Once absorbed, borate salts at physiological pH in aqueous solution are present as boric acid and there is no further metabolism. Boric acid is rapidly and evenly distributed by passive diffusion to tissues throughout the body. Boric acid does not acc umulate in soft tissues (including the testes) , although it may form (reversible) complexes with biomolecules. Boron levels in bone are somewhat higher than in soft tissues, and may clear more slowly , possibly due to binding to calcium hydroxyapatite. I n male rats given boric acid in the diet, boron levels in bone were 2

- 3

- fold higher than plasma levels at 1 week, by which time plasma and soft tissue levels had reached steady

- state. When treatment was stopped, levels of boron in bone declined at a slowe r rate than in other tissues . Although excretion of boric acid is rapid and essentially complete within days following dosing, bone boron was reduced by 90% from peak post

- dosing levels only after an 8

- week recovery.

The ADME of boric acid in humans is considered to be similar to that in the rat (summarized in IRIS, 2004). In a review of almost 800 case reports of patients who were admitted for boric acid poisoning, the elimination half

- life was calculated to be between 4

- 28 h ours (Litovitz et al.

, 1988 ). As with the rat, excretion is considered to depend largely on the rate of renal clearance.

The inhalation study by Wilding (1959) indicated that boron oxide was absorbed following inhalation exposure, since it was detected in the urine of rats at seve ral measurement times during a 22

- week exposure period. At 0.077 mg/L boron oxide, an average of 11.9 mg/kg bw/day boron was reportedly excreted, compared to 0.24 mg/kg bw/day in control rats.
However

, the data do not exclude the possibility that some of the measured boron was due to oral ingestion of airborne boron oxide particles. Boron levels measured one week after treatment ended were comparable to those in controls (earlier time points were not available). In this study, no accumulation of boron w as seen in tissue samples, including bone, at about 60 h ou rsBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 17 of 99 after exposure. Absorption of boron by production workers following inhalation exposure to borate dust showed increased urinary excretion of boron post

- shift relative to pre

- shift, but as with the rat study, it is unclear how much may have been ingested as particles (Culver, 1994).

4.2.1 Dermal Absorption

Guideline dermal toxicity or dermal absorption studies in rodents were not submitted for boric acid/borate salts, but acceptable/non

- guideline human in vivo and in vitro studies were submitted.
A dermal toxicity study would be of limited value for assessi ng dermal toxicity in light of the increased quantitative and qualitative susceptibility observed in developmental toxicity studies ; HED HASPOC determined that it was not needed (TXR No. 0057245)

. A dermal developmental toxicity study was not required to assess effects from dermal absorption because as discussed below, the available data on dermal absorption of boric acid and borate salts indicate that these compounds show negligible absorption across intact skin.

Human in vivo and in vitro dermal absorpt ion studies evaluated boric acid, borax and disodium octaborate tetrahydrate (DOT) following a 24

- hr exposure. In the in vivo study (MRID
48507005 ; reviewed and found to be conducted in an ethically acceptable manner; K. Sherman, memorandum dated January 27, 2014 ), adult male and female volunteers were exposed to 10 B

enriched 5% boric acid, 5% borax or 10% DOT. The total absorbed dose excreted in the urine (expressed as a percentage of the applied dose) was very low for all three compounds, at
0.226%±0.12 5 (boric acid) , 0.210%±0.194 (borax) and 0.122%±0.108 (DOT) . Urinary excretion was essentially the same when the same treatments were repeated on skin pretreated with 2% aqueous sodium dodecyl sulfate, a mild irritant.

The low dermal absorption in huma ns in vivo is consistent with the findings of an in vitro dermal absorption study (MRID 48549901) conducted by the same laboratory, although percent dose absorbed was higher (0.19% to 1.75% of the applied dose). As with the in vivo study,
information on a bsorbable dose remaining in treated skin (following removal of the stratum corneum) was not available. However, the findings of the in vivo absorption study are
considered to be more reliable than the in vitro studies, particularly since there was no indi cation of assessment of skin integrity in the latter.

A published dermal absorption study in the rabbit showed that powdered boric acid, or boric acid in talc or aqueous solution, was not absorbed across intact skin (Draize and Kelly, 1959). Boron levels in urine of the treated animals were comparable to tho se in controls. Similarly, no dermal absorption was seen in rats treated with boric acid as an ointment or aqueous jelly, but up to 1% of the dose was found in urine in rats exposed to the oleaginous ointment preparation (Nielsen, 1970). Epidemiological studies of workers with high occupational exposure to borate compounds (e.g., borax mining) provide only limited information (reviewed in U.S. EPA IRIS, 2004), but the lack of clearly evident exposure

- related effects other than respiratory symptoms
from in halation of dust is consistent with the finding of low dermal absorption seen in experimental studies.

Based on consideration of the available information on dermal absorption in animals and humans, absorption through intact skin is expected to be very li mited (less than 1%). This is alsoBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 18 of 99 consistent with the low K ow for these compounds (0.175). It is noted that other reviewing Agencies or organizations, including US EPA IRIS, the European Commission (EC) Directorate

General for Consumer Safety, ATSDR and WHO (IPCS INCHEM), have concluded that boron compounds are not absorbed, or very poorly absorbed, through the intact skin. The EC
considered dermal absorption of 0.5% to be a conservative value based on the available data

. Thus

, for the purposes of risk assessment

, dermal absorption is negligible

, with estimat es of even
less than 1% considered conservative

.

4.3 Toxicological Effects

The testes are the main target organ among all species tested. Seminiferous tubule degeneration, reduction in sperm coun t, atrophy and reduced testicular weights were observed following subchronic or chronic oral exposure in the mouse, rat and dog. In the dog, testicular effects were observed at comparable dose levels in subchronic and chronic studies. Rats may have shown a slight progression of effects with longer exposure duration based on comparative ( NOAELs and LOAELs in subchronic, chronic and reproduction studies, but this is difficult to determine due to the spacing of doses. Testicular atrophy resulted in infertil ity, as demonstrated in the rat and mouse multigeneration reproductive toxicity studies. Ovaries were also a target organ. In the rat reproduction studies

, reduction in the number of corpora lutea and diminished fertility in mating
of treated females wit h untreated males were observed, but the effect on fertility of females appears to be considerably less severe than in males at the same dose levels. However, effects on the female reproductive tract were not examined in all studies. A few epidemiologica l studies have examined the effects of industrial exposure to boron compounds on human fertility (summarized in US EPA IRIS, 2004), but due to limitations in study conduct, the data are inconclusive. However, no overt association of exposure with reproduc tive toxicity was
identified in the available epidemiological studies.

The mode of action (MOA) for testicular and ovarian toxicity is not known, but several published reports have examined aspects of toxicity to the testes in rats (Chapin and Ku, 1994;
K u et al. , 1991 and 1993; Ku and Chapin, 1994; Fail et al. , 1998). As noted above, boron does not accumulate in the testes, although tissue concentrations increase with dose. Boron has been shown to cause a slight reduction in plasma testosterone in rats, but not enough to inhibit spermiation. Co

- cultures of Sertoli cells/germ cells in these studies indicate in vitro effects on DNA synthesis of mitotic and meiotic germ cells as well as Sertoli cell energy metabolism. Rat

s tudies testing increasing dietary concentrations of boron showed that inhibition of spermiation

may prece d e , and occur at a lower dose than, atrophy. Inhibition of sperm release was observed as early as 5 days after dietary administration at high levels o f boric acid, followed by disorganized epithelium and release of immature germ cells by Day 21, and atrophic tubules by Day 28. Inhibition of spermiation was observed at lower dose groups (mild inhibition and severe inhibition, at 26 and 38 mg/kg bw/day b oron, respectively), as well as at higher dose levels (52 and 68 mg/kg bw/day boron) at which atrophy was observed, with a 17 mg/kg bw/day dose identified as a NOAEL for inhibition of spermiation. Males at the higher dosing levels were
examined at 8

- weeks post

- dosing and did not show recovery from atrophy. However, in the rat reproductive toxicity studies submitted to the Agency, the same dose was not associated with decreased fertility.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 19 of 99 The red blood cell also was affected by boric acid, based on mild d epression of hematocrit (Hct) and hemoglobin (Hgb) levels in subchronic and chronic studies in the rat and the dog. Hemosiderin accumulation in spleen, liver and kidney was reported in the dog following subchronic exposure. Clinical signs of toxicity

, wh ich included hunched posture, rapid respiration, thinness, swollen paws, inflamed eyes, and coarse fur/desquamation, were reported in males and females within the first few weeks of treatment in rat oral studies at doses causing testicular atrophy. Other effects that have been reported include slightly decreased body weight in the rat, dog and mouse

, and in mice, splenic depletion (probably secondary to stress). Immunotoxicity (decreased sheep red blood cell, or SRBC

, anti

- antibody

- forming plaque cells,

o r anti

- AFC

, response) was observed in a 28

- day mouse immunotoxicity study.

Dermal toxicity data were not submitted

, but the available information on dermal absorption, previously described

, indicates that absorption across intact skin is very low. Toxicity from dermal exposure is therefore not expected to occur.

Data on toxicity from inhalation exposure are very limited. A published report on inhalation exposure to boron oxide in the ra t and dog for 10

- 24 weeks did not identify adverse effects (Wilding, 1959) up to concentrations resulting in significant chamber dust. Mild respiratory irritation (nasal exudate, reddened nares) was observed in the rat at the highest test concentration

, b ut there were no reported histopathological effects on the lungs or trachea, nor on other tissues, including the testes. Dogs were tested at lower exposures and did not show effects on body weight, hematological or clinical chemistry parameters, but histo pathological evaluations were not performed. Epidemiological data on industrial exposure of humans to boron compounds (summarized in IRIS, 2004) indicate that workers exposed to high levels of borax dust showed some evidence of respiratory, sensory and ey e irritation. One study found no indication of effects on pulmonary function at exposures up to 14.6 mg/m 3 for at least 5 years; a second found evidence suggestive of respiratory illness from long

- term exposure.

There was no evidence of neurotoxicity i n a rat acute neurobehavioral screening study up to the limit dose, but there is evidence of potential clinical neurotoxicity in the rat and in humans. Dietary studies submitted to the Agency (subchronic, chronic and reproductive toxicity) in the rat

repo rted clinical signs of neuro toxicity at high dose levels that were consistent with neurological effects (hunched posture, abnormal gait, rapid respiration), but which could also be secondary to general malaise or other systemic effects. These findings wer e seen in the rat at or above doses that also caused severe testicular toxicity. Malformations of the central nervous system were seen in the rat developmental toxicity study at doses that caused an overall increase in fetal malformations. Case reports o f accidental human poisonings indicate that neurological effects (convulsions, tremors, headaches, restlessness) may occur with exposure to high levels of boric acid (summarized in IRIS, 2004). Other species (dog, mouse, rabbit) did not show clinical sign s at the doses tested.

There is evidence of increased qualitative and/or quantitative offspring susceptibility in the rat, mouse and rabbit. In the rat, decreased fetal weight and increased skeletal abnormalities were observed at the LOAEL, with dose

- r elated decreased survival and significant external, visceral and skeletal malformations at higher doses, in the absence of maternal toxicity. Similar developmental effects were seen in mice in the presence of less severe maternal toxicity (renalBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 20 of 99 tubular d ilatation/regeneration). Resorptions, post

- implantation loss, decreased fetal weight and cardiovascular malformations were observed in rabbits; however maternal toxicity was limited to vaginal bleeding, probably secondary to fetal loss.

In reproductive toxicity studies conducted in the rat and the mouse, decreased fertility, resulting in decreased litter sizes, decreased pup weight, and decreased offspring survival, were observed at doses causing testicular atrophy and mild decreases in body weight in p arental animals. In the rat, the number of corpora lutea were also decreased at the same dose. Although fertility of females was affected by exposure, the effects in males were more severe. The fertility effects in males and females are probably due to the testicular and ovarian effects discussed at the beginning of this section.

Boric acid/borate salts did not show evidence of carcinogenicity in the rat or mouse. Genotoxicity studies were negative.

Boric acid/borate salts generally show low acute tox icity by oral and dermal routes (Toxicity Categories III or IV). Boric acid is Category III for acute inhalation, due to limitations in generating test atmosphere concentrations and not mortality (none observed). Dermal and eye acute irritation potential vary. Sodium tetraborate decahydrate (borax) is Category I for eye irritation and IV for skin irritation, while boric acid is Category III for both.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

HED recommends that the FQPA SF be reduced to 1x

. This recommendation is based on the following considerations : (1) an adequate toxicology database that includes developmental and reproductive toxicity, neurotoxicity and immunotoxicity studies; (2) although e vidence of
increased quantitative and/ or qualitative susceptibility was observed, effects were well

characterized and clear NOAELs and LOAELs were established; (3) the doses selected for risk assessment are protective of potential developmental toxicity, including potential neurotoxic
effects (malformations of the central nervous system (CNS)) and of immunotoxic effects, and (4) exposure assessments use conservative inputs and models that do not underestimate exposure to
bor ic acid/sodium salts

.

4.4.1 Completeness of the Toxicology Database

The toxicology database is considered complete for purposes of an FQPA assessment. Acceptable developmental toxicity studies in rats , mice and rabbits, multi

- generation reproduction studies in rats and mice

, rat neurotoxicity (acute) and immunotoxicity s tudies are available for FQPA assessment. The studies were well

- conducted and a clear NOAEL and
LOAEL for these malformations was observed. Therefore, a database uncertainty factor (UF DB )
is not needed

.

Although developmental malformations of the nervous sys tem were observed in the rat (see
Section 4.4.2) , a developmental neurotoxicity ( DNT ) study was not required because these findings were reported at dose levels that were significantly higher than the selected point of departure ( POD ), and were also associated with an increase in overall malformations

.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 21 of 99 4.4.2 Evidence of Neurotoxicity

Clinical signs of toxicity that could indicate neurotoxicity (hunched posture, abnormal gait, rapid respiration) were observed in rat dietary studies, generall y beginning after 1

- 2 weeks to about one month of exposure. However

, these symptoms occurred alongside numerous other non

specific signs and may have reflected general poor health rather than direct effects on the nervous system. Neurotoxicity was not ob served in the rat acute neurotoxicity study (the subchronic neurotoxicity study was waived). In the rat developmental toxicity study, enlarged lateral ventricles of the brain, microphthalmia or anophthalmia were observed at doses that also caused a genera l increase in malformations of all tissues and decreased fetal survival. Published case reports of human poisonings with boric acid or borate salt compounds have also identified clinical signs consistent with CNS toxicity including convulsions, headaches, tremors and
restlessness.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

Quantitative and/or qualitative evidence of increased offspring susceptibility, as compared to adults, following in utero or postnatal exposure t o boric acid/borate salts was observed in developmental toxici ty studies and multi

- generation reproduction studies in all species tested

. In the rat, decreased fetal weight and increased skeletal abnormalities were observed at the LOAEL,
with dose

- related decreased survival and significant external, visceral and skeletal malformations at higher doses, in the absence of maternal toxicity. In the mouse, increased resorptions, decreased fetal weight and increased short rib XII were observed in the presence o f mild maternal renal histopathology. In the rabbit, increased fetal resorptions, mortality and visceral abnormalities were observed in the presence of maternal vaginal bleeding. In two

- and three

generation reproductive toxicity studies in the rat and m ouse, decreased fertility and decreased pup weight and survival were seen at doses causing testicular and ovarian toxicity in parental animals. However, in all the studies, effects were well

- characterized and clear NOAELs and
LOAELs were established and t he endpoints selected for risk assessment are protective of these
effects

.

4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database that would necessitate retention of the FQPA safety factor. D ata sources are reasonably representative of the scenarios for which they are used to estimate exposure and have been vetted through public peer review processes (e.g., FIFRA Scientific Advisory Panels (SAP) , HSRB ). Additionally, for children’s non

- dietary
i ncidental oral exposure, chemical

- specific residue data were submitted and utilized, which is
considered more accurate and reliable than default estimates.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

Dietary Exposure : Based on data demonstrating that residues of boron in/on treated commodities are indistinguishable from those in/on control samples, and on the expectation thatBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 22 of 99 the low application rates associated with agricultural uses are not expected to add significantly to background levels in drinking water, a quantit ative dietary risk assessment was not conducted

. T herefore

, acute and chronic dietary reference doses (aRfD and cRfD, respectively) have not
been selected.

Incidental Oral Exposure (Short

- , Intermediate

- , and Long

- term) : For applicable exposure durations an endpoint w as selected based on the 90

- day and 2

- year dog oral studies (considered together to provide the NOAEL and LOAEL) on borax (MRID 406923 08 and 40692310 ) . The
studies a re of the appropriate route and duration. The NOAEL of 8 .8 mg/kg bw/day (2

- year dog study , HDT ) was selected as the POD , based on hematological effects and testicular atrophy observed at the LOAEL of 32 mg/kg bw/day ( 90

- day dog study)

. The NOAEL from the 2

- year study was selected because it was higher than the NOAEL from the 90

- day study (4.1 mg/kg bw/day) as a result of dose

- spacing. Testicular atrophy was also observed at 40 mg/kg bw/day in a dog 38

- week study (only one dose tested). The hematological effects are relevant to all exposed populations, which may include young children and females age 13 to 49. The dose is protective of toxicity observed in several oral rat studies ( clinical findings , testicular atrophy) including the subchronic oral rat studies on borax (NOAEL 41 mg/kg bw/day, highest dose tested ( HDT ) ) and boric acid (NOAEL/LOAEL 38/125 mg/kg bw/day), as well as the rat chronic toxicity study on boric acid and borax (NOAEL/LOAEL 17/58 mg/kg/day) , and rat reproductive toxicity studies (parental/reproduction/offspring NOAELs/LOAELs 28 /82 mg/kg bw/day) and developmental toxicity (most sensitive study NOAEL/LOAEL 9.6/13.3 mg/kg bw/day) . The selected dose and endpoint are also protective of mild renal histopathology seen in pregnant mice (≥43 mg/kg bw /day) in the developmental toxicity study. In rabbits

, the NOAEL for maternal toxicity was 22 mg/kg bw/day; no maternal toxicity was observed in the rat up to 94 mg/kg bw/day.

Episodic/non

- dietary ingestion of granul e formulations: A POD was se lected to assess the potential ingestion of recently applied granular formulation products (e.g., in turf) by young
children (e.g., 1 < 2 years old) . For this scenario, a dose of 350 mg/kg was selected, based on clinical signs (depression, labored/rapid b reathing, diarrhea, red crusts on eyes) and mortality
observed in oral LD 50 studies for boric acid and borax at doses ≥439 mg/kg. The LD 50 studies

were select ed since no single

- dose effects relevant to this subpopulation were observed in other guideline t oxicology studies. Clinical signs of toxicity in repeated

- dosing studies were not observed by the first or second day of treatment. In several oral LD 50 studies (MRIDs 00056544, 00064207, 40692303), no effects were observed at doses of 350 mg/kg bw boron equivalents. This endpoint is further supported by the lack of toxicity observed in the rat acute neurotoxicity screening study at the highest dose level of 350 mg/kg boron equivalents.

Dermal Exposure (Residential and Occupational) : A dermal toxicity study is not available. An endpoint for assessment of risk from dermal exposure was not selected, based on in vivo dermal absorption data in humans and published studies in animals indicating that absorption across intact skin is negligible (< 1%). Estimation of a dermal NOAEL using the NOAELs from the most sensitive oral studies (NOAEL = 8.8 mg/kg/day, dog and 9.6 mg/kg/day, developmental rat) using a (conservative) DAF of 1% would yield a dose approaching the limit dose of 1000 mg/kg bw/day

.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 23 of 99 Inhalation Exposure ( Residential and Occupational): For all applicable exposure durations an oral study (NOAEL of 8.8 mg/kg/day, dog chronic study) was selected, taking into consideration a published report on inhalation toxicity in the rat. The require ment for a rat subchronic inhalation toxicity study was waived (HED HASPOC, TXR No. 0056768), based on data indicating physical limitations in generating test atmosphere concentrations high enough to elicit toxicity (Wilding et al., 1959). The published i nhalation study did not identify adverse systemic or portal of entry effects in the rat at test concentrations up to 0.47 mg/L boron oxide, which is equivalent to an estimated oral exposure of about 29 mg/kg bw/day boron in the ra t. [ Calculation: chamber concentration x species specific adjustment factor (respiratory volume and body weight) x exposure duration x 0.311 (factor to convert to boron equivalents for boron oxide) . Thus, f

or the rat, 0.47 mg/L x 47 (Fisher rat) x 6 hr exposure duration x [5 day s/7 days per week exposure] x 0.311 ).]

T he dog 90

- day and 2

- year dietary studies were considered together to derive the POD and endpoint. The NOAEL of 8.8 mg/kg bw/day, the HDT in the dog two year dietary toxicity study on borax, was selected for both sh ort

- and intermediate

- term inhalation exposure. The dose was selected based on hematological findings (decreased Hct/Hgb and increased hemosiderin deposition in the spleen, liver and kidneys) and testicular atrophy observed at the LOAEL of 32 mg/kg bw/day in the 90

- day study. Testicular atrophy was also observed at 40 mg/kg bw/day in a dog 38

- week study (only one dose tested). A lower NOAEL (4.1 mg/kg bw/day) was identified in the dog 90

- day dietary study, but was not selected since a higher NOAEL was
id entified for the longer exposure duration that is protective of effects in that study . The findings
of the 90

- day, 38

- week and 2

- year dietary studies on boric acid were essentially the same as the findings from studies on borax. The selected dose is prot ective of developmental toxicity observed in the rat at 13.3 mg/kg bw/day and the rabbit at 43 mg/kg bw/day with developmental NOAELs of 9.6 and 22 mg/kg bw/day, respectively. The inhalation absorption of boric
acid/borate salts is assumed to be 100%.

In the absence of observed toxicity in the rat inhalation study, the highest exposure concentration tested (0.47 mg/L) was assumed to be a NOAEL for portal of entry (POE) and systemic toxicity. Human equivalent doses (HEDs) were calculated for comparison to the oral dose of 8.8 mg/kg/day selected for risk assessment. These doses were not used for risk assessment because LOAELs were not identified in the available inhalation study. POE HEDs of 3.65 and 1.49 mg/kg bw/day (males) were obtained for occupati onal and non

- occupational HEDs, respectively (systemic HEDs were higher). Although lower than the oral dose, they are comparable due to the differences in UFs used for inhalation HEDs (30) and oral doses (100). The selected oral
dose is therefore conside red protective of potential POE effects from inhalation exposure , as well as developmental effects

.

Uncertainty Factors : For all exposure scenarios, uncertainty factors (UFs) of 10x for interspecies (UF A ) and 10x for intraspecies (UF H ) variation (total U F of 100x) were used. The 10x interspecies and 10x intraspecies factor s are considered to be conservative because boric acid/borate salts are expected to show similar absorption and tissue distribution among different species, and boric acid is not metabolized , thereby reducing potential variability for these parameters . The 10x UF A accounts for variability in renal clearance between species that may
affect elimination of boric acid/borate salts and provides additional protection for the close dose

-Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 24 of 99 spacing of the rat developmental NOAEL and LOAEL (9.6 and 13.3 mg/kg bw/day,

respe ctively), which are only slightly greater than the selected POD of 8.8 mg/kg bw/day

.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Incidental oral and inhalation exposures are being regulated based on the same effects (hematol ogical changes, testicular toxicity) observed following oral exposure in the dog ; therefore, when applicable, their combination is recommended.

4.5.3 Cancer Classification and Risk Assessment Recommendation

There was no evidence of carcinogenicity in cancer studies with mice and rats

. Boric acid/borate salts are classified as “not likely to be carcinogenic to humans” under the Agency revised (2005)
Cancer Guidelines. T he available studies were not conducted according to current guideline
standards fo r carcinogenicity studies , but were considered adequate for assessing carcinogenic
risk from boron

. A two year mouse carcinogenicity study conducted by the National Toxicology Program (NTP) tested at only two doses instead of three, but achieved a maximum tolerated dose ( MTD ) and was adequate to evaluate carcinogenicity

. Rat two year dietary studies on boric acid and borax tested smaller groups of animals than recommended, but when considered together,
animal numbers were sufficient. Dosing was adequate. Some tissues were not examined, but major organs and gross findings were evaluated , and no treatment

- related tumors were seen in
mice. Other factors support lack of carcinogenicity

. Genotoxicity studies did not indicate mutagenic or clastogenic potential. Epidemiological data do not indicate any boron exposure

related cancers in humans. Boron is a ubiquitous, naturally occurring element in food and drinking water to which humans are continuously exposed throughout their lifetime, further reducing concern for carcinogenicity.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

S ummary of Toxicological Dose s and Endpoints for Boric Acid/Borate Sal ts for Use in Dietary and Non

Occupational Human Health Risk Assessments . All Doses expressed as boron equivalents.

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicologi cal Effects

Acute Dietary Acute or chronic dietary risk assessments are not conducted, see Section 5.0. Chronic Dietary
Acute
Incidental
Oral (ingestion of granule
formulation s ) NOAEL = 350

mg/kg UF A = 10x

UF H =10x FQPA SF=1x Residential

LOC for MOE
= 100 Acute LD 50 (boric acid and borax, 3

studies)

– rat LOAELs ≥439 mg/kg, based on clinical signs of toxicity and mortalityBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 25 of 99 S ummary of Toxicological Dose s and Endpoints for Boric Acid/Borate Sal ts for Use in Dietary and Non

Occupational Human Health Risk Assessments . All Doses expressed as boron equivalents.

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicologi cal Effects

Incidental
Oral ( Short

- , Intermediate

- , Long

- term ) NOAEL= 8.8

mg /kg bw /day (2

- year feeding study

– dog, HDT) UF A = 10x

UF H =10x FQPA SF=1x Residential

LOC for MOE
= 100 Subchronic (90

- day) and chronic (2

- year)

feeding study (borax)

-- dog LOAEL (90

- day study) = 32 mg/kg bw/day, based on hematological effects and testicular atrophy

Dermal (all
durations ) A dermal risk assessment was not performed. Dermal absorption data in humans indicates

negligible absorption (less than 1%) and is consistent with published reports in laboratory animals showing low or no absorption. Estimation of a dermal NOAEL, using a vailable oral NOAELs and a DAF of 1%, would give doses approaching the limit dose (1000 mg/kg bw/day).

Inhalation (all
duration s ) NOAEL= 8.8

mg /kg bw /day (2

- year feeding study

– dog, HDT)
100%
inhalation absorption
assumed. UF A = 10x

UF H =10x FQPA SF=1x Residential

LOC for MOE
= 100 Subchronic (90

- day) and chronic (2

- year)

feeding study (borax)

-- dog LOAEL (90

- day study) = 32 mg/kg bw/day, based on hematological effects and testicular atrophy

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” bas ed on the lack of an increase in

treatment

- related increased tumors in rat and mouse carcinogenicity studies.

Point of Departure = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = ext rapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjust ed dose . RfD = refere nce dose. HDT

– highest dose teste d.

Summary of Toxicological Dose s and Endpoints for Boric Acid/Borate Salts for Use in Occupational
Human Health Risk Assessments . All doses expressed as boron equivalents.

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Dermal Short

Term ( all
durations ) A dermal risk assessment was not performed. Dermal absorption data in humans indicates

negligible absorption (less than 1%) and is consistent with published reports in laboratory animals showing low or no absorption. Estimation of a dermal NOAEL, using o ral NOAELs and a DAF of 1%, would give doses approaching the limit dose (1000 mg/kg bw/day). Dermal
risks are therefore not of concern.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 26 of 99 Summary of Toxicological Dose s and Endpoints for Boric Acid/Borate Salts for Use in Occupational
Human Health Risk Assessments . All doses expressed as boron equivalents.

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Inhalation
Short

- Term (1

- 30 days)
Intermediate

Term (1

- 6 months) NOAEL= 8.8

mg /kg bw /day (2

- year feeding study

– dog, HDT)
100%
inhalation absorption
assumed. UF A = 10x

UF H =10x Occupational

LO C for MOE
= 100 Subchronic (90

- day) and chronic (2

- year)

feeding study (borax)

-- dog LOAEL (90

- day study) = 32 mg/kg bw/day, based on hematological effects and testicular atrophy

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” base d on the lack of an increase in

treatment

- related tumors in rat and mouse carcinogenicity studies.

Point of Departure = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population ( intraspecies). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. HDT = highest dose tested.

4.6 Endocrine Disrupt or Screening Program

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic, and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, inclu ding effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates
acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision for boric acid and its sodium borate salts, EPA reviewed these data and selected the most sensitive endpoints for rel evant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), boric acid and it sodium borate salts are subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA ha s developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as th e Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential toBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 27 of 99 interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and
establish a dose

- response relationship between the dose and the E, A, or T effect

.

Under FFDCA section 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 (a.i.’s) and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some pesticides scheduled for Registration Review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our
website. 2

5.0 Dietary Ex posure and Risk Assessment

Boron is a ubiquitous, naturally occurring component of food and drinking water to which humans are continually exposed. It is an essential nutrient for plants, and t here is some eviden ce suggesting that it may be a required m icronutrient in mammals based on studies suggesting it is involved in the regulation of metabolism of minerals such as calcium; however, this has not been definitively established (Naghii and Samman, 1993) . Dietary exposure to humans is variable, dependin g upon the foods consumed and the source of drinking water.

A robust analysis of boron intake, using the 1994

- 1996 Continuing Survey of Food Intakes by Individuals (CSFII), presented “ usual ” (i.e., long

- term) boron intake distributions for various population sub

- groups as well as characterization of food group sources of boron (Rainey, et al, 2002). The analysis considered food only

– boron intake via drinking water was not estimated.
Mean usual intake via f

ood for adult males and females, respectively, was 1.28 mg/day and 1.00 mg/day , and 0.86 mg/day for children 1

- 3 years old. Fruits, beverages (excluding water), vegetables, and grains , i n that order

, contributed most to boron intake. These results are

co nsistent with other published literature e stimates of human daily dietary boron intake ranging from 0.26 to 7.1 mg/day, with a mean of 1.9 mg/day (equivalent to about 0.03 mg/kg bw/day for adults) (Moore, 1997; Rainey, 1999). Based on a review of the EPA’ s Office of Water Regulatory Determinations Support Document for boron , average background drinking water
concentration is approximately 0.1 mg/L (EPA, 2008). Using the standard HED water consumption estimate for adults

– approximately 1.4 L/day

– boron i ntake via water would be approximately 0.14 mg/day , a much lower amount than intake via food.

Boric acid/sodium salts is the active ingredient in one product (PREV

- AM, EPA Reg. No.
72662

- 3, 0.99% sodium tetraborate decahydrate) , with uses on a wide varie ty of agricultural

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of
chemicals

2 http://www2.epa.gov/endocrine

- disruption/endocrine

- disruptor

- screening

- program

- edsp

- overviewBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 28 of 99 food/feed crops at a low application rate (100 fl. oz./100 gal solution, or approximately 0.0018 lb boron equivalents per acre). HED previously recommended that the registrant submit side

- by

side residue trials on representative crops for PREV

- AM to provide confirmatory data to demonstrate that its use does not significantly increase boron levels beyond background (D346904, R. Loranger/D. McNeilly, 5M AY20 08). These studies were submitted in early 2015 (MRIDs 49735901

- 15)

.

The field tr ial data evaluated PREV

- AM applied at a rate of approximately 100 oz product /100 gallons in Western South Africa. Four to six applications were made at 7 day interval s. The samples were harvested one d ay after the last application. The data included res ults for only one control sample per commodity, he nce variability of the control sample is unknown. The boron levels in the untreated control were at or near the average in all five treated commodities involved in the study. Table 5.0 presents a summary of the results.

Table 5.0 Residue Data for Boron Field Trials

Crop Treatment

Rate Untreated Control Results ( ppm) Treated Samples (ppm)

Individual Results Average

Zucchini 100 oz./ 100 gal 16.66 21.0, 20.74, 18.17 20.0

Tomatoes 107 oz./ 100 gal 10.21 9.55, 10.17, 11.79 10.5 Spinach 100 oz./ 100 gal 30.19 36.97, 30.18, 28.95 30.0

Lettuce 107 oz./ 100 gal 25.08 25.77, 31.36, 31.73 29.6

Potatoes 100 oz./ 100 gal 0.7 0.7, 0.7, 0.8 0.73

Information on the magnitude and variability of background levels of boron compounds in plants
also needs to be consider ed in the context of differentiati on of residues resulting from pesticide

treatments. Based on a number of articles in the open literature ( Andersen, et al, 1994; Hunt, 1994; Nielsen, 1991 ), inc luding one detailing a 1994 F ood and Drug Administration (F DA ) T otal
D iet S tudy, the highest boron concentrations are typically in nuts, followed by fruits, and then vegetables. Examples of levels (ppm boron) in crops are as follows: peanuts 14

- 19, raisins 7

- 25, peaches 1.9

- 5.2, apples 1.2

- 4.3, cherries 1.5

- 7.0, tomatoes 0.75

- 2.1, potatoes 0.44

- 3.3, carrots
1.8

- 4.2, green snap beans 0.46

- 2.5, broccoli 0.9

- 3.1, celery 2.2

- 5.0, lettuce 0.3

- 0.9, spinach 1.2

- 10, avocado 5.4

- 21, prunes 19

- 27, an d whole wh eat bread 0.48

- 0.67.

Although boric acid/sodium salts are registered for use on numerous food/feed crops that may result in dietary exposure, no food or drinking water risk assessments were performed. Boron is a naturally occurring component of both food and water and is believed to be an essential dietary trace nutrient. Due to the expectation that residues in food and water resulting from pesticide use of boron would not significantly add to naturally

- occurring boron levels, an exemption from the requi rement of a tolerance for use on raw agricultural commodities was established in 1993 and previous regulatory decisions (e.g., the 1993 RED and 2006 TRED) did not inc lude dietary risk

assessments.

The field trial data described above confirm this expectat ion, demonstrat ing that residues in/on commodities from treatment with boric acid/sodium salts are indistinguish able from untreated
commodities

. Similarly, although these products are expected to be mobile in the soil and readily dissolve in water (presen t as undissociated acid), the low application rate of agricultural products is not expected to add significantly to the background levels naturally occurring inBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 29 of 99 drinking water

. Therefore, as in previous regulatory risk assessments, d ietary exposure

assess ments have not been conducted for the registration review of boric acid and its sodium
salts

.

6.0 Residential (Non

- Occupational) Exposure /R isk Characterization

There are numerous conventional pesticide residential uses of boric acid or its sodium salts as active ingredients, from insecticide and fungicide dusts and sprays to granular herbicides. Additionally, there are antimicrobial uses in swimming pools and as material and wood preservatives. Given these uses, both residential handler and post

- applic ation exposures are anticipated.

As described in Section 4.2.1 , dermal absorption is very low. Estimates from the human in vivo study were approximately 0.2% over 24 hours following administration of dermal loadings ranging from 10 to 39 ug/cm 2 . Dermal exposures are possible for boric acid/sodium salts

– some likely very high due to use of dust formulations at high application rates. However, because absorption ( as a fraction of the total amount applied ), over a given amount of time, decreases as dermal load (mass per skin surface area) increases (Kissel, 201 1 )

, use of the dermal absorption estimates from the human in vivo study would, even at 0.2%, be an overestimate of dermal absorption given the high dermal loadings that would correspond to high dermal exposures (e.g., 20,800 ug/cm 2 dermal load estimated for a dust application scenario)

. Thus, across all scenarios, due to negligible dermal absorption, toxicity from dermal exposure is not expected and dermal
risks are not of concern.

Additio nally, in the HED chapter for the 2006 boric acid/sodium salt TRED (L. Hansen, 26

- JUL

2006, D320894), exposures via non

- pesticide consumer use products (i.e., laundry detergent and general purpose cleaners) as well as its presence as an inert ingredient in pesticide products were also considered to characterize the residential exposure pathway for purposes of an aggregate
assessment. The TRED determinations included:

 Because boric acid/sodium salts were estimated to be on the order of 1% or less as an
ine rt ingredient, risk assessment of its use as an active ingredient in products at amounts as high as 100% would be protective of exposures via use of products containing them as
inerts.

 A quantitative assessment of non

- pesticide consumer use products was conducted and
found no risks of concern and contribution to aggregate exposure deemed negligible as exposures were estimated to be extremely low (MOEs were all greater than 10,000)

. HED considers the approach and methods used in the TRED for the inert and non

- pesticidal consumer use products to still be appropriate; therefore, as the toxicological endpoints and PODs used in the TRED assessment have not changed, no updates to this part of the TRED assessment
have been conducted.

To reflect updates in data a nd methodologies for other exposure scenarios since previous assessments, addressed in the following sections are inhalation exposures for consumers mixing/loading and applying boric acid/sodium salt products as well as post

- applicationBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 30 of 99 inhalation and inci dental oral exposures resulting from areas previously treated with boric acid products. P ost

- application incidental oral risk estimates for children were found to be of concern
for broadcast spray treatments to carpets (MOEs < 100), primarily due to the r elatively high application rates. All other handler and post

- application risk estimates resulting from pesticide
uses were not of concern

.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are assumed to complete all elements of an application without use of any protective equipment.

The exposure/risk assessment for residential handlers is based on the following scenarios :

 Indoor area treatments (carpets, floors, crack

- and

- crevice treatments, attics, wall voids, crawl spaces, etc.)

o Loading/applying dust/powder formulations with:

 Hand pressure dusters (e.g., bulb dusters, plunger dusters, hand crank dusters)

 Power dusters/blowers

 Shaker cans

o Applying granules/baits via hand dispersal

o Mixing/loading/applying wettable dusts/powder formulations with a ma nually pressurized handwand sprayer

o Mixing/loading/applying liquid concentrate formulations with a manually pressurized handwand sprayer

o Applying bait gels/pastes

 Outdoor area treatments (lawns, gardens, shrubs/bushes, and fruit/nut trees)

o Loading/applying granule formulations with push

- type rotary spreaders

o Applying granule formulations via hand dispersal or with spoons or cups

o Mixing/loading/applying liquid concentrate formulations with :

 Manually pressurized handwand sprayers

 Hose

- end sprayers

 Backpack sprayers

 Sprinkler cans

 Swimming pool treatments

o Hand dispersal of powder or granule formulations

 P aint ing (with paints containing boric acid or a sodium salt as a material preservative) using :

o Brush/roller

o Airless sprayer

A series of assumptions and expo sure factors served as the basis for completing the residential
handler risk assessments. Each are detailed in the occupational and residential risk assessmentsBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 31 of 99 (M. Crowley, 9

- NOV

- 2015 , D428582; T. Dole, 13

- NOV

- 2015 , D 419073 ), but are also
summarized below.

 Application Rate: v arious application rates are outlined in Appendix C

.

 Unit Exposures and Area Treated or Amount Handled: scenario/equipment/formulation

specific exposure factors known as “u nit exposure s” a s well as their corresponding
estimates for area treated or amount of solution handled are from HED’s 2012
Residential SOPs 3 or standard assumptions for antimicrobial treatments.

 Body weight: for boric acid and its sodium salts, as for other active ingredients with non

sex

- specific effects

, a body weight of 80 kg is used in risk assessment to represent an assessment of the general (adult male and female) population

. Th ough developmental and fetal effects were observed, the selected endpoint for the POD is protective of these
effects and is based on non

- sex specific findings

. Residential handler exposure is generally expected to be short

- term in duration , though given

many boric acid/sodium salt labels do n o t specify treatment frequency and the use of boric acid
and its sodium salts is likely on an as

- needed basis (particularly its residential insecticide use), there is potential for intermediate

- term handler exposure as well. However, the toxicological endpoint selected for the short

- term assessment is protective of bot h short

- and intermediate

- term durations

.

Inhalation exposures and risks were calculated for residential handlers assuming no respiratory protection; no estimates of inhalation risk were of concern.

Table 6

. 1

. 1 presents detailed exposure and risk calcu lations.

3 http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

- operating

- procedures

- residential

pesticideBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Table 6 .1.1

. Summary of Residential Handler Risk Estimates for Boric Acid and its Sodium Salts

Use Site Category Exposure Scenario App Rate 1 Amount
Handled/ Area
Treated 2 Unit Exposure

( m g/lb ai) 3 Dose (mg/kg/day) 4 Inhalation MOE 5 (LOC = 10 0) I nhalation (no respirator) Inhalation

(no respirator)

Indoor

treatments Mixing /

loading / applying with a manually pressurized
handwand L iquids 0.15 lb ai/ gallon dilute
solution 0.5 gallons

dilute
solution 1.1 0.001 8500

Wettable dusts/powders 0. 31 lb ai/ gallon dilute
solution 1.1 0.0021 4100

Applying granules/baits via hand

dispersal 0.000017 lb ai/ft 2 1000 ft 2 0.38 0.000081 110000

Loading /

a pplying dusts/powders Shaker can 0.22 lb ai/20 oz
container One 20 oz

container 18 0.05 180

Power
duster/blower 0.21 lb ai/lb dust 1 lb dust 18 0.024 370

Bulb Duster 0.21 lb ai/lb dust 0.25 lb dust 1.7 0.0011 7900

Plunger Duster 0.21 lb ai/lb dust 0.5 lb dust 1.7 0.0022 3900

Applying bait gels/pastes No exposure/risks expected from gel/paste formulations.

Outdoor

treatments (lawns, gardens, and trees) Loading /

applying granules Rotary spreader 1.52 lb ai/acre 0.5 acres 0.0026 0.000025 360000

Belly grinder 0.034 lb ai/1000 ft 2 1200 ft 2 0.039 0.00002 430000

Spoon 0.034 lb ai/1000 ft 2 1200 ft 2 0.013 0.00054 1300000Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 33 of 99 Table 6 .1.1

. Summary of Residential Handler Risk Estimates for Boric Acid and its Sodium Salts

Use Site Category Exposure Scenario App Rate 1 Amount
Handled/ Area
Treated 2 Unit Exposure

( m g/lb ai) 3 Dose (mg/kg/day) 4 Inhalation MOE 5 (LOC = 10 0) I nhalation (no respirator) Inhalation

(no respirator)

Cup 0.034 lb ai/1000 ft 2 1200 ft 2 0.087 0.000046 190000

Applying granules via hand dispersal 0.034 lb ai/1000 ft 2 1200 ft 2 0.38 0.0002 44000

Mixing / loading / applying liquids Manually

pressurized
handwand 0.000073 lb ai/gallon

dilute solution 5 gallons
dilute
solution 0.018 8.2E

- 08 110000000

Hose

- end

sprayer 0.003 lb ai/acre 0.5 acres 0.022 4.1E

- 07 21000000

Backpack

sprayer 0.000073 lb ai/gallon

dilute solution 5 gallons
dilute
solution 0.14 6.4E

- 07 14000000

Sprinkler can 0.000073 lb ai/1000 ft 2 1000 ft 2 0.022 2.0E

- 08 440000000

Painting Brush/roller

1.4% ai 20 lbs paint (2 gal x 10 lbs/gal) 0.20 0.0007 13000

Airless sprayer 150 lbs paint (15 gal x 10 lbs/gal) 0.56 0.015 590

Swimming
Pools Hand dispersal Powders 0.30 lbs ai/gallon

water 20,000

gallons water 0.043 0.003 2,900

Granules 0.0017 0.00013 68,000

1 Based on registered l abel s outlined in Appendix C . All rates expressed in terms of boron

. 2 Based on HED’s 2012 Residential SOPs ( http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

- operating

- procedures

- residential

- pesticide ) o r standard assumptions for antimicrobial uses

. 3 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A /day or gallons/day) ÷ BW (kg). Expressed
in terms of boron.
4 Inhalation MOE = Inhalation POD (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

6 .2 Residential Post

- application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previ ously treated with boric acid or a borate sodium salt. T he exposure/risk assessment for residential post

- application exposures is based on the following
scenarios:

 Inhalation exposure for adults and children (1 < 2 years old) following indoor treatments (carpets, floors, crack

- and

- crevice, bedding/mattresses)

 Incidental oral children’s (1< 2 years old) exposure via:

o C ontact with treated:

 Turf/lawns

 Carpets and floors

 Wood /lumber (used in decks and playground equipment )

o Ingestion of applied granule formulations

 Incidental water ingestion for adults and children (6 < 11 and 11 < 16 years old) while swimming in treated pools

The lifestages selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residen tial SOPs 4 or, for exposures while swimming in treated pools, as outlined in the antimicrobial occupational and residential exposure assessment ( T. Dole, 13

- NOV

- 2015, D419073)

. While not the only lifestage potentially exposed for these post

application sc enarios, the lifestage that is included in the quantitative assessment is health protective for the exposures and risk estimates for any other potentially exposed lifestage

.

A series of assumptions and exposure factors served as the basis for completing t he residential post

- application risk assessment. These are outlined in more detail in (M. Crowley, 9

- NOV

2015, D428582 ; T. Dole, 13

- NOV

- 2015, D419073), but are summarized briefly below.

 Application Rate: v arious application rates are outlined in Appendix C

.

 Transfer Coefficients, Exposure Time, and other Exposure Factors:
scenario/formulation

- specific exposure factors known as “transfer coefficients” a s well as exposure time and other post

- application exposure factors (e.g., hand

- to

- mouth contact
factors , water ingestion while swimming ) are from HED’s 2012 Residential SOPs 5 or standard assumptions for antimicrobial treatments as outlined in the antimicrobial occupational and residential exposure assessment

.

 Body weight: for boric acid and its sod ium salts, as for other active ingredients with non

sex

- specific effects, a body weight of 80 kg is used in risk assessment to represent an assessment of the general (adult male and female) population. Th ough developmental
and fetal effects were observed , the selected endpoint for the POD is protective of these

4 http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

- operating

- procedures

- residential

pesticide

5 http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/standard

- operating

- procedures

- residential

pestic ideBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 35 of 99 effects and is based on non

- sex specific findings . For children , the following body weights were used where applicable:

o 1 < 2 years old : 11 kg

o 6 < 11 years old: 32 kg

o 11 < 16 years old: 57 kg

 Physiochemical Properties: chemical

- specific molecular weights and v apor pressure s

were utilized as necessary (see Appendix B )

.

 Residue Transferability :

o For post

- application exposure via contact with treated turf/lawns, default estimates of 1% for liqui ds and 0.5% for solid formulations were used.

o For post

- application exposure via contact with treated indoor carpets and hard floors, registrant

- submitted studies were used. The studies estimated transferability using the “California roller method” 6 , a met hod consistent with
default estimates described in the 2012 Residential SOPs. Across all the studies, which included varying types and conditions of carpets, transferability (as a percentage of the application rate) of boric acid/sodium salts ranged from 0.03% to 0.95%. To represent typical conditions for short

- /intermediate

- term post

application risk assessments, transferability of 0.1% is used for dust treatments to carpets (selected from MRID 47579901) and 0.4% for dust treatments to hard
floors and li quid treatments to carpets or hard surfaces (selected from MRID 47579902, the only result available for these conditions).

o The default transferable surface residue for treated wood is 1 μg/cm 2 , the highest estimate of residue transfer from data that was ge nerated by the Consumer Product Safety Commission (CPSC) evaluation of children’s exposure to chromate copper arsenate (CCA) treated wood.

Post

- application exposures are generally considered short

- term in nature , though exposures for competitive swimmers v ia use in swimming pools may present long

- term exposures . However, the toxicity study from which the inhalation and incidental oral toxicological endpoint s were selected to assess post

- application exposures are of sufficient duration to be protective of both
short

- intermediate

- and long

- term exposure durations

.

Where appropriate, post

- application inhalation and incidental oral risk estimates are combined within the same exposure scenario since they are based on the same toxicological effect. Risk
estimates of concern were identified for hand

- to

- mouth exposures for children following indoor bedbug treatments (MOE = 8) and indoor carpet spray treatments (MOE = 51). These routes are also combined with inhalation exposure, but as inhalation exposure i s much lower in comparison
to the hand

- to

- mouth exposure, the risk estimates are unchanged. Table 5.2.1 below outlines in more detail the exposure scenarios and exposure and risk calculations.

The application rates for boric acid/sodium salts are relat ively high compared with other pesticides used for similar purposes. In particular, the bed bug treatment broadcast application rate (based on EPA Reg. No. 64405

- 6) is approximately 6 pounds of boron per 1000 square foot

6 Ross, J.H., Fong, H.R., Thongsinthusak, T., Margetich, S. and Krieger, R. 1991. Measuring Potential Dermal Transfer of Surface Pesticide Residue Generated from Indoor Fogger Use: Using the CDFA Roller Method. Interim Report II. Chemosphere, Vol . 22. Nos.9

- 10:975

- 984Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 36 of 99 of carpet. Crack

- and

- crevice trea tments

– which result in substantially less surface residue than
broadcast treatments

– did not result in risk estimates of concern for incidental oral exposure
scenarios.

Table 6 .2.1 Residential Post

- application Exposure and R isk Estimates for Boric Aci d/Sodium Salts

Lifestage Post

- application Exposure Scenario Application Rate 1 Dose (mg/kg/day) 2 MOE 3

(LOC=100)

Use Site Route of Exposure Route

specific Combined 5

Adult Bed Bug

treatments Carpets Liquids Inhalation 0.71 lb DOT/gallon dilute
solution (0.0058 lb boron/ft 2 ) 0.00051 17000

--

Swimming pools Ingestion of water 35 mg boron/liter 0.0 34 26 0

-- Child (11 < 1 6 years old) Swimming pools Ingestion of water 35 mg boron/liter 0.031 280

--

Child (6 < 11 years old) Swimming pools Ingestion of water 35 mg boron/liter 0.055 160

--

Child (1 < 2 years old) Bed Bug

treatments Carpets Liquids Inhalation 0.71 lb DOT/gallon dilute
solution (0.0058 lb boron/ft 2 ) 0.0022 4000

--

Carpets 4 Liquids Hand

- to

- Mouth 0.0058 lb boron/ft 2 1.12 8 8

Object

- to

- Mouth 0.0058 lb boron/ft 2 0.037 240 220

General
Indoor

treatments Carpets 4 Liquids Hand

- to

- Mouth 0.0009 lb boron/ft 2 0.17 51 51

Dusts Hand

- to

- Mouth 0.00068 lb boron/ft 2 0.033 270

-- Liquids Object

- to

- Mouth 0.0009 lb boron/ft 2 0.023 380 350

Dusts Object

- to

- Mouth 0.00068 lb boron/ft 2 0.004 2000

--

Hard floors 4 Liquids Hand

- to

- Mouth 0.0009 lb boron/ft 2 0.043 200 190

Dusts Hand

- to

- Mouth 0.00068 lb boron/ft 2 0.033 270

-- Liquids Object

- to

- Mouth 0.0009 lb boron/ft 2 0.012 760 620

Dusts Object

- to

- Mouth 0.00068 lb boron/ft 2 0.009 1000

--

Crack

- and

crevice Carpets 4 Liquids Hand

- to

- Mouth 0.0009 lb boron/ft 2 0.017 510 460

Dusts Hand

- to

- Mouth 0.00068 lb boron/ft 2 0.0033 2700

-- Liquids Object

- to

- Mouth 0.0009 lb boron/ft 2 0.0023 3800 2000

Dusts Object

- to

- Mouth 0.00068 lb boron/ft 2 0.0004 20000

--

Hard floors 4 Liquids Hand

- to

- Mouth 0.0009 lb boron/ft 2 0.0043 2000 1400

Dusts Hand

- to

- Mouth 0.00068 lb boron/ft 2 0.0033 2700

-- Liquids Object

- to

- Mouth 0.0009 lb boron/ft 2 0.0012 7600 2600

Dusts Object

- to

- Mouth 0.00068 lb boron/ft 2 0.0009 10000

--

Outdoor (lawn, garden, tree sprays) Granules Hand

- to

- Mouth

1.52 lb ai/acre 0.0023 3800

-- Object

- to

- Mouth 0.00014 63000

-- Soil Ingestion 5.1E

- 05 170000

--

Solid Formulation Ingestion 8% boron

(49% sodium metaborate) 2.36 160

--

0.9% boron (5% boric acid) 0.24 1500

--

Liquids Hand

- to

- Mouth

0.003 lb ai/acre 0.00005 19000

--

Object

- to

- Mouth 0.000001 6300000

-- Soil Ingestion 1E

- 07 8.7E07

-- Treated wood used in decks and

play sets Hand

- to

- mouth 5.25 % ai solution 0.018 490

--

1 Based on registered labels outlined in Appendix C . All rates expressed in terms of boron, except for post

- application inhalation via volatilization, where application rate expressed is expressed in terms of disodium octaborate tetrahydrate in order to calculate volatilizati on of sprays using molecular weight and vapor pressure parameters.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 37 of 99 2 Dose (mg/kg/day) algorithms provided in the 2012 Residential S OPs ( http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

risks/standard

- operating

- procedures

- residential

- pesti cide ) . Expressed in terms of boron.
3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day). LOC=100.
4 As previously described, transferability from carpet and hard floors following dust treatments estimated at 0.1% and 0.4% respectively and transferability followin g liquid treatments on carpets and hard floors estimated at 0.4%.
5 Combined MOE = POD (mg/kg/day) ÷ [Inhalation Dose + Oral Dose (mg/kg/day) ]

. Combined exposures are only applicable for children 1< 2. When a combined MOE is shown the inhalation component is via the scenario for liquid applications to carpet or hard floors (d ose = 0.0022 mg/kg/day, MOE=4000).

7.0 Non

- Occupational Bystander Post

- Application Inhalation Exposure and Risk
Estimates

Vol atilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungi cide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.regulations.gov/#!docu mentDetail;D=EPA

- HQ

- OPP

- 2009

- 0687

- 0037 ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219).

Du ring Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies) or further analysis are required for boric acid and its sodium salts

. However, for some additional characterization of bystander exposure and risk vi a volatilization, post

- application inhalation exposure following indoor sprays were assessed and no risks of concern were
identified

.

8.0 Non

- Occupational Spray Drift Exposure and Risk Estimates

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up off

target and can lead to exposures to those it may directly contact. They can also deposit on
surfaces where contact with residues can eventually lead to indirect exposures ( e.g

. , children playing on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling onto 50

- feet

- wide lawns coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications that, by definition, should not res ult in direct exposures to individuals because of existing label language and other regulatory requirements intended to prevent them. 7 Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly through contact with impacted areas, such as residential lawns, when compliant applications are conducted. Given this premis e, exposures for children (1 < 2 years old) and adults who have contact with
turf where resid ues are assumed to have deposited via spray drift thus resulting in an indirect

7 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 38 of 99 exposure are the focus of this analysis analogous to how exposures to turf products are
considered in risk assessment.

In order to evaluate the drift potential and associate d risks, an approach based on drift modeling coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, a residential turf assessment based on exposure to deposited residues has been completed to
address drift from the agricultural applications of boric acid/sodium salts

. In the spray drift scenario, the deposited residue value was determined based on the amount of spray drift that may occur at varying distances from the edge of the treated field using the AgDrift ® (v2.1.1) model
and the Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift Policy

. Once the deposited residue values were determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

.

Boric acid and its sodium salts have existing direct uses on turf, thus it was considered whether
the risk assessment for that use may be health protective of exposures resulting from spray drift. If the maximum application rate on crops adjusted by the amount of drift expected is less than or equal to existing turf application rates, the existing turf assessment is considered p rotective of spray drift exposure. The existing maximum single application rate of boric acid/sodium salts for various agricultural food/feed crops is 0.0018 lb ai/acre. The highest degree of spray drift noted for any application method immediately adjac ent to a treated field (Tier 1 output from the aerial application using fine to medium spray quality) results in a deposition fraction of 0.26 of the application rate.

A quantitative spray drift assessment for boric acid/sodium salts is not required because the

max imum application rate to a crop/ta rget site multiplied by the adjustment factor for drift of
0.26 is less than the maximum direct spray residential turf application rate of 0.003 lb ai/acre (i.e., 0.0018 lb ai/A x 0.26 ≤ 0.003 lb ai/A ) . The turf post

- application MOEs based on the revised SOPs for Residential Exposure Assessment were assessed and no risks of concern were
identified.

9 .0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate ( i.e., add together ) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are either added together and compared to quantitative estimates of ha zard (e.g., a NOAEL or PAD) or , in situations when routes are compared to different hazard estimates or have different levels of concerns, the risk
estimates (e.g., MOEs) are aggregated. When aggregating exposures and risks from various sources, HED consi ders both the route and duration of exposure.

Because residues of boron in/on food from pesticide use of boric acid/sodium salts is indistinguishable from naturally

- occurring sources, there is no dietary pesticide exposure estimate for the purposes of agg regating exposure. Residential/non

- dietary risks of concern for children 1 < 2 years old were identified only for post

- application incidental oral exposuresBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 39 of 99 resulting from broadcast spray treatments to carpets. B ecause the contribution of background
diet ary intake of boron is implicitly accounted for in the background dietary intake by the laboratory animals in the toxicology studies, the residentia l /non

- dietary risk assessment represents the aggregate risk assessment

.

10 .0 Cumulative Exposure/Risk Chara cterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to bor ic acid and its sodium salts and any other substances

, and bor ic acid and its sodium salts d o not appear to produce a toxic metabolite produced by other substances. For the purposes of this risk assessment, therefore, EPA has not assumed that boric acid and its sodium salts ha ve a common mechanism of toxicity wit h other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/cumulative

- assessment

risk

- pesticides

.

11 .0 Occupational Exposure/Risk Characterization

There are numerous conventional u ses of boric acid or its sodium salts as active i ngredients, from insecticide and fungicide dusts and sprays to granular herbicides. Additionally, there are antimicrobial uses in swimming pools and as material and wood preservatives.

Given these uses, both occupational handler and post

- application expo sures are anticipated. As
described above , though dermal exposures are possible, due to negligible dermal absorption, toxicity from dermal exposure is not expected and dermal risks are not of concern . Therefore,

a ddressed below are inhalation exposures f or workers mixing/loading and applying boric acid products as well as post

- application inhalation resulting from areas previously treated with boric acid products

.

I nhalation exposures for some occupational handler scenarios have risk estimates of concern (MOEs < 100), requiring respirator s to mitigate risks. For dust applications to structural building components (e.g., attics, crawl spaces, soffits, etc.) and agricultural bu ildings (e.g., poultry houses) , standard respirator s (i.e., filtering face

- pieces) do not mitigat e inhalation risk estimates
of concern

. No post

- application risks ar e of concern.

11 .1 Occupational Handler Exposure/Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target beingBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 40 of 99 treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios :

 L oading granules to support tractor

- drawn spreader applications

 Mixing/loading liquids to support applications via:

o Airblast sprayers

o Grou ndboom sprayers

 Loading/applying granules with:

o Backpacks

o Belly grinders

o Spoons or cups

o Rotary spreaders

 Mixing/loading/applying liquid solutions with:

o Airless sprayer

o Brush/roller

o Backpack sprayers

o Manually

- pressurized handwand sprayers

o Mechanically

- pressurized handgun sprayers

 Mixing/loading dusts/powders with water and applying with manually pressurized handwands and mechanically pressurized handguns

 Applying bait gels/pastes

 Applying dusts with:

o Shaker cans

o Bulb dusters

o Plunger dusters

o Power dusters/blowers

 Applying granules via:

o Hand dispersal

o Tractor

- drawn spreaders

 Applying sprays with :

o Airblast sprayers

o Groundboom sprayers

 Pouring solid/powders

 Preservative incorporation into wood via brush, trowel, injection, pressure treatment, dip
diffusion treatment , and mechanized sprays

A series of assumptions and exposure factors served as the basis for completing the residential
handler risk assessments. These are outlined in more detail in (M. Crowley, 9

- NOV

- 2015, D428582; T. Dole, 13

- NOV

- 2015, D 419073 ) , but are summarized briefly below

.

 Application Rate: v arious application rates are outlined in Appendix C

.

 Unit Exposures and Area Treated or Amount Handled: scenario/equipment/formulation

-Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 41 of 99 specific exposure factors known as “u nit expo sure s” a s well as their corresponding
estimates for area treated or amount of solution handled are from HED’s ExpoSAC Policy #9.1 or standard assumptions for antimicrobial treatments.

 Body weight: for boric acid and its sodium salts, as for other active i ngredients with non

sex

- specific effects, a body weight of 80 kg is used in risk assessment to represent an assessment of the general (adult male and female) population. Th ough developmental and fetal effects were observed, the selected endpoint for the POD is protective of these
effects and is based on non

- sex specific findings

.

HED typically classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six
months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural /commercial uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for
more than a one

- month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a produ ct over a period of weeks (e.g., completing multiple applications for mult iple client s within a region) , or, in the case of antimicrobial material and wood preservatives, months. Additionally, given that labels for boric acid and its sodium salts products generally do not specify retreatment intervals and its nature as a multi

- use pestici de (as an insecticide, herbicide, and fungicide), it is not unreasonable to consider applicators handling this active ingredient relatively frequently. Thus, both short

- and
intermediate

- term exposures are anticipated , as well as long

- term exposures speci fically for the antimicrobial material and wood preservatives

. T he toxicological endpoint selected is protective
of all durations

.

Product labels vary with respect to work attire and levels of personal protective equipment, with some labels not providing any specifications to others requiring use of chemical/water

- resistant gloves or respirators. Inhalation exposure is assessed assuming no respiratory protection and then, when risks of concern might indicate a need for them, assessed assuming different t ypes of respirators.

The occupational handler exposure and risk estimates indicate th e following scenarios have
inhalation risk estimates of concern (MOEs < 100) without respiratory protection:

 L oading granules to support tractor

- drawn spreader applications in industrial/commercial

areas

 Applying granules to industrial/commercial areas via:

o Hand dispersal

o Tractor

- drawn spreaders

o Spoons or cups

 Applying dusts with:

o Bulb dusters to food handling establish ments, warehouses, residential living spaces, and structural building components

o Plunger dusters to structural building components

o Power dusters/blowers poultry houses

o Shaker cans to tree stumpsBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 42 of 99  Mixing/loading/applying liquid solutions with mechanically

- pr essurized handgun sprayers and airless sprayers to structural building components

 Mixing/loading dusts/powders with water and applying with:

o Mechanically pressurized handguns to poultry houses

o Manually pressurized handwands to residential living spaces and structural building components

 Pouring in powder formulations to treat swimming pools

Hand dispersal of granules in industrial/commercial areas and shaker can applications of dusts to tree stumps do not result in risk estimates of concern (MOE ≥ 100) with a respirator that offers 90% reduction in inhalation exposure (e.g., a half

- face cartridge/canister style mask) . All other scenarios of concern without a respirator do not result in risk estimates of concern with a respirator that offers 80% re duction in inhalation exposure ( e.g. a quarter

- face dust/mist filtering face mask)

.

For the following two scenarios, inhalation exposures are of a magnitude that no standard respiratory protection 8 reduces exposures to a level where inhalation risks are n ot of concern (MOEs ≥ 100):

 Applying dusts with:

o Plunger dusters to structural building components and poultry houses

o Power dusters/blowers to poultry houses

Overall, application rates for boric acid/sodium salts products are relatively high compared to other pesticides with similar use patterns

– for the scenarios above, some on the order of 100 pounds of active ingredient or more per acre or almost 1⁄2 pound of active ingredient per gallon of dilute solution. These high application rates, as well as, for applicable scenarios, the fact that exposure data indicate dust formulations present some of the highest inhalation exposures, is driving the presence of inhalation risks.

Table 11 .1.1 presents detailed exposure and risk calculations

.

8 While a self

- contained breathing apparatus or a powered

- air supply respirator will likely sufficiently reduce exposures, it is assumed tha t these are infeasible/impractical options.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 43 of 99 Table 11

. 1

. 1

. Summary of Occupational Handler Risk Estimates for Boric Acid and its Sodium Salts

Exposure
Scenario Crop / Target Category App Rate 1 Amount
Handled/ Area
Treated 2 I nhalation 3

Unit Exposure ( u g/lb ai) 4 Dose

(mg/kg/day) 5 MOE 6

(LOC = 10 0 )

Mixing / loading / applying
l iquids Backpack

sprayer Nursery, Landscaping (turf,

trees, plants) 0.000073 lb
ai/ gallon dilute
solution

40 gallons dilute

solution 69.1 2.5E

- 06 3,500,000

Greenhouse 140 5.1E

- 06 1,700,000

Structural Building Components 0.32 lb ai/gallon
dilute solution 30 0.0048 1800

Manually

pressurized
Handwand On

- site wood treatment 0.525 lb ai/gallon 30 0.0079 1100

Residential Living Spaces 0.15 lb ai/gallon
dilute solution 1100 0.083 110

Nursery, Landscaping (turf, trees, plants), Greenhouse

0.000073 lb
ai/ gallon dilute
solution 40 gallons dilute

solution 30 1.1E

- 06 8,000,000

Mechanically

pressurized handgun Field Crops (typical

acreage), Landscaping (trees, plants), Nursery, Orchards/vineyards 1000 gallons
dilute solution 8.68 7.9E

- 06 1,100,000

Greenhouse 120 1.1E

- 04 80,000

Structural Building Components 0.32 lb ai/gallon
dilute solution 79 (NR) 15.8 (PF5) 0.316 (NR)

0.063 (PF5) 28 (NR)

140 (PF5)

Landscaping (turf) 0.003 lb ai/acre 5 acres 1.9 3.6E

- 07 25,000,000

Airless sprayer Structural Building Components 0.32 lb ai/gallon
dilute solution 40 gallons dilute

solution 560 (NR)

112 (PF5) 0.09 (NR)

0.018 (PF5) 98 (NR)

490 (PF5)Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 44 of 99 Table 11

. 1

. 1

. Summary of Occupational Handler Risk Estimates for Boric Acid and its Sodium Salts

Exposure
Scenario Crop / Target Category App Rate 1 Amount
Handled/ Area
Treated 2 I nhalation 3

Unit Exposure ( u g/lb ai) 4 Dose

(mg/kg/day) 5 MOE 6

(LOC = 10 0 )

Brush/roller 280 0.045 200

Brush/roller On

- site wood treatment 0.85 lb ai/gallon
dilute solution 5 gallons dilute

solution 280 0.015 590

Mixing / loading / applying
wettable
dusts/ powders Mechanically

pressurized handgun Poultry house 0.15 lb ai/gallon
dilute solution 1000 gallons

dilute solution 79 (NR)

15.8 (PF5) 0.149 (NR)

0.03 (PF5) 59 (NR)

300 (PF5)

Manually

pressurized
Handwand Residential Living Spaces 0.18 lb ai/gallon
dilute solution 40 gallons dilute

solution 1100 (NR)

220 (PF5) 0.099 (NR)

0.0198 (PF5) 89 (NR)

440 (PF5)

Structural building components 0.31 lb ai/gallon
dilute solution 1100 (NR) 220 (PF5) 0.17 (NR)

0.0341 (PF5) 52 (NR)

260 (PF5)

Tree stumps 0.0023 lb ai/ft 2 1,000 ft 2 of tree stumps 30 0.00085 10,000

Loading/ applying
dusts Bulb duster Crack and crevice (residential areas, warehouses, food handling establishments) 0.00068 lb ai/ft 2 10,000 ft 2 1690 (NR) 338 (PF5) 0.144 (NR)

0.029 (PF5) 61 (NR)

310 (PF5)

0.22 lb ai/20 oz
container One 20 oz

container 0.0047 1900

Plunger duster Structural building components 0.0065 lb ai/ft 2 10,000 ft 2

1690 (NR) 338 (PF5) 169 (PF10) 1.38 (NR)

0.275 (PF5) 0.138 (PF10) 6.4 (NR)

32 (PF5) 64 (PF10)

Industrial/commercial areas 0.00068 lb ai/ft 2 10,000 ft 2 0.144 (NR) 0.029 (PF5) 61 (NR)

310 (PF5)

Poultry house 0.01 lb ai/ft 2 10,000 ft 2 2.18 (NR) 0.435 (PF5) 0.218 (PF10) 4 (NR)

20 (PF5) 40 (PF10)

Power
duster/blower Poultry house 0.01 lb ai/ft 2 10,000 ft 2 17,500 (NR) 3500 (PF5) 17500 (PF10) 22.5 (NR)

4.5 (PF5) 2.25 (PF10) < 1 (NR)

2 (PF5)
4 (PF10)Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 45 of 99 Table 11

. 1

. 1

. Summary of Occupational Handler Risk Estimates for Boric Acid and its Sodium Salts

Exposure
Scenario Crop / Target Category App Rate 1 Amount
Handled/ Area
Treated 2 I nhalation 3

Unit Exposure ( u g/lb ai) 4 Dose

(mg/kg/day) 5 MOE 6

(LOC = 10 0 )

Shaker can Greenhouse, Nursery,

Landscaping (plants/flowers), Warehouse, Poultry house,
Foundations/Perimeters 0.22 lb ai/20 oz
container One 20 oz

container 17,500 (NR)

3500 (PF5) 17500 (PF10) 0.048 180

Tree stumps 0.0023 lb ai/ft 2 1,000 ft 2 of tree
stumps 0.495 (NR) 0.099 (PF5) 0.05 (PF10) 18 (NR)

89 (PF5) 180 (PF10)

Mixing / loading liquids Groundboom Golf course (tees and greens)

0.0018 lb ai/acre 5 acres

0.219 2.5E

- 08 360,000,000

Golf course (fairways, tees, and greens), Field

- grown ornamentals, Orchard/vineyards 40 acres 2.0E

- 07 44,000,000

Nursery, Greenhouse 60 acres 3.0E

- 07 30,000,000

Field crops (typical acreage) 80 acres 3.9E

- 07 22,000,000

Field crops (high acreage) 200 acres 9.9E

- 07 8,900,000

Airblast Nursery 20 acres 9.9E

- 08 89,000,000

Orchards/vineyards 40 acres 2.0E

- 07 44,000,000

Applying

sprays Groundboom Golf course (tees and greens) 0.0018 lb ai/acre 5 acres 0.34 3.8E

- 08 230,000,000Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 46 of 99 Table 11

. 1

. 1

. Summary of Occupational Handler Risk Estimates for Boric Acid and its Sodium Salts

Exposure
Scenario Crop / Target Category App Rate 1 Amount
Handled/ Area
Treated 2 I nhalation 3

Unit Exposure ( u g/lb ai) 4 Dose

(mg/kg/day) 5 MOE 6

(LOC = 10 0 ) Golf course (fairways, tees, and greens), Field

- grown ornamentals, Orchard/vineyards 40 acres 3.1E

- 07 29,000,000

Nursery, Greenhouse 60 acres 4.6E

- 07 19,000,000

Field crops (typical acreage) 80 acres 6.1E

- 07 14,000,000

Field crops (high acreage) 200 acres 1.5E

- 06 5,800,000

Airblast Nursery 20 acres

4.71 2.1E

- 06 4,100,000

Orchards/vineyards 40 acres 4.2E

- 06 2,100,000

Mixing/ loading granules Tractor drawn

spreader Golf course (fairways, tees,

and greens) 1.5 lb ai/acre 40 acres 1.7 (NR) 0.34 (PF5) 0.0013 6900

Industrial/commercial areas 105 lb ai/acre 60 acres 0.134 (NR) 0.027 (PF5) 66 (NR)

330 (PF5)

Applying granules/
baits Hand dispersal Residential areas, food handling establishments 0.017 lb ai/1000 ft 2 10,000 ft 2

470 (NR) 94 (PF5) 47 (PF10) 0.001 8500

Foundations/perimeters 1.5 lb ai/acre

1 acre 0.009 1000

Industrial/commercial areas 105 lb ai/acre 0.618 (NR) 0.123 (PF5) 0.062 (PF10) 14 NR)

72 (PF5) 140 (PF10)Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 47 of 99 Table 11

. 1

. 1

. Summary of Occupational Handler Risk Estimates for Boric Acid and its Sodium Salts

Exposure
Scenario Crop / Target Category App Rate 1 Amount
Handled/ Area
Treated 2 I nhalation 3

Unit Exposure ( u g/lb ai) 4 Dose

(mg/kg/day) 5 MOE 6

(LOC = 10 0 )

Belly grinder Landscaping (turf),

Foundations/perimeters 1.5 lb ai/acre 1 acre

62 0.0012 7600

Industrial/commercial areas 105 lb ai/acre 1 acre 6.51 110

Tractor drawn spreader Golf course (fairways, tees,

and greens) 1.5 lb ai/acre 40 acres 1.2 (NR) 0.24 (PF5) 0.0009 9800

Industrial/commercial areas 105 lb ai/acre 60 acres 0.095 (NR) 0.019 (PF5) 93 (NR)

470 (PF5)

Rotary spreader Golf course (fairways, tees,

and greens), Landscaping

(turf) 1.5 lb ai/acre 5 acres

10 0.0009 9400

Industrial/commercial areas 105 lb ai/acre 5 acres 0.066 130

Spoon Foundations/perimeters 1.5 lb ai/acre 1 acre 121 (NR) 24.2 (PF5) 0.0023 3900

Industrial/commercial areas 105 lb ai/acre 1 acre 0.159 (NR) 0.032 (PF5) 55 (NR)

280 (PF5)

Cup Foundations/perimeters 1.5 lb ai/acre 1 acre

12.5 0.00024 37000

Industrial/commercial areas 105 lb ai/acre 1 acre 0.0164 5400

Backpack Industrial/commercial areas 105 lb ai/acre 1 acre 23.8 0.031 280

Airless sprayer Interior/exterior surfaces 1.4% ai by weight 50 gallons 560 0.049 180Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 48 of 99 Table 11

. 1

. 1

. Summary of Occupational Handler Risk Estimates for Boric Acid and its Sodium Salts

Exposure
Scenario Crop / Target Category App Rate 1 Amount
Handled/ Area
Treated 2 I nhalation 3

Unit Exposure ( u g/lb ai) 4 Dose

(mg/kg/day) 5 MOE 6

(LOC = 10 0 ) Loading/ applying paints Brush/roller 5 gallons 280 0.0025 3500

Applying gels/pastes Crack and crevice (residential areas,

warehouses, food handling establishments) No exposure/risks expected from gel/paste formulations.

Pouring

- in Powders

Swimming pools 0.3 lb ai/1000 gallons water 660,000 gallons

water 43 (NR)

8.6 (PF5) 0.11 (NR)

0.021 (PF5) 80 (NR)

420 (PF5)

Granules 1.7 0.0042 2100

Preservative incorporation Paints,

inks/dyes, coatings Pouring

- in powders/solids 1.4% ai by weight
of finished material 20,000 lbs

finished material 43 0.015 590

Wood/lumber Pressure treatment

( Treatment operator

– max. scenario) 5.25% ai solution 46 ug/m3 0.00 58 15 00

Dip Diffusion (cleaning crew

– max. scenario) 6.3 % ai solution 890 ug/% ai 0.070 130

Sapstain Treatment (cleaning crew

– max. scenario) 3.5% ai solution 890 ug/% ai 0.039 230

1 Based on registered label on registered labels outlined in Appendix C . All rates expressed in terms of boron.
2 Based on Exposure Science Advisory Council Policy #9.1 and standard assumptions for antimicrobial pesticides use. 3 NR = no respirator; PF5 = “Protection Factor 5”, indicating a reduction in exposure of 80% ; PF10 = “Protection Factor 10” indicating a reduction in exposure of 90%. Unless noted, results reflect no respirator (NR).
4 Based on the “Occupational Pesticid e Handler Unit Exposure Surrogate Reference Table” ( September 201 5 ).
5 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Are a Treated (A/day) ÷ BW (kg). Expressed in terms of boron.
6 Inhalation MOE = Inhalation POD (mg/kg/da y) ÷ Inhalation Dose (mg/kg/day)Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

11. 2 Occupational Post

- application Exposure/Risk Estimates

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation prope rties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure

.

Given uses of boric acid/sodium salts, occupational post

- application exposures are anticipated.
Add ressed below are inhalation exposures /risks only; though dermal exposures are possible, because absorption is negligible, toxicity via the dermal route is not expected; therefore dermal risks are not quantitatively addressed. Note also, as boric acid and its sodium salts are classified as “Not Likely to be Carcinogenic to Humans” only non

- cancer risks are quantified

.

11. 2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The agency sought expert advic e and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2009

- 0687

- 0037 ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review, the agency will utiliz e this analysis to determine if data (i.e., flux studies) or further analysis is required for boric acid/sodium salts

.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments.

For applications within greenho uses, t he Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)] . Additionally, c ommercial applicators do not typically return to the treated areas after an indoor commercial pesticide application (sites such as warehouses, food handling establishments, and hotels, etc.) and thu s an occupational post

- application inhalation exposure assessment was not perfor med for commercial applicators.

11 .2.2 Occupational Post

- application Dermal Exposure/Risk EstimatesBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 50 of 99 As dermal risks are not of concern, r estricted

- entry intervals (REIs) for b oric acid/sodium salts default to technical grade active ingredient acute toxicity

- based requirements. Currently, REIs on product labels vary considerably from 4 hours to 48 hours. These differences may reflect the different acute toxicity profiles of th e various borate sodium salts, or the presence of an additional active ingredient in the product.

1 2 .0 Public Health and Pesticide Epidemiology Data

The Agency has reviewed the available incident data for boric acid and its sodium salts (Memo,
E. Evans and S. Recore, 1

- OCT

- 2015 ; D 429234 ). Boric acid was previously reviewed in 2005 (M. Hawkins and H. Allender, 9/22/05, D 320914 ). At the time, 20 incidents were reported for boric acid in Main IDS from 1992 to September 2005. A review of SENSOR

- Pesticides from
1998

- 2003

, found 21 cases involving boric acid, 1 case involving sodium tetraborate decahydrate, and 4 cases involving disodium octaborate tetraborate.

The current IDS analysis from January 1, 2010 through June 8, 2015, shows 10 i ncidents reported to Main IDS involving the single active ingredient boric acid. An additional 17 incidents were reported involving more than one active ingredient. Three hundred and sixty (360) incidents of minor severity and 78 incidents with no or unk nown effects were reported to Aggregate IDS involving boric acid. In addition, a query of SENSOR

- Pesticides 2004

- 2011 identifies a total of 104 cases involving boric acid.

Although there were a moderate number of boric acid incidents reported to Main and Aggregate IDS (n=466) and SENSOR

- Pesticides (n=104), most of these incidents were classified as low severity. The effects experienced were generally minimally traumatic and resolv ed rapidly

, usually irritation of the skin, eye or respiratory system . Bas ed on the low severity of incidents reported to both IDS and SENSOR

- Pesticides, there does not appear to be a concern at this time. The Agency will continue to monitor the incident data and if a concern is triggered, additional analysis will be conducted.

1 3 .0 References

13.1 OPP Memoranda

OPP Memoranda Relevant to Registration Review.

Author Barcode Date Title

M . Crowley D 428582 9

- Nov

- 2015 Boric Acid/Sodium Salts of Boric Acid. Occupational and Residential Exposure and Risk Assessment for Registration
Review

. T. Dole D 419073 13

- NOV

- 2015 Occupational and Residential Exposure Assessment of the Antimicrobial Uses of Boric Acid and Salts for the Registration
Review Draft Risk Assessment
E. Evans and S. Recore D 429234 1

- Oct

- 2015 Boric Acid and its Sodium Salts: Tier I Update Review of
Human Incidents and Epidemiology for Draft Risk Assessment

J

. Leshin TXR# 0057 245 Dec

- 2015 Boric Acid and Sodium Borate Salts: Summary of Hazard and Science Policy Council (HASPOC) Meeting on September 3, 2015: Recommendations on the Requirement of a Subchronic Dermal Toxicity Study

K

. Rury TXR# 0056768 5

- FEB

- 2014 Boric Acid/Borate Salts: Summary of Hazard and Science Policy Council (HASPOC) Meetings of August 15, 2013 andBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 51 of 99 OPP Memoranda Relevant to Registration Review.

Author Barcode Date Title
November 21, 2013: Recommendations on the Need for Subchronic Inhalation and Subchronic Neurotoxicity Studies
M. Hawkins and H.
Allender D320914 22

- SEP

- 2005 Review of Boric Acid Incident Reports

K. Sherman Not applicable 27

- JAN

- 2014 Ethics Review of Boric Acid Dermal Absorption Study

L. Hansen D359933 6

- MAY

- 2009 Boric Acid/Sodium Salts of Boric Acid. Human Health Assessment Scoping Document in Support of Registration
Review

L. Hansen D320894 26

- JUL

- 2006 Boric Acid/Sodium Borate Salts: HED Chapter of the
Tolerance Reassessment Eligibility Decision Document. R. Loranger/D. McNeilly D346904 5

- MAY

- 2008 Borax (Sodium Tetraborate Decahydrate). Label Amendment to add Additional Agricultural Crops, Additional Ornamental, and Golf Course Use to the Label for Prey

- AM Ultra (EPA Reg.
No. 72662

- 3) and The Related Request for Exemption from the Requirement for a Tolerance

13.2 MRID Submissions

00005622 Weir, R.J. (1966) Final Report: Two

- Year Dietary Feeding

- Dogs. Hazleton

Laboratories, Falls Church, VA, Project No. 182

- 106, July 8, 1966; submitted by United States Borax. Unpublished report.

00005644 Meyding, G.D. (1961) Boric Acid: Acute Oral Administration

– Rats. Hazleton

Nuclear Science Laboratories, Inc., Palo Alto, CA. Project No. January 25, 1961; Submitted by United States Borax. Unpublished Report.

00006719 Hazleton Laboratories, Inc. (1962) Toxicity of Borax and Boric Acid. Received

June 25, 1969 under 1624

- 96; submitted by United States Borax and Chemical Corp., Los Angeles, CA. Unpublished report.

000642 0 4 Paynter, O.E., Kundzin, M and Kundzin, T. (1963) Boric Acid 90

- Day Dietary

Feeding

- Dogs. Hazleton Laboratories, Falls Church, VA, January 17, 1963; submitted by U .S. Borax Research Corp., Unpublished report.

00064205 Weir, R.J. (1967) Final Report: 38

- Week Dietary Feeding

- Dogs. Hazleton

Laboratories, Falls Church, VA, February, 1967; submitted by United States Borax. Unpublished report.

00064207 Keller, J.G. (1962) Boric Acid: Acute Oral Administration

– Rats. Hazleton

Laboratories, Inc., Fall s Church, VA. March 19, 1962; submitted by United States Borax. Unpublished report.

00064208 Keller, J.G. (1962) Acute Oral Administration

-- Dogs: Boric Acid. Received

March 5, 1981 under 1624

- 117; prepared by Hazleton Laboratorie s, Inc., submitted by United States Borax & Chemical Corp., Los Angeles, CA. Unpublished report.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 52 of 99 00064209 Estep, C.L. and Teske, R.H. (1968) Acute Application of Sample 713 123A to the

Eyes of Rabbits: S

- 152A. Received Mar 5, 1981 under 1624

- 117; prepar ed by Hill Top Research, Inc., submitted by United States Borax & Chemical Corp., Los Angeles, Calif. Unpublished report.

00068025 Paynter, O.E., Kundzin, M. and Kundzin, T. (1962) Boric Acid 90

- Day Dietary

Feeding

- Rats. Hazleton Laboratories, Falls Chu rch, VA, December 12, 1962; submitted by United States Borax. Unpublished report.

00068882 Weir, R.J. and Crews, L.M. (1966) Final Report: Three

- Generation Reproduction

Study

- Rats. Hazleton Laboratories, Falls Church, VA, Project No. 182

- 105, July 8, 196 6; submitted by United States Borax. Unpublished report.

00068883 Weir, R.J. and Wright, D. (1966) Final Report: Two

- Year Dietary

AdministrationAlbino Rats. Hazleton Laboratories, Falls Church, VA, Project
No. 182

- 104, July 8, 1966; submitted by United S tates Borax. Unpublished report.

00106011 Conine, D., Weiner, A., Kreuzmann, J. et al. (1982) Acute Dermal Toxicity

Screen in Rabbits: Primary Skin Irritation Study in Rabbits of Boric Acid (OA
107

- 3) for U.S. Borax Research Corporation: Hill Top Research Project No. 82

- 0280

- 21. Received Jul 12, 1982 under 1624

- 116; prepared by Hill Top Research, Inc., submitted by United States Borax & Chemical Corp., Los Angeles, CA. Unpublished report.

40692301 Meyding, G.D. (1961) Acute Oral Administration

- Rats with Sodium Tetraborate

Decahydrate. Hazleton

- Nuclear Science Corp., Palo Alto, CA. No study number provided. January 25, 1961. Unpublished report.

40692302 Meyding, G.D. (1961) Acute Oral Administration

- Rats with Sodium Tetraborate

Decahydrate. Hazleton Laboratories, Inc., Vienna, VA. No study number provided. August 2, 1961. Unpublished report.

40692303 Keller, J.G. (1962) Acute Oral Administration

– Rats with Borax (Sodium

Tetraborate Decahdyrate). Hazleton Laboratories, Inc., Vienna, VA. No study number provided. March 16, 1962. Unpublished report.

40692304 Keller, J.G. (1962) Acute Oral Administration

– Dogs with Borax (Sodium

Tetraborate Decahydrate). Hazleton Laboratories, Inc., Vienna, VA. No study number provided. March 16, 1962. Unpubl ished report.

40692505 Paynter, O.E. (1962) 90

- Day Dietary Administration

– Rats with 20 Mule Team

Borax (Sodium Tetraborate Decahydrate). Hazleton Laboratories Inc., Falls Church, VA. No study No. provided, December 13, 1962. Unpublished report.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 53 of 99 406923 06 Weir, R.J. (1963) 90

- Day Dietary Administration

– Rats with 20 Mule Team

Borax (Sodium Tetraborate Decahydrate). Hazleton Laboratories, Inc., Vienna, VA. No study number provided. February 15, 1963. Unpublished report.

40692307 Paynter, O.E. (1963) 9 0

- Day Dietary Feeding

– Dogs with 20 Mule Team Borax

(Sodium Tetraborate Decahydrate). Hazleton Laboratories, Inc., Vienna, VA. No study number provided. February 15, 1963. Unpublished report.

40692308 Weir, R.J. (1967) 38

- Week Dietary Feeding

– Dogs wi th 20 Mule Team Borax

(Sodium Tetraborate Decahydrate). Hazleton Laboratories, Inc., Falls Church, VA. No study number provided. February 28, 1967. Unpublished report.

40692309 Weir, R.J. and Crews, L.M. (1967) Two Year Dietary Administration

– Albino

R ats. Borax (Sodium Tetraborate Decahydrate) and Addendum. Hazleton Laboratories, Inc., Falls Church, VA. Laboratory Project ID 182

- 104, April 10, 1967 (original study on July 8, 1966). Unpublished report.

40692310 Weir, R.J. and Crews, L.M. (1967) Two Year Dietary Feeding

– Dogs. Borax

(Sodium Tetraborate Decahydrate) and Addendum. Hazleton Laboratories, Inc., Falls Church, VA. Laboratory Project ID 182

- 104, April 10, 1967 (original study on July 8, 1966). Unpublished report.
40692311 Weir, R.J. and Crews, L.M. (1966) Three

- Generation Reproductive Study

– Rats

with Borax (Sodium Tetraborate Decahydrate) and Addendum. Hazleton Laboratories, Inc., Vienna, VA. Project No. 182

- 105. July 8, 1966. Unpublished report.

41589101 Fail, George, Grizzle et a l. (1990) Reproductive Toxicity of Boric Acid in CD

- 1

Swiss Mice. NTP, NIEHS, Research Triangle Park, N.C. Study Number 90

- 105, April 13, 1990. Unpublished report.

41725401 Field, E.A., Price, C.J., Marr, M.C. et al. (1990) Final Report on the

Developmental Toxicity of Boric Acid (CAS No. 10043

- 35

- 3) in Sprague

- Dawley Rats. EPA Rg. No. 1624

- 117. Research Triangle Institute and National Toxicology Program. Study Number Rt88

- BORT, May 1, 1990. Published report.

417 25402 Field, E.A., Price, C.J., Marr, M.C. et al. (1990) Final Report on the

Developmental Toxicity of Boric Acid (CAS No. 10043

- 35

- 3) in CD

- 1 Swiss Mice. EPA Reg. No. 1624

- 117. Research Triangle Institute and National Toxicology Program. Study Number M 188

- BORT, December 14, 1990. Published report.

41861301 Dieter, M., Bishop, J., Eustis, S. Haseman, J. et al. (1991) Toxicology and

Carcinogenesis of Boric Acid in B6C3F1 Mice, NTP Technical Report Series 324. E.G. and G. Mason Research Institute, Study No. TR324, April, 1991. Published report.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 54 of 99 42038901 Steward, K.R. (1991) Salmonella /Microsome Plate Incorporation Assay of Boric

Acid. SRI International, Inc., Menlo Park, CA. Study No. 2389

- A200

- 91, August 12, 1991. Unpublished report.

42038902 Rudd, C.J. (1991) Mous e Lymphoma Cell Mutagenesis Assay (tk +/

- /tk

- /

- ) of Boric

Acid. SRI International, Menlo Park, CA. Study Number 2389

- G300

- 91, August 23, 1991. Unpublished report.

42038903 Bakke, J.P. (1991) Evaluation of the Potential of Boric Acid to Induce

Unscheduled DNA Synthesis in In Vitro Hepatocyte DNA Repair Assay Using
the Male F

- 344 Rat. SRI International, Menlo Park, CA. Study Number 2389

- V50091, August 21, 1991. Unpublished report.

42038904 O’Loughlin, K.G. (1991) Bone Marrow Erythrocyte Micronucleus A ssay of Boric

Acid in Swiss

- Webster Mice. SRI International, Menlo Park, CA. Study Number
2389

- C400

- 91, August 19, 1991. Unpublished report.

42164201 Price, C., Marr, M. and Myers, C. et al. (1991) Developmental Toxicity of Boric

Acid in New Zealand White Rabbi ts. NTP and Chemistry and Life Sciences, Research Triangle Park, NC. Study No. Rb90

- BPORA, October 30, 1991. Published report.

42164202 Price, C.; Marr, M. and Myers, C.; et al. (1991) Laboratory Supplement for Final

Report on the Development Toxicity of Boric Acid in New Zealand White
Rabbits. National Institute of Environmental Health Science and Research Triangle Institute, Lab Project Number: RB90

- BORA. Unpublished report.

43340101 Price, C.J., Marr, M.C. and Myers, C.B. (1994) Determination of NOAEL for

Developmental Toxicity in Sprague Dawley Rats Exposed to Boric Acid in Feed on Gestation Days 0

- 20 and Evaluation of Post Natal Recovery Through Post Natal Day 21. Reproduction and Developmental Toxicology Labs, RTI, RTP, North Carolina. Study Number 65C5657

- 200, August 8, 1994. Unpublished report.

43500701 Wnorowski, G. (1994) Acute Inhalation Toxicity Limit Test on Boric Acid (in

Rats). Product Safety Labs, East Brunswick, NJ. Study No. 3311, November 28, 1994. Unpublished report.

43553201 Reagan, E. and Becci, P. (1985) Acute Dermal Toxicity Study of 20 Mule Team,

Lot USB

- 11

- 84 Sodium Tetraborate Decahydrate in New Zealand White Rabbits.
Food and Drug Research Laboratories, Inc., Waverly, NY. Study Report No. FDRL 8403A, February 20, 1985. Unpublished report.

43553202 Reagan, E. and Becci, P. (1985) Primary Eye Irritation Study of 20 Mule Team,

Lot USB

- 11

- 84 Sodium Tetraborate Decahydrate i n New Zealand White Rabbits.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 55 of 99 Food and Drug Research Laboratories, Inc., Waverly, NY. Study Report No. FDRL 8403A, February 8, 1985. Unpublished report.

43354202 Reagan, E. and Becci, P. (1985) Primary Dermal Irritation Study of 20 Mule

Team, Lot USB

- 11

- 84 Sodium Tetraborate Decahydrate in New Zealand White Rabbits. Food and Drug Research Laboratories, Inc., Waverly, NY. Study Report No. FDRL 8403A, January 23, 1985. Unpublished report.

44383601 Wnorowski, G. (1994) Acute Inhalation Toxicity Limit Te st on Boric Acid (in

Rats). Product Safety Labs, East Brunswick, NJ. Study No. 5257, July 11, 1997. Unpublished report.

46852201 Draize, J.H. and Kelley, E.A. (1959) The Urinary Excretion of Boric Acid

Preparations following Oral Administration and Topical Appli cations to Intact and Damaged Skin of Rabbits. Toxicol and Applied Pharmacol 1:267

- 276.

48507005 Hui, X., Wester, R., and Maibach, H. (1995). In vivo percutaneous absorption

of boric acid, borax, and disodium octaborate tetrahydrate (DOT) in human skin. Dept. of Dermatology, Surge Laboratory, University of California, San Francisco, CA 93143. Study Number H832

- 11830

- 01. December 17, 1995.
MRID 485 07005. Unpublished report.

48549901 Hartway, T.; Wester, R., Maibach, H. (1996) In v itro percutaneous absorption

of boric acid, Borax, and disodium octaborate tetrahydrate (DOT) in human skin. Department of Dermatology Surge Laboratory, University of Cali fornia; Study Number 95SU02, November 11, 1996. Unpublished report.

48773701 Johnson, W. (2012) Single

- dose oral (gavage) neurotoxicity limit test of boric

acid in Sprague

- Dawley rats. IIT Research Institute (IITRI), Chicago, IL. IITRI Project No. 2328

- 0 01, March 7, 2012. Unpublished report.

48786601 Curry P. (2012) Evaluation of the Potential Immunogenic Activity of Boric Acid

Using the Sheep Red Cell Plaque Forming Assay in Mice. Project number: 2328/002. IIT Research Institute, Chicago, IL. Unpublishe d report.

48798001 Curry P. (2012) Evaluation of the Potential Immunogenic Activity of Boric Acid

Using the Sheep Red Cell Plaque Forming Assay in Mice. Project number: 2337/001. IIT Research Institute, Chicago, IL. Unpubl ished report.

49735901 Residue De termination of Prev

- AM When Applied on Baby Marrows in the

Western Cape. Trial Code: 2010

- 101R. Field trial summary report submitted by Screeners Development CC. June 25, 2010.

49735902 Residue Determination of Prev

- AM When Applied on Spinach in the We stern

Cape. Trial Code: 2010

- 103R. Field trial summary report submitted by Screeners Development CC. June 25, 2010Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 56 of 99 49735903 Residue Determination of Prev

- AM When Applied on Potatoes in the Western

Cape. Trial Code: 2010

- 105R. Field trial summary rep ort submitted by Screeners Development CC. June 25, 2010

.

49735904 Analyses Report for Lettuce Field Trial Code 2010

- 104R (MRID 49735909).

BemLab Report No. NR6125/2010. June 10, 2010.

49735907 Analyses Report for Potato Field Trial Code 2010

- 105R (MRI D 49735903).

BemLab Report No. V R 116 /201 1 . J anuary 1 , 201 1

. .

49735908 Residue Determination of Prev

- AM When Applied on Tomatoes in the Western

Cape. Trial Code: 2010

- 102R. Field trial summary report submitted by Screeners Development CC. June 25, 201 0

.

49735909 Residue Determination of Prev

- AM When Applied on Lettuce in the Western

Cape. Trial Code: 2010

- 104R. Field trial summary report submitted by Screeners Development CC. June 25, 2010

.

49735911 Analyses Report for Spinach Field Trial Code 2010

- 103R (MRID 49735902).

BemLab Report No. NR4659/2010. May 19, 2010

.

49735914 Analyses Report for Baby Marrow Field Trial Code 2010

- 101R (MRID

49735901). BemLab Report No. NR4355/2010. May 10, 2010

.

49735915 Analyses Report for Tomato Field Trial Code 2010

- 102R (MRID 49735908).

BemLab Report No. NR4663/2010. May 17, 2010

13.3 Published Literature and Other Documents

Agency for Toxic Substances and Disease Registry (ATSDR) (1992) Toxicological Profile for Boron and Compounds. U.S. Public Health Service.

Anderson, D.L., Cunningham, W.C. and Lindstrom, T.R. (1994) Concentrations and Intakes of H, B, S, K, Na, Cl and NaCl in Foods. J. of Food Comp. and Anal . 7:59

- 82.

Chapin, R.E. and Ku, W.W. (1994) The Re productive Toxicity of Boric Acid. Environ. Health Perspect. 102(Suppl. 7):87

- 91.

Chapin, R.E. et al. (1997) The effects of dietary boron on bone strength in rats. Fund. Appl.
Toxicol. 35:205

- 215.

Culver, B.D. et al. (1994) The relationship of blood

- a nd urine

- boron to boron exposure in
borax

- workers and the usefulness of urine

- boron as an exposure marker. Environ. Health Perspect. 102 (Suppl. 7):133

- 137.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 57 of 99 Draize, J.H. and Kelley, E.A. (1959) The Urinary Excretion of Boric Acid Preparations following O ral Administration and Topical Applications to Intact and Damaged Skin of Rabbits. Toxicol. Appl. Pharmacol. 1: 267

- 276.

European Commission, Directorate

- General for Health and Consumers, Scientific Committee on Consumer Safety (2010) Opinion on Boron Co mpounds. SCCS/1249/09, Revision of 28 September 2010.

ECETOX European Centre for Ecotoxicology and Toxicology of Chemicals. (1995) Technical Report No. 63.

Fail, P.A., Chapin, R.E., Price, C.J. et al. (1998) General, Reproductive, Developmental and
Endo crine Toxicity of Boronated Compounds. Reprod. Toxicol 12:1

- 18.

Hunt, C.H., (1994) The Biochemical Effects of Physiologic Amounts of Dietary Boron in
Animal Nutrition Models. Environmental Health Perspectives 102, Supplement 7, Nov 1994.

Kissel, JC. (2 011) The mismeasure of dermal absorption. J Expo Sci Environ Epid. 21(3): 302

- 309.

Ku, W.W. et al. (1991) Tissue Disposition of Boron in Male Fischer Rats. Toxicol. Appl.
Pharmacol 111:145

- 151.

Ku, W.W. et al. (1993) Testicular Toxicity of Boric Acid (B A): Relationship of Dose to Lesion Development and Recovery in the F344 Rat. Reprod. Toxicol. 7:305

- 319.

Ku, W.W. and Chapin. R.E. (1994) Mechanism of the Testicular Toxicity of Boric Acid in Rats.
In Vivo and In Vitro Studies. Environ. Health Perspect

. 102(Suppl. 7):99

- 105.

Litovitz, T.L. et al. (1988) Clinical manifestations of toxicity in a series of 784 boric acid ingestions. Am. J. Emerg. Med. 6:209

- 213.

Moore, J.A. (1997) An Assessment of Boric Acid and Borax Using the IEHR Evaluative Process
f or Assessing Human Developmental and Reproductive Toxicity of Agents. Expert Scientific
Committee. Reprod. Toxicol. 11(1):123

- 160.

Naghii, M.R. and Samman, S. (1996) The boron content of Selected Foods and the Estimation of its Daily Intake Among Free

- L iving Subjects. J. Am. College Nutr. 15(6):614

- 619.

National Academy of Sciences Dietary (2001) Reference Intakes

- Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon,
Vanadium and Zinc. 2001. Foo d and Nutrition Board, Institute of Medicine, p. 773.

National Institute for Occupational Safety and Health (NIOSH). (2001) International Chemical Safety Cards (ICSC): Boric Acid

-- 0991; Sodium tetraborate decahydrate

-- 0567; Sodium
tetraborate

-- 1229. http://www.cdc.gov/niosh/npg/npg.htmlBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 58 of 99 Nielsen, F.H. (1991) Nutritional Requirements for Boron, Silicon, Vanadium, Nickel and Arsenic: Current Knowledge and Speculation. FASEB J. 5:2661

- 2667.

Nielsen, G.H. (1970) Percutaneous Absorption of Boric Acid from Boron

- Containing Preparations in Rats. Acta Pharmacol. et Toxicol. 28:413

- 424

.

Rainey, C.J., Nyquist, L.A., and Strong, R.E. et al. (1999) Daily Boron Intake from the
American Diet. J. Am. Diet Assoc. 99(3):335

- 340.

Rainey , et al, ( 2002 ) Dietary Boron Intake in the United States: CSFII 1994

- 1996. J. Food Comp and Anal. 15, 237

- 250.

U.S. EPA (1993) Reregistration Eligibility Decision Decision (RED): Boric Acid and its Sodium Salts. Office of Prevention, Pesticides, and Toxic Substances (7508W). EPA 738

- R

- 93

- 017.

U.S. EPA (2008) . Regulatory Determinations Support Document for Selected Contaminants from the Second Drinking Water Contaminant Candidate List (CCL 2). Office of Water. EPA
815

- R

- 08

- 012. June 2008.

Vanderpool, R.A., Hof, D. and Johnson, P.E. (1994) Use of inductively coupled plasma

- mass spectrometry in boron

- 10 stable isotope experiments with plants, rats, and humans. Environ Health Perspect. 102 (suppl. 7):13

- 20.

Wilding, J.L. et al. (1959) The Toxicity of Boron Oxide. American Industrial Hygiene
Association J. 20(4):284

- 289.

World Health Organization (WHO). (1998) Environmental Health Criteria 204: Boron.
International P rogramme on Chemical Safety (IPCS). Geneva, Switzerland. ISBN 92 4 157204

World Health Organization (WHO) (2003) WHO Guidelines for drinking

- water quality.
WHO/SDE/WSH/03.04/54.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 59 of 99 A ppendix A : Toxici t y Profile and Ex e cutive Summaries

A.1 Toxicology Data Requirements

R equirements (40 CFR 158.340) for food use for boric acid/borate salts are in Table A. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1 Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ........................ 870.1200 Acute Dermal Toxicity

................................ ................... 870.1300 Acute Inhalation Toxicity

................................ ............... 870.2400 Primary Eye Irritation

................................ ..................... 870.2500 Primary Dermal Irritation

................................ ............... 870.2600 Dermal Sensitization

................................ ....................... yes
yes
yes
yes
yes

no yes

yes
yes
yes
yes

--

870.3100 Oral Subchronic (rodent)

................................ ................ 870.3150 Oral Subchronic (nonrodent)

................................ .......... 870.3200 21/28

- Day Dermal

................................ .......................... 870.3250 90

- Day Dermal

................................ ............................... 870.3465 28 or 90

- Day Inhalation

................................ .................. yes
yes

no 1

no

no 2 yes

yes

--

--

--

870.3700a Developmental Toxicity (rodent)

................................ .... 870.3700b Developmental Toxicity (nonrodent)

.............................. 870.3800 Reproduction

................................ ................................ .. yes
yes
yes yes

yes
yes

870.4100a Chronic Toxicity (rodent)

................................ ............... 870.4100b Chronic Toxicity (nonrodent)

................................ ......... 870.4200a Oncogenicity (rat)

................................ ........................... 870.4200b Oncogenicity (mouse)

................................ ..................... 870.4300 Chronic/Oncogenicity

................................ ..................... yes
yes
yes
yes
yes yes

yes
yes
yes
yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

...................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................. 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.... 870.5395 Mutagenicity

— Mammalian Erythrocyte Micronucleus

. 870.5550 Mutagenicity

— Unscheduled DNA Synthesis

................ 870.5915 Mutagenicity

— In Vivo Sister Chromatid Exchange yes
yes
yes
yes
yes

no yes

yes
yes
yes
yes

--

870.6100a Acute Delayed Neurotox icity . (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ............ 870.6200a Acute Neurotoxicity Screening Battery (rat)

.................. 870.6200b 90 Day Neurotoxicity Screening Battery (rat)

................ 870.6300 Develop. Neuro toxicity

................................ ................... no

no
yes

no 3

no --

-- yes

--

--

870.7485 General Metabolism

................................ ....................... 870.7600 Dermal Penetration

................................ ......................... no 5

yes --

yes

870.7800 Immunotoxicity................................................Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 60 of 99 Table A.1 Test Technical

Required Satisfied

yes yes

1 Dermal absorption data and published reports were used to assess dermal toxicity potential.
2 Subchronic inhalation data requirement waived by HED HASPOC (K. Rury, February 15, 2015, TXR No. 0056768)
3 90

- day neurotoxicity screening battery requirement waived by the HED HASPOC (see above citation). Requirement fulfilled by published reports

A.2 Toxicity Profiles

Table A.2.a Acute Toxicity Profile

- Boric Acid

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral rat 00006719 LD 50 males = 3450 mg/kg females = 4080 mg/kg III

870.1100 Acute oral beagle dog 00064208 LD 50 > 631 mg/kg III

870.1200 Acute dermal rabbit 00106011 LD 50 >2 g/kg III

870.1300 Acute inhalation rat 43500701 LC 50 >2.03 mg/L (no deaths) 1 III

870.2400 Acute eye irritation rabbit 00064209 Conjunctival irritation clearing by Day 4 III

870.2500 Acute dermal irritation rabbit 00106011 Primary irritation score = 0.1; 1/6 erythema at 72

hrs III

1 exposure levels were limited by inability to produce higher test atmosphere concentrations

Table A.2.b Acute Toxicity Profile

- Sodium tetraborate decahydrate (Borax)

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral rat 40692303 LD 50 males = 4550 mg/kg females = 4980 mg/kg III

870.1100 Acute oral dog 40692304 LD 50 > 974 mg/kg III

870.1200 Acute dermal rabbit 43553201 LD 50 > 2000 mg/kg III

870.1300 Acute inhalation rat 43500801 LC 50 >2.03 mg/L (no deaths) III

870.2400 Acute eye irritation rabbit 43553203 Corrosive I

870.2500 Acute dermal irritation rabbit 43553202 Non

- irritating IVBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 61 of 99 Table A.2.c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results (Note: all dose levels for NOAELs and

LOAELS in this table are expressed as mg/kg bw/day

of boron equivalents)

870.3100

90

- Day oral toxicity (rat) 00068025 (1962) Acceptable/nonguideline together

with 00068883 0, 0.03, 0.1, 0.3, 1.0 or 3.0%
boric acid in diet for 90 days. Equivalent to 0, 3.9, 13, 38, 124 or 500 mg/kg bw/day boron NOAEL = 38 mg/kg bw/day LOAEL = 124 mg/kg bw/day, based on clinical signs of toxicity, decreased body weight, testicular atrophy/reduced testicular weights, reduc ed ovarian weights.

870.3100
90

- Day oral toxicity (rat) 40692305 (1963) Acceptable/nonguideline together
with 40692306 0, 0.0463, 0.154, 0.463, 1.54 or
4.63% sodium tetraborate decahydrate in diet for 90 days. Equivalent to 0, 4.0, 14, 42, 125 or 455 mg/kg bw/day boron NOAEL = 42 mg/kg bw/day LOAEL = 125 mg/kg bw/day based on clinical signs of toxicity, decr. weight gain and food consumption, decr. testes and ovarian weights, testicular a trophy.

870.3100

90

- Day oral toxicity (rat, male rat only) 40692306 (1963) Acceptable/nonguideline together

w/40692305

- 0, 0.015, 0.0463, 0.154 or
0.463% sodium tetraborate decahydrate in diet for 90 days. Equivalent to 0, 1.3, 4.3, 13.1 or 41 mg/g/day boron NOAEL = 41mg/kg bw/day (males only tested) LOAEL >41 mg/kg bw/day (HDT).

870.3150

90

- Day oral toxicity (dog) 00064204 (1963) Acceptable/nonguideline together
with 40692308 and 00005622 0, 0.01, 0.1 or 1.0% boric acid in diet for 90 days. Equivalent to 0, 0.46, 4.2 or 35 mg/kg bw/day

boron NOAEL = 4.2 mg/kg bw/day LOAEL = 35 mg/kg bw/day, based on testicular atrophy

870.3150

90

- Day oral toxicity (dog) 40692307 (1963) Acceptable/nonguideline 0, 0.0154, 0.154, 1.54% sodium tetraborate decahydrate in diet for 90 days. Equivalent to 0, 0.34/0.25, 4.1/2.6 or 32/23 [M/F] mg/kg bw/day boron NOAEL = 4.1mg/kg bw/day M/2.6 mg/kg bw/day F LOAEL = 32 mg/kg bw/day M/23 mg/kg bw/day F, based on decr. HCT/Hgb, testicular atrophy, decr. testes weight and incr. hemosiderin pigment in spleen, liver, kidneys.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 62 of 99 Table A.2.c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results (Note: all dose levels for NOAELs and

LOAELS in this table are expressed as mg/kg bw/day

of boron equivalents)

870.3700a Prenatal developmental (rat) 41725401 (1990) Acceptable/guideline when

consid ered together with MRID

43340101 0, 0.1, 0.2, 0.4% GD 0

- 20 and
0.8% GD 6

- 15 boric acid in diet. equivalent to 0, 14, 29 or 58 mg/kg bw/day boron and 94 mg/kg bw/day boron Maternal NOAEL = 94 mg/kg bw/day Developmental NOAEL <14 mg/kg bw/day LOAEL = 14 mg/kg bw/day based on slightly decr. fetal body weight. At 29 mg/kg bw/day, skeletal abnormalities observed and at 58 and 94 mg/kg bw/day, high incidence skeletal and visceral abnormalities, and mortality

870.3700a Prenatal developmental (rat ) 43340101 (1994) Acceptable/guideline 0, 0.025%, 0.050%, 0.075%,
0.10% or 0.20% boric acid

. Equivalent to 0, 3.3, 6.3, 9.6, 13.3 or 25 mg/kg bw/day boron Maternal NOAEL = 25 mg/kg bw/day (HDT) LOAEL = not determined (slightly decreased gravid

uterine weight considered secondary to fetal toxicity) Developmental NOAEL = 9.6 mg/kg bw/day LOAEL = 13.3 mg/kg bw/day based on slightly decr. fetal body weight, rib XIII abnormalities

870.3700a Prenatal developmental (mouse) 41725402 (1990) Acceptable/guideline 0, 0.1, 0.2, 0.4%
boric acid in diet equivalent to 0, 43, 79 or 176 mg/kg bw/day

boron Maternal NOAEL not established <43 mg/kg bw/day LOAEL = 43 mg/kg bw/day based on renal tubular dilatation/regeneration. Developmental NOAEL = 43 m g/kg bw/day LOAEL = 79 mg/kg bw/day based on decr. fetal wt, incr. resorptions, incr. malformations (short rib XIII, fused rib).

870.3700b Prenatal developmental (rabbit) 42164201, 42164202 (1991) Acceptable/guideline 0, 62.5, 125 or 250 mg/kg bw/day
boric acid by gavage. Equivalent to 0, 11, 22 or 44 mg/kg bw/day boron Materna l NOAEL = 22 mg/kg bw/day LOAEL = 44 mg/kg bw/day based on incr. intrauterine bleeding, decreased unadjusted weight gain during treatment (due to decr. gravid uterine weight). Developmenta l NOAEL = 22 mg/kg bw/day LOAEL = 44 mg/kg bw/day based on incr. mortality (resorptions, postimplantation loss), decr. fetal weight, intraventricular septal defect, enlarged aorta.

870.3800 Reproduction and fertility effects (rat) 00068882 ( 1966) Acceptable/nonguideline 0, 0.067, 0.20 or 0.67% boric
acid in the diet. Equivalent to 0, 8.5/9.7, 27/29 or 85/92 mg/kg bw/day [M/F] boron Parental/Systemic NOAEL = 27 mg/kg bw/day LOAEL = 85 mg/kg bw/day based on clinical signs, decr

. body weight, testicular atrophy, decr. testes weight, decr. corpora lutea. Reproductive NOAEL = 27 mg/kg bw/day LOAEL = 85 mg/kg bw/day based on decr. fertility (no litters). Offspring NOAEL = 27 mg/kg bw/day LOAEL = 85 mg/kg bw/day based on no litters p roduced.

870.3800 40692311 (1966) Acceptable/nonguideline Parental/Systemic NOAEL = 28 mg/kg bw/dayBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 63 of 99 Table A.2.c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results (Note: all dose levels for NOAELs and

LOAELS in this table are expressed as mg/kg bw/day

of boron equivalents)

Reproduction and fertility effects (rat) 0, 0.103, 0.308 or 1.03% sodium tetraborate decahydrate in the diet. Equivalent to 0, 8.1/9.2,

2 8 / 31 or 82/92 [M/F] mg/kg bw/day boron LOAEL = 82 mg/kg bw/day based on clinical signs, decr. body weight, testicular atrophy, decr. testes weight, decr. corpora lutea. Reproductive NOAEL = 28 mg/kg bw/day LOAEL = 82 mg/kg bw/day based on decr. fertilit y (no litters). Offspring NOAEL = 28 mg/kg bw/day LOAEL = 82 mg/kg bw/day based on no litters produced.

870.3800 Reproduction and fertility effects (mouse) 41589101 (1990) Acceptable/guideline 0, 1000, 4500 or 9000 ppm boric
acid in diet (for P1 matings only 0 and 1000 ppm groups). Equivalent to 0, 27, 111 or 221 mg/kg bw/day boron Parental/Systemic NOAEL = 27 mg/kg bw/day LOAEL = 111 mg/kg bw/day based on decr. testicular weight, atrophy and degeneration of seminiferous tubules. Reproductive NOAEL = 27 mg/kg bw/day LOAEL = 111 mg/kg bw/day based on decr. fertility. Offspring NOAEL = 27 mg/kg bw/day LOAEL = 111 mg/kg bw/day based on decr. pup wt., decreased survival and fewer pups born

870.4100b Chronic toxicity (dog) 00064205 (1967) Acceptable/nonguideline when considered together with
00005622 and 4366910.
0 or 0.67% boric acid decahydrate in diet for 38 weeks. Equivalent to 0 or 40 mg/kg bw/day boron NOAEL not established (≥ 40 mg/kg bw/day) LOAEL = 40 mg/kg bw/da y, based on testicular atrophy,

870.4100b Chronic toxicity (dog) 40692308 (1967) Acceptable/nonguideline when considered together with 40692307,

- 09.
0 or 1.03% sodium tetraborate decahydrate in diet for 38 weeks. Equivalent to 0 or 40 mg/kg bw /day boron NOAEL not established (<40 mg/kg bw/day) LOAEL = 40 mg/kg bw/day based on decr. body wt. gain, testicular atrophy.

870.4100b Chronic toxicity (dog) 00005622 (1966) Acceptable/nonguideline when considered together with

00005624 and 00064203 0, 0.033, 0.067 or 0.20% boric
acid in diet for two years. Equivalent to 0, 1.6, 3.6 or 10.2 mg/kg bw/day boron, males and 0, 1.8, 4.0 or 11.6 mg/kg bw/day boron, females NOAEL = 10.2 mg/kg bw/day LOAEL not established (≥10.2 mg/kg bw/day)Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 64 of 99 Table A.2.c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results (Note: all dose levels for NOAELs and

LOAELS in this table are expressed as mg/kg bw/day

of boron equivalents)

870.4100b Chronic toxicity (dog) 40692310 (1967) Acceptable/nonguideline when considered together with

40692308. 0, 0.051, 0.103 or 0.309%

sodium tetraborate decahydrate in the diet for two years . Equivalent to 0, 1.5, 2.9 or 8.8 mg/kg bw/day boron NOAEL = 8.8 mg/kg bw/day LOAEL not established (>8.8 mg/kg bw/day)

870.4200 Carcinogenicity (rat) 00068883 (1966) Acceptable/nonguideline 0, 0.01, 0.1 or 1.0% boric acid in the diet for two years. Equivalent to 0, 5.2, 16 or 58 mg/kg bw /day boron, males; 0, 6.3, 19 or 70 mg/kg bw/day boron, females NOAEL = 16 mg/kg bw/day LOAEL = 58 mg/kg bw/day, based on clinical signs, decreased body weight, decreased testicular weight, testicular atrophy, increased anovulatory/involuted ovaries, dec reased RBC parameters. no evidence of carcinogenicity

870.4200 Carcinogenicity (rat) 40692309 (1966) Acceptable/nonguideline 0, 0.130, 0.308, 1.030% sodium tetraborate decahydrate in diet for two years. Equivalent to 0, 7.3, 17 or 58 mg/kg bw /day

boron NOAEL = 17 mg/kg bw/day LOAEL = 58 mg/kg bw/day based on decr. body weight (observed by 3

- 4 weeks), testicular atrophy, slightly decreased hematocrit/hemoglobin. no evidence of carcinogenicity

870.4300 Carcinogenicity (mouse) 41861301 (1991) Acceptable/nonguideline 0, 2500 or 5000 ppm boric acid

. Equivalent to 0, 66 or 192 mg/kg bw/day boron in males and 0, 85

or 212 mg/kg bw/day in females.

Note : equivalent average daily

doses of boron represent actual

calculations for males and

females based on food consumption values from the
report . The study report suggested that due to feed spillage, actual compound consumption may be lower, at approximately 48/96 mg/kg bw/day. NOAEL = not established < 66 mg/kg bw/day in males ; 85 mg/kg bw /day in females

LOAEL = 66 mg/kg bw/day in males, based on slightly increased mortality and splenic lymphoid depletion ; 212 mg/kg bw/day in females, based on d ecr. body weights

. I n males a t 192 mg/kg bw/day, decreased body weights, ; testicular atrophy, and interstitial cell atrophy were also

observed.

. no evidence of carcinogenicityBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 65 of 99 Table A.2.c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results (Note: all dose levels for NOAELs and

LOAELS in this table are expressed as mg/kg bw/day

of boron equivalents)

870.5300 Gene Mutation

Mouse in vitro lymphoma forward gene mutation

assay 42038902 (1991) Acceptable/guideline

1200

- 5000 μg/mL boric acid +/

- S9 Negative for induction of mutagenic response in two independently performed mouse L5178Y cell lymphoma forward mutation assays. Marginal cytotoxicity at 3500

- 5000 μg/mL

870.5100 Gene Mutation S. typhimurium reverse gene mutation assay 42038901 (1991) Acceptable/guideline

10

- 2500 μg/plate boric acid Negative for induction of mutagenic response in S. typhimurium strains TA1535, TA1537, TA1538, TA98 or TA100 in the presence or absence of S9 up to 2500 μg/plate. No cytotoxicity was observed.

870.5385 Cytogenetics

Mouse in vivo
micronucleus assay 42038904 (1991) Acceptable/guideline 900, 1800 or 3500 mg/kg boric

acid Negative for induction of clastogenic response to the bone marrow of Swiss mice. No systemic toxicity or target cytotoxicity observed up to 3500 mg/kg.

870.5550 Other Effects

Rat liver in vitro
unscheduled DNA synthesis 42038903 (1991) Acceptable/guideline

5

- 5000 μg/mL boric acid Negative for increased unscheduled DNA synthesis in cultured rat hepatocytes. Slightly increased percent cells in repair at ≥2500 μg/mL in repeat assay were secondary to increased cytotoxicity at those dose levels.

870.6200a Acute oral neurotoxicity screening (rat) 48773701 (2012) Acceptable/guideline 0 or 2000 mg/kg boric acid (limit test) NOAEL = 2000 mg/kg (350 mg/kg bw/day boron equivalents) A LOAEL for neurotoxicity or systemic toxicity was not
determined.

870.7600
In vivo dermal absorption (human) 48507005 (1995) Acceptable/nonguideline 1.8 mL aqueous 5% boric acid,
5% borax or 10% disodium octaborate tetrahydrate (DOT) on
30 cm x 30 cm dorsal skin area for 24 hr exposure, 8 human
volunteers. Exposures and collection repeated on skin exposed to 2% sodium dodecyl sulfate as an
irritant. Ab sorbed dose as measured in urine (7

- day collection post

- exposure)

- /+ SDS skin treatment:
Boric acid

– 0.226/0.239% AD
Borax

– 0.210/0.185% AD
DOT

– 0.122/0.1

- 07% AD

Recoveries = 49 to 64% AD

870.7600
In vitro dermal absorption (human cadaver skin) 485 49901 (1996) Acceptable/nonguideline 0.05, 0.5 and 5.0% boric acid
5% borax and 5% DOT. All tested at 1000 μL/cm 2 and % boric acid also at 2 μL/cm 2 on a total of 6 skin samples Absorbed dose in receptor fluid only (skin samples not tape

- stripped):
Boric acid

– 1.75, 0.70, 0.28 and 1.20% AD at 5% (2 μL/cm 2 ), 5% (1000 μL/cm 2 ), 0.5% and 0.05%, respectively Borax, 5%

– 0.41% AD DOT, 5%

– 0.19% ADBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 66 of 99 Table A.2.c Subchronic, Chronic and Other Toxicity Profiles for Boric Acid and Borate Salts

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results (Note: all dose levels for NOAELs and

LOAELS in this table are expressed as mg/kg bw/day

of boron equivalents)

Recoveries = 72 to 86% AD

870.7800 Immunotoxicity (mouse) 48786601 (2012) 0 or 1000 mg/kg boric acid

, IV injection Acceptable/guideline

48798001 (2012) 0, 250, 500, 750 or 1000 mg/kg bw/day Systemic toxicity NOAEL = 1000 mg/kg bw/day (175 mg/kg bw/day boron equivalents)boron equivalents) Systemic toxicity LOAEL = not determined

Immunotoxicity NOAEL = 250 mg/kg bw/day (43.8 mg/kg bw/day boron equivalents) Immunotoxicity LOAEL = 500 mg/kg bw/day (87.6 mg/kg bw/day boron equivalents) based on decreased
SRBC anti

- AFC response)

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

– All Populations Including Females Age 13

- 49 and
Children

An aRfD was not established for boric acid/borate salts for assessment of dietary risk for all populations. A dietary risk assessment was not conducted because boron i s a naturally occurring element in food and drinking water, and the contribution of residues from food and drinking water due to pesticidal uses is expected to be negligible. Boric acid/borate salts have been granted a tolerance exemption.

However, an aR fD for young children has been established in order to assess risk from accidental ingestion of granular formulations (e.g., for turf applications).

Studies Selected: Rat acute oral LD 50 studies on boric acid and borax
MRID No s : 00005644, 00064207, 406 92303 Dose and Endpoint for Risk Assessment: NOAEL s = 350 mg/kg (all studies), based on clinical signs of toxicity (depression, shallow/rapid respiration, diarrhea, red crusts on eyes) and mortality) at ≥439 mg/kg. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: The rat oral LD 50 studies were selected because no single

- dose effects relevant to this subpopulation (young children) were identified in other studies of the toxicology database. The NOAELs for these effects in the acute
oral LD 50 studies are consistent with the acute ne urotoxicity study, which did not identify toxicity up to 350 mg/kg boron equivalents (limit dose of the ai, HDT). A UF A and UF H of 10x (total UF 100x) were selected.

A.3.2 Chronic Reference Dose (cRfD)

– All Populations Including Females Age 13

- 49 and
Children

A cRfD was not established because a dietary risk assessment is not required (see aRfD, above).Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 67 of 99 A.3.3 Incidental Oral Exposure (Short

- Term, 1

- 30 days and Intermediate

- Term, 1

- 6 month)

Studies Selected: Dog 90

- day and 2

- year dietary studies on borax
MRID No s : 40692307 and 40692310 Dose and Endpoint for Risk Assessment: NOAEL= 8.8 mg/kg bw /day (dog 2

- year dietary study and HDT), based on hematological effects and testicular atrophy in the dog 90

- day study at 32 mg/kg bw/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability) Comments about Study/Endpoint/ Uncertainty Factors: An incidental oral endpoint is required for assessment of short

- term hand

- to

- mouth incidental exposure to young children, but also for assessment of ingestion of swimming pool water by recreational (short

- term exposure) and competiti ve (intermediate

- term exposure) swimmers. The selected studies are of the appropriate route and duration. The NOAEL from the chronic dog study was selected, rather than the lower NOAEL of 4.1 mg/kg bw/day from the 90

- day study, because a higher NOAEL

was identified for the longer exposure duration as a result of dose spacing. The dose and endpoints are further supported by subchronic and chronic dietary studies conducted on boric acid, which identified testicular toxicity at essentially the same NOAEL an d LOAEL. Although the studies are old and had limitations that complicated interpretation of the data (e.g., small numbers of animals at each time point, lack of reporting of experimental details, etc.), the selected dose is protective of effects in other studies, including developmental toxicity observed in the rat at the LOAEL of 13.3 mg/kg bw/day (NOAEL = 9.6 mg/kg bw/day) and at higher doses in the rabbit and mouse, and of testicular toxicity and other effects observed in the rat and mouse, observed in various studies at ≥43 mg/kg bw/day. The selected endpoints are protective of all exposed populations, including young children and females age 13 to 49. A UF A and UF H of 10x (total UF 100x) were selected.

A.3.4 Dermal Absorption

As summarized in Section 4.3.2, the available data in humans and animals indicate that boric acid/borate salts are very poorly absorbed across intact skin. In vivo dermal absorption data in humans indicates that absorption is likely to be < 1% across intact skin. Published studies in the rat and rabbit also support negligible absorption.

A.3.5 Residential and Occupational Dermal Exposure (Short

- and Intermediate

- Term; 1

- 30 days and 1

- 6 months)

A dermal exposure assessment was not performed. Although dermal exposure is anticipated for many use patterns during application and post

- application, studies in humans and laboratory animals indicate that the absorption of boric acid and its sodium bora te salts across intact skin is negligible. Estimation of a dermal NOAEL using the most sensitive available oral NOAELs (8.8

- 9.6 mg/kg bw/day) and using a conservative DAF of 1% would yield doses near the limit dose of 1000 mg/kg bw/day.

A.3.6 Residential and Occupational Inhalation Exposure

Studies Selected: Dog 90

- day and 2

- year dietary studies on boraxBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 68 of 99 MRID No s : 40692307 and 40692310 Dose and Endpoint for Risk Assessment: NOAEL= 8.8 mg/kg bw/day (dog 2

- year dietary study and HDT), based on testicula r atrophy in the dog 90

- day study at 32 mg/kg bw/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: Oral data were selected for this exposure scenario. A subchro nic inhalation toxicity study was not available because the requirement was waived. The NOAEL from the chronic dog study was selected, rather than the lower NOAEL of 4.1 mg/kg bw/day from the 90

- day study, because a higher NOAEL was
identified for the lon ger exposure duration as a result of dose spacing. The dose and endpoint are further supported by subchronic and chronic dietary studies conducted on boric acid, which identified testicular toxicity at essentially the same NOAEL and LOAEL. Although the s tudies are old and had limitations that complicated interpretation of the data (e.g., small numbers of animals at each time point, lack of reporting of experimental details, etc.), the selected dose is protective of effects in other studies, including deve lopmental toxicity observed in the rat at the LOAEL of 13.3 mg/kg bw/day (NOAEL = 9.6 mg/kg bw/day) and at higher doses in the rabbit and mouse, and of testicular toxicity and other effects observed in the rat and mouse, observed in various studies at ≥43 mg/kg bw/day. Absorption via the inhalation route is assumed to be
100%. The UF A and UF H of 10x (total UF 100x) were selected.

Although a subchronic inhalation study was not conducted, a published inhalation study in the rat and dog on boron oxide (Wild ing et al. , 1959), submitted in support of the waiver request, provided some information on inhalation exposure up to 22 weeks and was considered in determining the inhalation exposure dose and endpoint. No adverse effects, including histopathological fin dings, were identified in the rat up to exposure concentrations of 0.470 mg/L (dogs were tested at a lower concentration and showed no effects on body weight or clinical chemistry/hematology parameters; histopathology was not examined). Rats showed eviden ce of mild respiratory sensory irritation at this dose, based on nasal discharge, which was not considered adverse. In order to compare the selected oral dose to the inhalation study, the highest exposure concentration was assumed to be a NOAEL in the abs ence of a LOAEL. Human equivalent doses (HEDs) were estimated from this study (HASPOC memo, TXR No.
0056768 ):

Estimated Occupational and Non

- occupational Human Equivalent Concentrations (HEC) and Doses (HED), expressed in Boron Equivalents, for Rats Exposed to Boron Oxide via Inhalation (Wilding study) Exposure group, mg/L boron oxide
Males Females
0.077 0.175 0.470 0.077 0.175 0.470 Occupational (adjusted for boron equivalents) HEC, systemic (mg/L) 0.056 0.129 0.344 0.060 0.134 0.359 HEC, POE (mg/L) 0.003 0.0071 0.0184 0.00145 0.00322 0.010 HED, systemic (mg/kg/day) 11.10 25.57 68.19 11.89 26.56 71.17

HED, POE (mg/kg/day) 0.59 1.41 3.65 0.29 0.64 1.98
Non

- occupational (adjusted for boron equivalents) HEC, systemic (mg/L) 0.0134 0.0306 0.0820 0.0142 0.032 0.086 HEC, POE (mg/L) 0.00071 0.0017 0.00438 0.000346 0.000768 0.00245 HED, systemic (mg/kg/day) 4.55 10.4 27.87 4.83 10.87 29.22

HED, POE (mg/kg/day) 0.24 0.58 1.49 0.12 0.26 0.83Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 69 of 99 For occupational HED calculations, HED = HEC (mg/L) x 11.8 (conversion factor, L/hr

- kg BW) x 1 x 2.1 (assigned activity factor, handheld spray a pplication) x 8 hr/day exposure. F or non

- occupational HED calculations, HED = HEC (mg/L) x 11.8 (conversion factor, L/hr

- kg BW) x 1. 2 (assigned activity factor, residential handler) x 24 hr/day exposure . Shaded values highlight the HEDs for highest exposure level tested in this study.

Estimated portal of entry (POE) HEDs at the highest dose tested were calculated at 3.65 and 1.49 mg/kg/day for occupational and non

- occupational exposure (males), respectively. Although the doses are lower than the oral NOAEL, the total UF is also lower (30 vs. 100 for oral exposure) and therefore after inclusion of the UFs for assessing risk, the inhal ation and oral doses are comparable. The oral studies were therefore used to select an endpoint because a LOAEL was identified and the NOAEL is protective of potential POE effects.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

– Rat

(1) Borax

In a subchronic oral toxicity study (MRID 40692305), sodium tetraborate decahydrate (borax technical, about 105% of theoretical purity) was administered to 10 Charles River Sprague Dawley rats/sex/dose in the diet at dose levels of 0, 0.0463%, 0.154%, 0.46 3%, 1.54% or 4.63% (equivalent to an average daily intake of 0, 34, 113, 339, 1057 or 4610 mg/kg bw/day test material; 0, 4.0, 14, 42, 125 or 544 mg/kg bw/day boron equivalents) for 13 weeks.

At 0.0463%, complete testicular atrophy in 4/10 males was reported, with these animals also showing reduced testicular weights. However, since a dose

- response was not observed at 0.154% (0/10) or 0.463% (1/10), this was not considered a treatment

- related finding (further supported by lack of testicular effects at similar dose levels in another rat subchronic study, MRID 40692306, and a chronic rat study, MRID 40692309). The incidence of testicular atrophy at the low dose, together with a reduction in body weight gain in the early weeks of the study, but not after week 4 of the study, could be due to an error in dosage or animal group mixup at the study start, but the reason is unknown. At 0.463%, one male showed spermatogenic arrest. At 1.54%, clinical s igns of toxicity, beginning during the first week of treatment and continuing throughout treatment (including rapid respiration, hunched posture, thinness, swollen paws, inflamed eyes, coarse fur/desquamation; during the later weeks, protruding penis and s hrunken scrotum in males and an unsteady gait in 3 females were observed; incidence for most signs not given in report), decreased body weight/weight gain (beginning in the first weeks of the study) in males (

- 53%/

- 67% at termination below controls) and fe males (

- 19%/

- 32% below controls at termination), decreased weekly food consumption (on a g/animal/day basis reduced about 40

- 50% below controls) and complete testicular atrophy in 10/10 males were observed. Testicular and ovary weights were significantly reduced (

- 77% and

- 42%, respectively); relative weights were also reduced (by

- 54% and

- 32%, respectively). At 4.63%, all animals on study died
between weeks 1

- 5 and were in poor condition within the first week, including rapid respiration, swollen paws, coarse fur, hunched position and unsure gait, bloody nasal discharge, inflamed eyes and emaciation. Histopathological examination was not performed on the high doseBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 70 of 99 animals due to autolysis. The LOAEL is 1.54% (1057 mg/kg/day test material; 125 mg/kg/da y boron equivalents), based on decreased body weight, clinical signs and testicular atrophy. The NOAEL is 0.463% (339 mg/kg/day test material; 42 mg/kg/day boron equivalents).

This 90

- day oral toxicity study in the rat is classified as acceptable/non

- gui deline . Although the study was not conducted according to standard Agency guidelines (lacking clinical chemistry and hematology data, and microscopic evaluation of some tissues), when taken together with a
second 90

- day study in the rat (MRID 40692306) and a two

- year rat study (MRID 40692309), are considered adequate for regulatory purposes and satisfy the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in the rat. A new study is not required at
this time.

(2) Borax

In a subchronic oral toxicity study (MRID 40692306), sodium tetraborate decahydrate (borax technical, analyzed at about 105% of theoretical) was administered to 10 male Charles River Sprague Dawley rats/dose in the diet at dose levels of 0, 0.0154%, 0.0463%, 0. 154% or 0.463% (equivalent to 0, 11.7, 35.5, 115 or 362 mg/kg/day test material; 0, 1.3, 4.3, 13.1 or 41 mg/kg/day boron equivalents) for 13 weeks. Clinical chemistries (blood, urine), hematology and ophthalmologic evaluations were not performed.

There w ere no treatment

- related effects observed on clinical signs, mortality, body weight/weight gain, food consumption, organ weights or gross/microscopic pathology at any
dose tested. The NOAEL for systemic toxicity in male rats is 0.463% (41 mg/kg/day
elemen tal boron). A LOAEL was not determined in this study.

This 90

- day oral toxicity study in the rat is classified as acceptable/nonguideline . The study was conducted using only males and numerous parameters were not examined. It does not on its
own satis fy the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in the rat. However, it provides useful information to supplement a second 90

- day rat subchronic study on borax (MRID 40692306) and support selection of a subchronic NOAEL in the rat (42 mg/kg/day boron equivalents) and may be used for regulatory purposes.

(1) Boric acid

In a subchronic oral toxicity study (MRID 00068025), boric acid (technical grade, 98.97% a.i .) was administered to 10 Charles River Sprague

- Dawley rats/sex/dose at dietary concentrations of 0, 0.03, 0.1, 0.3, 1.0 or 3.0% (equivalent to average daily intakes of 0, 3.9, 12.8, 38.0, 123.6 or 500 mg/kg/day boron equivalents).

At 0.3%, one male showed complete atrophy of about 1/3 of the tubules (not used to determine LOAEL based on single finding). At 1.0%, clinical signs of toxicity indicating poor cond ition, beginning at week 3 and continuing through treatment (hunched posture, labored breathing, piloerection, desquamation, inflamed eyes, swollen paws), significantly reduced mean body weight (at termination,

- 42% less than controls for males and 15% bel ow controls for females),Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 71 of 99 reduced testicular size in all males, markedly reduced mean abs/rel testicular weights (

- 76%/

- 56% less than controls), complete atrophy of the testes with increased epithelial cells (all males), reduced mean abs/rel ovarian weight s (

- 27%/

- 20%) with no microscopic correlates. Males showed a slight increase in lipid content and cell size of the adrenal zona reticularis but this finding was not considered adverse. At 3.0%, excessive toxicity was observed in all animals (hunched posi tion, desquamation of skin on tail and paws, rapid/labored breathing, shrunken testes, unsure gait, weight loss) and all animals died (males by 3 weeks, females by 6 weeks). At necropsy, blood in the lungs, congestion of kidneys, livers and adrenals were seen. The LOAEL is 1.0% (123.6 mg/kg/day boron equivalents), based on clinical signs of toxicity and decreased body weight in both sexes, and testicular atrophy and decreased testicular weight. The NOAEL is 0.3% (38 mg/kg/day boron equivalents).

This 90

- day oral toxicity study in the rat is classified as acceptable (nonguideline) . Although the study was not conducted according to standard Agency guidelines (lacking clinical chemistry and hematology data), the data, when taken together with a two

- year rat study (MRID 00068883), are considered adequate for regulatory purposes and satisfy the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in the rat. A new study is not required at this time.

870.3150 90

- Day Oral Toxicity

- Dog

1. Borax

In a subchronic oral toxicity study (MRID 40692307), sodium tetraborate decahydrate (technical borax, analyzed at 105% of theoretical value) was administered for 13 weeks to 5 beagle dogs/sex/dose in the diet at dose levels of 0, 0.0154, 0.154 or 1.54% (in males, equivalent to average daily intakes of 0, 2.9, 35 or 268 mg/kg/day test material and 0, 0.34, 4.1 or 32 mg/kg/day boron equivalents; in females, to 0, 2.1, 22 or 192 mg/kg/day test material; 0, 0.25, 2.6 or 23 mg/kg/day boron equivalen ts). Clinical chemistry evaluations were limited to blood urea nitrogen and non

- fasting glucose, and urinalysis.

At 1.54% in males, testicular atrophy (complete in 4 males and partial in one) and significantly reduced testes weight (abs/rel.,

- 44%/

- 45% be low controls), slightly but statistically significantly decreased hematocrit/hemoglobin at 13 weeks in both sexes (

- 15%/

- 11% males and

- 6%/

- 11% females; not reduced at earlier times) and increased hemosiderin pigment in spleen, liver and kidneys was observ ed. Relative thyroid weights in males were significantly lower at the high dose (

- 23%) but no effects were seen in females. An increase in the width of the adrenal cortex in females and a slight increase in epithelial nests of the thyroid in males were re ported; slightly widened adrenal cortex in females and slightly increased proportion of epithelial nests in males were also reported at 0.154% but were of uncertain toxicological significance and were not used to establish a LOAEL for this study. The repo rt also noted that at 0.154%, 5/5 males showed artifactual distortion of tubules in the outer third of the testes. Based on this description, this
observation was not considered an adverse effect of treatment. It was also not observed in the dog 2

- year s tudy at similar or higher dose levels. There were no treatment

- related changes in mortality, clinical signs of toxicity, body weight, food consumption or clinical chemistries (body weight gains were slightly lower at high dose but overall weights showed n o differences). TheBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 72 of 99 LOAEL is 1.54% (in males, 268 mg/kg/day test material and 32 mg/kg/day boron equivalents; in females, 192 mg/kg/day test material and 23 mg/kg/day boron equivalents), based on testicular histopathology and slightly decreased hematocrit /hemoglobin. The NOAEL is 0.154% (in males, 35 mg/kg/day test material and 4.1 mg/kg/day boron equivalents; in females, 22 mg/kg/day test material and 2.6 mg/kg/day boron equivalents).

This 90

- day oral toxicity study in the dog is classified as acceptable/nonguideline and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3150; OECD 409) in the dog when considered together with 38

- week and 2

- year dietary dog studies on borax, and
the 90

- day, 39

- week and 2

- year dog stu dies on boric acid. This study was not conducted according to standard guideline procedures

- several clinical chemistry parameters were not examined and histopathological examination was missing some tissues. However, the study is considered to be acceptab le for regulatory purposes.

2. Boric acid

In a subchronic oral toxicity study (MRID 00064204), boric acid (purity not specified in this report; batch received same date, Oct. 12, 1961, as batch used in chronic dog studies from same laboratory having purity o f 99.94%) was administered in the diet to 5 beagle dogs/sex/dose for 90 days at dietary concentrations of 0, 0.01, 0.1 or 1.0% (equivalent to average daily intakes of 0, 0.46, 4.2 or 35 mg/kg/day boron equivalent).

At 0.1%, males showed artifactual distort ion of the outer third of the testes and lower testes weights (abs /rel. 14.3 g/0.15% vs. 17.2 g/0.20%, controls). Because this was apparently an artifact of fixation, did not appear to have affected spermatogenesis and was not seen in the 2 year dog stud y at comparable doses, it was not used to establish the LOAEL. Similarly, appearance of squamous metaplasia in the thyroids of 2 males was not seen in other studies at
similar boron concentrations and was not considered treatment

- related. Slight changes in the adrenal glands of females (better developed reticularis) were not considered to be adverse. At 1.0%, males showed a significant reduction in mean abs/rel testes weight (10.4 g/0.12% vs. 17.2 g/0.20%, controls) and severe testicular atrophy in all males, with complete degeneration of the spermatogenic epithelium in 4/5 males. Abs/rel liver weights in females were significantly increased (345 g/4.1% vs 235 g/2.5%) but no correlating microscopic findings were reported and
increased width of the adren al zona reticularis and glomerulosa was reported. There were no apparent treatment

- related effects on survival, clinical symptoms, nor clear effects on body weights (one mid and one high dose female showed body weight fluctuations, which appeared to
be se condary to poor acceptance of the test diet), hematology, clinical chemistry parameters or gross pathology. The LOAEL is 1.0% boric acid (35 mg/day boron equivalents), based on testicular atrophy. The NOAEL is 0.1% boric acid (4.2 mg/kg/day boron equival ents).

This study is classified as acceptable (nonguideline ) and satisfies the guideline requirement for
a 90

- day oral toxicity study in the dog (OPPTS 870.3150; OECD 409) when considered together with 38

- week and 2

- year dietary dog studies on boric acid

. It was not conducted according to current standard study guideline procedures

- several clinical chemistry parameters were not examined and histopathological examination was missing some tissues. Furthermore,Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 73 of 99 artifactual effects in mid dose male testes com plicated interpretation of the data. However, it is considered to be acceptable for regulatory purposes in consideration with the chronic studies.

870.3200 21/28

- Day Dermal Toxicity

– Rat

Study not available

870.3465 90

- Day Inhalation

– Rat

Study not available

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

- Rat

(1) Boric acid

In a n oral dev elopmental toxicity study (MRID 43340101 ) , boric acid (technical, 99% a.i., lot no. 872703) was administered to 28

- 32 p regnant Sprague

- Dawley rats/dose/phase group in the diet at dose levels of 0, 0.025%, 0.05%, 0.075%, 0.10% or 0.20% (equivalent to average daily intakes of 0, 19, 36, 55, 76 or 143 mg/kg bw/day boric acid and 0, 3.3, 6.3, 9.6, 13.3 or 25 mg/kg bw /day from days 0 through 20 of gestation. The study was conducted in two phases: in Phase I, developmental toxicity was examined in fetuses from dams sacrificed on GD 20. In Phase II, dams were treated at the same dose levels, then allowed to deliver th eir litters. Dams and pups were sacrificed on postnatal day 21 for evaluation of persistence of developmental effects. In addition, liver and kidney weights of dams were recorded.

Maternal toxicity : In both the pre

- and postnatal phases, no maternal toxicity was observed for survival, clinical signs of toxicity, body weight, food consumption, cesarean parameters or gross pathology. At 0.2% boric acid, slightly reduced gravid uterine weight was obs erved (

- 10% below controls, not statistically significant). The decrease was considered secondary to decreases in fetal weights and therefore not indicative of direct maternal toxicity. Right kidney weights were increased about 10% in Phase I dams, but t he change was not seen during Phase II
and was considered adverse. The maternal N OAEL is 143 mg/kg bw/day boric acid (25 mg/kg bw/day boron equivalents, HDT). A maternal LOAEL wa s not determined (>25 mg/kg bw/day boron equivalents)

.

Developmental toxic ity : Study Phase I: At 13.3 mg/kg bw/day boron equivalents, mean fetal body weight was decreased in males and females (

- 6.1% and

- 7.1% below controls, both p<0.05). An increased incidence of short rib XIII (fetal 17% vs. 9%, controls, p<0.05; litter
inc idence not increased) and wavy rib XIII (fetal 10%/litter 6% vs. 0%, controls, p<0.05) was observed. Historical control data provided for short rib (0.14%) and wavy rib (0.2%) showed a very low incidence. These findings were also increased in MRID 417254 01 at 14 mg/kg/day. In Phase II, the incidence of short rib XIII was also increased at 25 mg/kg/day (affecting 16 fetuses in 6 litters, vs. 0 in controls). Pup weights were comparable in all dose levels at PND Day 21.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 74 of 99 The developmental LOAEL is 76 mg/kg bw/day boric acid (13.3 mg/kg bw/day boron equivalents) , based on decreased fetal weight and rib abnormalities . The developmental
NOAEL is 33 mg/kg bw/day (9.6 mg/kg bw/day boron equivalents)

.

The developmental toxicity study in the rat is classified ac ceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the

rat.

(2) Boric acid

In a developmental toxicity study (MRIDs 41725401, main report and 42377101, supplement), 29 pregnant Crl CD (BR)VAF/Plus outbred Sprague

- Dawley rats/dose group were administered boric acid (technical, 98

- 99% a.i.) in the diet at concentrations of 0, 0.1, 0.2 or 0.4% (equivalent to an average daily dose of 0, 78, 163 or 330 mg/kg/day boric acid and 0, 14, 29 or 5 8 mg/kg/day of boron equivalents) from gestation days 0 through 20 (dosing schedule designed to allow plasma boron levels to reach steady state prior to implantation to mimic low

- dose exposure from food). Additional control and high dose groups of 14 preg nant rats each were administered the test diet at 0% or 0.8% from gestation days 6 through 15 (equivalent to an average daily dose of 539 mg/kg/day boric acid and 94 mg/kg/day boron equivalents). In addition, dams’ kidney and liver weights were measured a nd kidneys were examined microscopically.

Maternal toxicity : (Treatment GD 6

- 20)

- At 0.2%, statistically significantly increased relative kidney weight (right and left) was observed (about +10% above controls), with a similar but

non

- significant increas e in absolute right and left kidney weight; relative liver weight was also increased (+5%, p<0.05); however, these marginal changes, seen at comparable increases at higher dose levels, were not considered to be adverse. At 0.4%, a statistically significan t reduction in body weight gain (

- 10% below controls) and gravid uterine weight (

- 30% below controls) were observed, but body weight was not decreased when adjusted for the gravid uterine weight. Water intake was increased between GD 18

- 20 (23%). Statist ically significantly increased left kidney weight (+8%; right similar increase but not significant) was also seen. One or two animals per dose had evidence of mild renal nephropathy but a dose

- response was not observed and the findings were not considered adverse. At 0.8%, (treatment only GD 6

- 15), mean body weight gain and gravid uterine weight during treatment were about

- 58 to

- 59% lower than controls, but did not show a change when corrected for uterine weight. Food consumption was slightly lower (

- 1 3%) than controls and water intake was decreased between
GD 6

- 9 (

- 17%). No treatment

- related effects on survival or clinical signs were reported. Mild nephropathy in 0, 2, 1, 2, 1 and 0 females (control to high dose of 0.8%, respectively) was also
consi dered incidental due to lack of dose response. The maternal toxicity NOAEL is 0.8% (539 mg/kg/day boric acid; 94 mg/kg/day boron equivalents). A LOAEL was not determined in this study.

Developmental toxicity : At 0.1%, mean fetal body weight was statist ically significantly reduced (

- 6% less than controls). The incidences of wavy rib XIII and short rib XIII were increased (% litter incidence/% fetuses per litter 14.29/1.0% and 17.86%/2.43%, respectively, compared to 3.57%/0.36% in controls). The increas es were not statistically significant but historical control fetal incidence was very low for both abnormalities, suggesting a treatment

- related effect at thisBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 75 of 99 dose. At 0.2%, decreased mean fetal weight (

- 13% below controls), and statistically significant ly increased incidences of the litter incidence of short rib XIII, wavy rib XIII and cleft sternum were reported. At 0.4%, increased fetal resorptions, rib XIII agenesis (24 fetuses vs. 0 in controls), enlarged lateral ventricles in the brain (21 vs. 0 fe tuses in controls; fetal incidence 0.5%) were observed (fetal weight

- 37% below controls). At the high dose of 0.8% (GD 6

- 15 exposure only), prenatal mortality (live fetuses per litter mean 9.71 vs. 15.39

- 15.69 in other groups) was observed. Numerous gro ss malformations (short and curly tail, anophthalmia, microphthalmia), visceral malformations (cardiovascular defects, convoluted retina, enlarged lateral ventricles of the brain) were observed along with rib XIII agenesis, short rib XIII and cleft

sternum . At 0.4% and 0.8%, 100% of the litters were affected with skeletal malformations and variations; visceral malformations were reported in 36% and 86% of litters, respectively. The developmental toxicity LOAEL is 0.1% (78 mg/kg/day boric acid; 14 mg/kg/da y boron equivalents), based on decreased fetal weight and marginally increased incidence of Rib XIII variations. A developmental toxicity NOAEL was not determined in this study. However, a subsequent developmental toxicity study was con ducted by the same lab (MRID 433 401 01 ) and identified a NOAEL/LOAEL of 9.6/13.6 mg/kg/day, based on comparable findings.

This developmental toxicity study in the rat is classified acceptable/nonguideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat, when it is considered together with another rat developmental toxicity study, MRID 43340101, which identified a NOAEL/LOAEL of 9.6/13.3 mg/kg/day for developmental toxicity based on the same effects. The test ma terial was administered via the diet instead of gavage to mimic human dietary exposure.

870.3700a Prenatal Developmental Toxicity Study

– Mouse

In a developmental toxicity study (MRID 41725402), boric acid (lot no. 872703, 98

- 99% a.i.)
was administered to 29 female CD

- 1 Swiss mice /dose in the diet at dose levels of 0 %

, 0.1%, 0.2% or 0.4% (equivalent to 0, 248, 452 or 1003 mg/kg/day boric acid and 0, mg/kg/day boron equivalents) from days 0 through 17 of gestation , inclusive

. In additio n to the standard evaluations performed in developmental toxicity studies, randomly selected kidneys from 10 dams/dose group were prepared for microscopic examination.

Maternal toxicity : At 0.1%, an increased incidence of renal tubular dilatation was rep orted (from control to high dose, 0/10, 2/10, 8/10 and 10/10, respectively). The lesions were classified as mild dilatation, with minimal regeneration in some of the animals also present at an incidence increasing with dose. At 0.4%, maternal body weight gain was significantly reduced (

- 21% below controls), although corrected weight gains were unaffected; therefore this change was not considered adverse. Relative kidney weights (left and right individually) were significantly increased by about 30% (left kidney absolute weights also increased by 15%), with pale kidneys observed grossly. A transient increase in food and water consumption (both +15%) was reported on Days 15

- 17. There were no treatment

- related effects on clinical signs or mortality. The

m aternal LOAEL is 0.1% (248 mg/kg bw/day boric acid; 43 mg/kg/day boron equivalents), based on renal pathology. A maternal NOAEL was not established in this study.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 76 of 99 Developmental toxicity : At 0.2%, mean fetal weight was significantly reduced (11% below

c ontrols, p<0.05) and the percent with short rib XIII per litter was increased (7.5%, increasing to 20% at 0.4%, compared to 0% in controls). The total number of fetuses affected at 0.2% and 0.4% were 2/309 and 10/250, respectively. At 0.4%, the percent o f litters with resorptions and % resorptions per litter were increased (+65% and +216%, respectively). The developmental LOAEL is 0.2% (452 mg/kg bw/day boric acid; 79 mg/kg/day boron equivalents), based on decreased fetal weight and increased incidence o f short rib XIII. The developmental NOAEL is 0.1% (248 mg/kg/day boric acid; 43 mg/kg bw/day boron equivalents).

This developmental toxicity study in the mouse is classified acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rodent. The test material was administered in the diet instead of by gavage to mimic human dietary exposure, and from GD 0

- 17 instead of 6

- 17. These variations do not adversely affect the
conduct of the st udy. The study is considered acceptable for regulatory purposes.

870.3700b Prenatal Developmental Toxicity Study

- Rabbit

In a developmental toxicity study (MRID 42164201,

- 02 ) , boric acid (technical, 99% a.i., lot no. 872703) was administered to 30 pre gnant, artificially inseminated New Zealand White rabbits/dose by gavage in distilled water (5 mL/kg bw dose volume) at dose levels of 62.5, 125 or 250 mg/kg/day administered daily from gestation days 6 through 19, inclusive (equivalent to 0, 11, 22 or 44 mg/kg/day of boron equivalents). Several animals were removed from all dose groups (due to abortions, experimental error, injury); pregnancy was observed (control to high dose, respectively) in 18/24, 23/26, 20/23 and 22/23 does.

Maternal toxicity : At 250 mg/kg bw/day, vaginal bleeding was observed, between GD 19

- 30, in a total of 14 does, none of which had live fetuses on GD 30. Does showed weight loss during treatment (

- 137 g vs. gain of 93 g, controls), but the decrease was due primarily to decrease d gravid uterine weight related to fetal loss, based on corrected weight gains. Food consumption during treatment was reduced by 37% compared to controls. There were no treatment

- related increases in maternal mortality. The maternal LOAEL is 250 mg/kg b w/day (44 mg/kg bw/day boron equivalents) , based on increased vaginal bleeding associated with fetal loss and decreased food consumption . The maternal NOAEL is 125 mg/kg bw/day (22 mg/kg bw/day boron equivalents)

.

Developmental toxicity : At 250 mg/kg bw /day, the total number of live litters was greatly reduced, with only 6 litters (14 fetuses) available for evaluation. Fetal resorptions/dam were increased (7.8, p<0.05, vs. 0.72, controls) due to increases in early resorptions. A total of 140 early reso rptions, vs. 4 in controls, were observed. Post

- implantation loss was high (92.6 vs 7.0, controls). Mean fetal weight showed a decrease (41.1 g vs. 44.8 g, controls, not significant). In the surviving fetuses, an increase in visceral malformations, prim arily intraventricular septal defects or abnormalities of the great vessels, was observed. There were no treatment

- related
increases in external or skeletal malformations or variations. The developmental LOAEL is 250 mg/kg/day (44 mg/kg bw/day boron equi valents) , based on increased fetal loss, decreased fetal weight and increased malformations . The developmental NOAEL is 125 mg/kg bw/day (22 mg/kg bw/day boron equivalents)

.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 77 of 99 The developmental toxicity study in the rabbit is classified as acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in
the rabbit.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

– Rat

(1) Borax

In an oral three

- generation reproduction study (MRID 40692311), sodium tetraborate decahydrate (borax tech., analyzed at 103

- 105% of theoretical boron content) was administered to 8 male and 16 female Charles River CD rats/dose in the diet at continuous dose levels of 0, 0.103%, 0.3 08% or 1.03% (in males, equivalent to 0, 0, 72, 218 or 729 mg/kg/day test material and 0, 8.1, 28 or 82 mg/kg/day boron equivalents; in females, equivalent to 0, 81, 241 or 814 mg/kg/day test material and 0, 9.2, 31 or 92 mg/kg/day boron equivalents). Aft er a 14

- week premating period, one male and two females were mated for up to 21 days. Two matings per generation were performed to produce two litters. An exception to the protocol was taken for the 1.03% P1 repeat matings due to no conceptions in the fi rst mating: untreated males were used with the treated females for the subsequent P1 matings. The high dosing group was not continued for P2 and P3 generations due to insufficient successful matings from either attempted P1 mating.

Parental toxicity : At 1.03%, clinical signs (coarse fur, scaly tails, hunched posture) and decreased body weight were observed in P1 males during much of premating (up to

- 14% to

- 16% below controls)(but not in later parental generations). Testicular atrophy with severely
decr eased testes abs/rel weights was observed in all P1 males. In females, the number of functioning ovaries was lower than normal (4/15), although the controls were not examined for comparison. No subsequent generations were tested at this dose level. The parental toxicity LOAEL is 1.03% (males/females 729/814 mg/kg/day test material; 82/92 mg/kg/day boron equivalents), based on clinical signs, decreased body weight and testicular atrophy/reduced ovarian function. The NOAEL is 0.308% (males/females 218/241 mg/kg/day test material; 28/31 mg/kg/day boron equivalents).

Offspring toxicity : At 1.03%, no litters were born. In the second mating with untreated males, there were only 2 litters and 1 abortion; no pups survived past Day 3 postpartum (died or canniba lized). The offspring toxicity LOAEL is 1.03% (males/females 729/814 mg/kg/day test material; 82/92 mg/kg/day boron equivalents), based on fetal/pup mortality. The NOAEL is 0.308% (males/females 218 /241 mg/kg/day test material; 28/31 mg/kg/day boron equi valents).

Reproductive toxicity : At 1.03%, no litters were produced in the first P1 mating. The second P1 mating with untreated males resulted in 2 litters and 1 abortion out of 16 matings. All pups were either cannibalized or died by Day 3 postpartum . Testes of parental P1 males showed complete atrophy and P1 females had a lower than normal number of functioning ovaries (4/15 with corpora lutea; however controls were not examined); the study authors concluded that the latterBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 78 of 99 finding was insufficient to completely account for the low fertility observed with untreated males and that some other effect on ovarian function or implantation was occurring. The reproductive toxicity LOAEL is 1.03% (males/females 729/814 mg/kg/day test material; 82/92 mg/kg/da y boron equivalents), based on reduced fertility. The NOAEL is 0.308% (males/females
218 /241 mg/kg/day test material; 28/31 mg/kg/day boron equivalents).

This study is classified as acceptable/nonguideline and satisfies the guideline requirement for a
multi

- generation reproductive study (OPPTS 870.3800; OECD 416) in the rodent (rat). Although the study had several deficiencies (incomplete histopathology evaluation, 2:1 matings, less than 20 pregnant females /group, lack of gestation period data and low lactation indices in control animals), the data are considered acceptable for regulatory purposes and a new study is not required at this time, based on consideration of this data together with other studies on reproductive/developmental toxicity of boric acid and systemic toxicity in the rat.

(2) Boric acid

In an oral three

- generation reproductive toxicity study (MRID 00068882), boric acid (technical grade, 98.7% a.i.) was administered continuously in th e diet to 8 male and 16 female Sprague Dawley rats/dose at concentrations of 0, 0.067%, 0.20% or 0.67% (equivalent to average daily boron intakes of 0, 8.5, 26.6 or 85 mg/kg/day, males and 0, 9.7, 29 or 91.6 mg/kg/day, females). Matings (2 females per mal e) were conducted over three generations, with two matings performed per generation. The high dosing group was not continued for P2 and P3 generations
due to lack of litters.

Parental toxicity : At 0.67%, clinical signs of toxicity were reported, body weights of males and females were decreased and at autopsy, testes of males were visibly atrophied (not examined microscopically but confirmed by lack of spermiation in other feeding studies). Ab out half of
the females showed evidence of reduced ovulation. The parental toxicity LOAEL is 0.67% (85/92 mg/kg/day boron equivalents), based on clinical signs of toxicity, decreased body weights, testicular atrophy and reduced ovulation. The NOAEL is 0. 20% (27/29 mg/kg/day boron equivalents).

Reproductive toxicity : At 0.67%, no litters were produced. As noted for parental toxicity, testes were atrophied and ovaries showed signs of reduced ovulation. A cross

- mating of the treated
females with males adm inistered untreated diet was unsuccessful, indicating effects on the female reproductive system as well as the male (the authors did not consider the reduced ovulation sufficient to explain the complete lack of fertility, indicating a more pronounced effec t on males). The reproductive toxicity LOAEL is 0.67% (85/92 mg/kg/day boron equivalents), based sharply reduced fertility related to testicular atrophy, reduced ovulation. The NOAEL is 0.20% (27/29 mg/kg/day boron equivalents).

Offspring toxicity : At 0 .67%, no litters were produced. A cross

- mating of treated females with untreated males resulted in reduced numbers of P1 litters and pup survival. The offspring toxicity LOAEL is 0.67% (85/97 mg/kg/day boron equivalents), based on reduced pup
survival fr om a treated female/untreated male mating. The NOAEL is 0.20% (27/29 mg/kg/day boron equivalents).Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 79 of 99 This study is classified acceptable/nonguideline and satisfies the guideline requirement for a
multi

- generation reproductive study (OPPTS 870.3800; OECD 41 6) in the rodent (rat). Although the study had several deficiencies (incomplete histopathology evaluation, 2:1 matings, less than 20 pregnant females/group, lack of gestation period data and low lactation indices in control animals), the data are considere d acceptable for regulatory purposes and a new study is not required at this time, based on consideration of this data together with other studies on reproductive/developmental toxicity and systemic toxicity of boron in the rat.

870.3800 Reproduction and Fertility Effects

– Mouse

In a two

- generation oral reproduction study (MRID 41589101), boric acid (99% a.i., batch/lot #872703) was administered in the diet to 38 CD

- 1 Swiss mice/sex at 0 mg/kg/day and to
19

- 20 CD

- 1 Swiss mice/sex/dose at continuous dose levels of 0, 1000, 4500 or 9000 ppm (equivalent to 0, 152, 636 or 1262 mg/kg/day test material and 0, 27, 111 or 221 mg/kg/day boron equivalents). For the F1 generation, only 0 and 1000 ppm doses were administered due to reduced fertility seen in the F0 generation at the higher doses. The study was performed by NTP according to the reproductive assessment by continuous breeding (RACB) protocol. Animals were given a one week premating period and a 14

- week cohabitation period, followed by a holding period . Litters born during cohabitation were removed by 24 hr postpartum; those born later remained with the dams for 21 days. In addition, a cross

- over mating period between
20/sex/dose of control and mid dose males and females to determine the affected sex and an offspring assessment, in which F1 offspring from the continuous F0 mating litters were selected, were performed.

Parental toxicity : At 4500 ppm (F0 parental animals only), decreased body weight in females (at week 18,

- 23%; considered largely secon dary to lower fertility rather than direct toxicity) and sharply decreased abs/rel testes weight (

- 40 to

- 50% of controls) and degeneration of seminiferous tubules (17/20 males) were observed; a decrease in cauda epididymides and prostate weights were also noted. Sperm showed a significantly lower concentration per mg caudal tissue (

- 72%), motility (

– 32%) and a higher percentage of abnormal sperm (61% vs. 11%, controls). A slight but statistically significant reduction in adrenal/kidney weight was also
obs erved in females (

- 9%). At 9000 ppm, mean body weight gain was significantly decreased in males and females. In addition to severe reduction in testicular weights and seminiferous tubule atrophy, 12/15 males produced no sperm and those that did had only 5 0% of sperm being motile. Lacrimation, exophthalmos and cloudiness of the eyes were observed. In F1 parental animals at 1000 ppm in the second generation fertility assessment, slight decreases in sperm concentration and percent abnormal (not significant) were reported, but no effects on fertility were observed, and the changes were not considered adverse. A parental systemic LOAEL is 4500 ppm (636 mg/kg/day test material; 111 mg/kg/day boron equivalents), based on decreased testicular weight in males and possibly adrenal/kidney weight decrease in females. The parental systemic NOAEL is 1000 ppm (152 mg/kg bw/day test material; 27 mg/kg/day boron equivalents).

Offspring toxicity : At 4500 ppm (F1 pups only), mean pup weight was decreased (

- 14% below controls at birth) and reductions in the average number of litters per pair (2.3 vs. 4.7, controls),Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 80 of 99 number of live pups per litter (8.67 vs. 13.52, controls) and % alive at birth (

- 11 %) were observed. A slight reduction (3

- 4%) in female and combined male and female pup weight (but not male) adjusted for litter size in the second generation (F2) mating at 1000 ppm was
considered incidental. The offspring LOAEL is 4500 ppm (636 mg/kg/d ay test material; 111 mg/kg/day boron equivalents), based on reduced pup weight and decreased live pups at birth. The offspring NOAEL is 1000 ppm (152 mg/kg bw/day test material; 27 mg/kg/day boron equivalents).

Reproductive toxicity : At 4500 ppm (F0 ma ting), fertility was sharply reduced (44% vs. 94%, controls). The number of days to litter in the F0 continuous breeding portion increased after the second litter, with the number of dams producing litters and live pups per litter also decreasing
with eac h litter. In the crossover mating evaluation, mating/fertility indices were sharply reduced in matings of treated males with control females (30%/5% vs. 79%/74%, controls) but also slightly affected in matings of treated females with control males (70%/64 %), thereby indicating that although effects were greater on males, some effect on females was also present. Testicular effects are described under parental toxicity, above. At 9000 ppm, no litters were produced and males showed decreased sperm concentra tion and motility, as described above under parental toxicity. The reproductive LOAEL is 4500 ppm (636 mg/kg/day test material; 111 mg/kg/day boron equivalents), based on reduced fertility and reduced sperm concentration. The reproductive NOAEL is 1000 pp m (152 mg/kg bw/day test material; 27 mg/kg/day boron equivalents).

This study is classified as acceptable/nonguideline and satisfies the guideline requirement for a
multi

- generation reproductive study (OPPTS 870.3800; OECD 416) in the rodent (mouse). The study was not conducted according to Agency guidelines and some deficiencies are noted (including only one dose level in the P1 mating, incomplete histopathology, nonguideline mating protocol). However, this study, conducted by the NTP, provides suffi cient information to characterize the reproductive toxicity of boric acid and is considered acceptable for regulatory purposes. Findings are consistent with 3

- generation reproduction studies in the rat on boric acid and borax (MRIDs and 40692311, respecti vely).

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity/Carcinogenicity

– Rat

(1) Borax

In an oral carcinogenicity study (MRID 40692309), borax (sodium tetraborate decahydrate tech.,
103.2

- 105.4% of theoretical value) was administered to 70 control and 35 treated Sprague

Dawley Charles River cesarean

- derived rats/sex/dose in the diet at dose levels of 0 (control), 0.103%, 0.308% or 1.03% (equivalent to 0, 65, 154 or 515 mg/kg/day test material; 0, 7.3, 17 or 58 mg/kg bw/day for elemental boro n) for two years. Interim sacrifices of 5 animals/sex/dose were performed at weeks 28 and 56.

At 1.030%, clinical signs attributed to treatment and observed beginning at weeks 4

- 6 included dry scaly tails, rough fur, hunched appearance, wheezing, blood y nasal and ocular discharge,Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 81 of 99 drooping, inflamed eyelids, swollen paw pads, abnormally long claws and shrunken scrotum. The report noted that most animals showed effects by 26 weeks and that severity increased with
time. Detailed incidence data were not provided in the study report. Mean body weight/weight gain were reduced in both males (

- 16%/

- 19% below controls) and females (

- 33%/

- 41% below controls), with decreases observed beginning in the first weeks of treatment. Significant
reductions in absolute and relative testes weight (between

- 60 to

- 80% below controls) at 6, 12 and 24 months’ sacrifice were observed. The latter correlated with grossly visible small testes, testicular tubular atrophy (primarily severe, observed in all animals examined at 6, 12 and 24 months) and a possible increase in testicular calcific arteriosclerosis. Hematocrit and hemoglobin were slightly decreased in both sexes at several time points, beginning at month 2 (Hct

- 5% to

- 13% and Hgb

- 10 to

- 14%; sporadic statistically si gnificant changes seen). There

were no treatment

- related effects on survival (control to high dose males 58%, 76%, 64% and 72%; females 67%, 68%, 58% and 80%), clinical chemistry or urinalysis parameters. The systemic toxicity LOAEL is 1.03% (515 mg/kg/d ay test material and 58 mg/kg/day elemental boron), based on decreased body weight, clinical signs of toxicity, decreased RBC parameters and testicular pathology. The NOAEL is 0.308% (154 mg/kg/day test material and 17 mg/kg/day elemental boron).

At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls. Dosing was considered adequate based on observations of clinical signs, decreased body weight, slight hematological changes and testicular atrophy.

Thi s carcinogenicity study in the rat is classified as acceptable/nonguideline and satisfies the guideline requirement for a chronic toxicity/carcinogenicity study [OPPTS 870.4200; OECD 451] in rats. The study was conducted prior to EPA’s GLP guidelines and therefore certain aspects of the study design are lacking. It is noted that some clinical chemistry parameters were not evaluated and that ophthalmologic examinations and microscopic examination of the eyes were not performed. In addition, the percent sur vival of mid dose males as presented in the study report (76.9%) differed from calculation from the individual animal survival data (64%); however, this discrepancy has been clarified by the registrant and 64% is the correct value.

(2) Boric acid

In an oral chronic toxicity/carcinogenicity study (MRID 00068883), boric acid (technical, 98.7% a.i.) was administered in the diet to 35 Sprague Dawley rats/sex/dose at 0.067, 0.20 or 0.67% (equivalent to average daily intakes of 0, 5.2, 16 or 58 mg/kg/d ay, males and 0, 6.3, 19 or 70 mg/kg/day, respectively, females). In addition, control groups of 70/sex were administered untreated diet. Interim sacrifice groups (5/sex/dose) were evaluated at 26 and 52 weeks. Samples of blood, urine and feces were coll ected at 26, 52 and 104 weeks for boron balance analyses; select tissue samples were also collected from 5 animals/sex at sacrifice times for boron analyses.

At 0.67%, clinical signs of toxicity beginning at 4

- 6 weeks (hunched posture, desquamation of

ta il and paws, swollen paws, inflamed eyes, respiratory effects and shrunken scrotum), decreased mean body weights, low red blood cell volume and hemoglobin in males and decreased abs/rel testes weight and severe testicular atrophy (by 26 weeks, progressing in severity with time). InBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 82 of 99 females, anovulatory ovaries were observed. At 104 weeks control, low and mid dose males also showed signs of atrophy. The incidence was not increased but severity showed a slight increase; however, given the advanced age of t he rats, this was not considered clearly treatment

- related. Boron balance studies showed that there was no significant accumulation in tissues, although levels of treated animals were higher than controls. Boron blood levels increased with dose.
The LOA EL is 0.67% (58 mg/kg/day boron equivalents), based on clinical signs, decreased body weight, hematological changes in males, testicular atrophy and possibly increased anovulatory ovaries. The NOAEL is 0.20% (16 mg/kg/day boron equivalents).
There was no evidence of a treatment

- related increase in tumors. Dosing was considered adequate based on significant toxicity at the highest dose tested.

This carcinogenicity study in the rat is classified as acceptable/nonguideline and satisfies the guideline requir ement for a chronic toxicity/carcinogenicity study [OPPTS 870.4200; OECD 451] in rats. It is noted that some clinical chemistry parameters were not evaluated, ophthalmologic examinations were not performed and some tissues were not examined microscopicall y. However, it is considered an acceptable study for regulatory purposes.

870.4100b Chronic Toxicity

- Dog

(1) Borax

In a chronic toxicity study (MRID 40692310), borax (sodium tetraborate decahydrate, lot number and purity not provided but analyzed boron content 103.2

- 105.4% of theoretical value)
was administered to four beagle dogs/sex/dose in the diet at dose levels of 0, 0.051%, 0.103% or
0.309% (equ ivalent to average daily intakes of 0, 13, 26 or 77 mg/kg bw/day test material and 0, 1.5, 2.9 or 8.8 mg/kg bw/day boron equivalents ) for 104 weeks. Of the 4 animals/sex/dose, one male and one female/dose group were sacrificed at week 52 for an interim ev aluation; and one male and one female from the control and high dose group only were sacrificed at week 117 for a recovery assessment, with removal of the test diet at week 104. Only limited clinical chemistry parameters were evaluated and ophthalmologic examinations were not performed. Urine and blood were examined for boron levels in 1 animal/sex/dose at various time points between one and 27 months. Samples of sperm were collected from 2 controls and 2 high dose males prior to sacrifice. Samples of b rain, liver, kidney, body fat and muscle were collected from all animals at sacrifice for the same purpose.

There were no treatment

- related effects on mortality, clinical signs of toxicity, body weight, food consumption, hematology, clinical chemistry, or gan weights or gross/microscopic pathology that were considered to be clearly associated with treatment. At 0.302%, one of two males sacrificed at 104 weeks showed testicular atrophy and reduced testicular weight along with no sperm. The study pathologi st determined that based on the characteristics of the histological findings, the atrophy was of recent origin and therefore not likely to be treatment

- related. A second high dose male had low sperm count; however the reliability of the sperm assessment i s unclear since the method for sperm collection was not described, and sperm were seen in this animal at study termination. Slight to moderate findings of atrophy or depression of spermatogenesis were reported in low and mid

- dose (1

- 2/3) dogs, but these e ffects were not considered likely to be
treatment related since a clear dose

- response was not observed, slight atrophy was also observedBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 83 of 99 in the control male at 117 weeks, and the effects were not observed at similar dose levels in the dog 90

- day studies. Furthermore, no testicular effects were observed in the control or treated males sacrificed at 52 weeks. Examination of excreta and tissues for boron showed that (1) steady

- state levels were achieved within 1

- 2 weeks; (2) tissue accumulation did not occur to a significant level. However, levels in the testes, the main target organ, were not evaluated. One 0.103% female was pregnant and gave birth during week 64 to two live and two dead pups. The NOAEL is 77 mg/kg bw/day borax (8.8 mg/kg/day boron equiva lents; HDT). A LOAEL was not established (>77 mg/kg/day).

This chronic study is classified as acceptable/nonguideline and , when considered together with
the 90

- day and 38

- week dietary toxicity studies on borax in the dog (MRIDs 40692307 and

- 08),
satisfi es the guideline requirement for a chronic oral study [OPPTS 870.4100, OECD 452] in the dog (nonrodent). The conclusions are also supported by subchronic and chronic dog studies conducted concurrently on boric acid. The study was conducted prior to enact ment of the US EPA GLP guidelines. The number of dogs per dose group (4 at study initiation) was reduced at the 104 week terminal sacrifice due to assignment of 1 animal/sex/group each to a 52

- week
interim sacrifice and to a 117

- week recovery sacrifice, b ut since the testicular lesions are observed by 90 days’ exposure (MRID 40692307), for purposes of evaluating this effect (and other toxicity), the dogs from the 52 and 104

- week sacrifice times may be considered together.
Test material concentration was n ot examined in the diet preparations. Evaluation of clinical and chemistries and hematology was incomplete. Although this two year dietary study in the dog was originally classified as “Supplementary” due to lack of effects, the HED RfD Committee
determi ned that taken together with the 38

- week study and the 90

- day study, there are sufficient data to adequately characterize the chronic toxicity of borate to the dog (memoranda dated November 24, 1993 and June 12, 1995).

(2) Borax

In a chronic toxicity study (M RID 40692308), sodium tetraborate decahydrate (borax technical, lot no. and purity not provided but analyzed at 103.29 to 105.10% of theoretical boron content) was administered to 4 beagle dogs/sex/dose in the diet at dose levels of 0 or 1.03% (for
males/f emales, equivalent to 0 or 348/400 mg/kg/day test material; 0 or 40/46 mg/kg/day boron equivalents) for up to 38 weeks. Two animals/dose/sex were sacrificed at week 26, one treated
male and female and two controls/sex at week 38 and one treated animal/sex was maintained on basal diet for a three week recovery phase and sacrificed at week 41.

At 1.03%, decreased body weight gain was observed in males and females (

- 10 to

- 11% below controls). In males, testicular atrophy and decreased testicular weight were observed. At 26 weeks, 2/2 males showed generalized spermatogenic arrest at the spermatocyte stage, progressing to complete atrophy of the seminiferous epithelium in some tubules, whereas 1⁄2 controls showed scattered atrophy. At 38 weeks, 1 control male showed severe degeneration of
the seminiferous tubules and 1 showed 10

- 15% of tubules undergoing degenerative changes; 1
treated male showed 5

- 10% of the tubules undergoing degenerative changes. At 41 weeks, 1 treated male showed a moderate tubular degene ration and evidence of complete cessation of spermatogenesis. Absolute and relative testicular weights of treated animals were also reducedBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 84 of 99 (35% to

- 45%). No increases in boron levels were reported in blood, brain, liver, fat, kidney or muscle in dogs sa crificed at 26 or 38 weeks, but an increase in urinary boron was observed. Excretion was complete before 4 days after cessation of treatment. There were no treatment

related effects on survival, clinical signs of toxicity. The LOAEL is 1.03% (40/46 mg/kg /day, males/females), based on decreased body weight gain in males and females and testicular atrophy in males. A NOAEL was not determined in this study.

This chronic study in the dog is classified acceptable/nonguideline when considered together
with the findings of a two

- year dietary study in the dog (MRID 40692310) ; by itself it does not satisfy the guideline requirement for a chronic oral study [OPPTS 870.4100, OECD 452] in the dog. The study was conducted prior to enactment of EPA GLP Guidelines. Only a single dose was tested, a small number of animals were available for each time point evaluation and only limited clinical chemistry parameters were evaluated. At this time, the data requirement for a chronic oral toxicity study in the dog is consi dered to be satisfied and no additional data are required.

(3) Boric acid

In a 38

- week oral toxicity study (MRID 00064205), boric acid (technical grade, $ 99.4% a.i.) was administered in the diet to 4 beagle dogs/sex/dose at concentrations of 0 or 0.67% (equi valent to average daily dietary intakes of 0 or 40 mg/kg/day boron equivalent, respectively). At week 26, 2 dogs/sex dose were sacrificed. At week 38, the remaining 2 control animals/sex and one treated animal/sex were sacrificed. The remaining treated animals (1/sex) were administered untreated diet for 25 days, then evaluated for recovery. Hematologic and clinical chemistry parameters were examined at week 0, 4, 12, 26 and 38. Sperm sample collection was attempted for all males on the study at week 26 but only a few samples were successfully collected. In addition, boron levels were examined in blood, urine and feces collected throughout the study and tissue levels were analyzed at sacrifice times. At 0.67%, complete atrophy of the seminiferous epit helium was observed in both males sacrificed at 26 weeks, compared to slight atrophy in one control male. At 38 weeks, both the control and treated male showed testicular atrophy and arrest of spermiation, although effects
were more severe in the treated male. The male retained on the untreated diet for an additional 25 days did not show testicular effects, suggesting reversibility may occur. There were no apparent treatment

- related effects on survival, clinical signs of toxicity, body weight. Sperm
col lection at week 26 resulted either in no sample obtained or no sperm seen (variable sperm counts were seen in 3 control males, with no sample obtained from one). Boron balance studies indicated that there was not significant accumulation in tissues. Urin ary levels were increased but boron was excreted out within a few days of stopping the test diet. The systemic toxicity LOAEL is 0.67% (40 mg/kg/day boron equivalents), based on testicular atrophy and arrest of spermiation. The NOAEL was not determined s ince only a single dose was tested.

This chronic study in the dog is classified acceptable/nonguideline when considered together with the findings of a 90

- day and a two

- year dietary study in the dog (MRIDs 00064203 and 00005622) ; by itself it does not sat isfy the guideline requirement for a chronic oral study [OPPTS 870.4100, OECD 452] in the dog. Only a single dose was tested, a small number of animals were available for each time point evaluation, only limited clinical chemistry parametersBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 85 of 99 were evaluate d and histopathology was not complete. At this time, the data requirement for a chronic oral toxicity study in the dog is considered to be satisfied and no additional data are required.

(4) Boric acid

In a chronic oral toxicity study (MRID 00005622), boric acid (technical grade, $ 98.7% a.i.) was administered in the diet to 4 beagle dogs/sex/dose at concentrations of 0.033, 0.067 or 0.20% for up to two years (equivalent to average daily intakes of 0, 1.6, 3.6 or 10.2 mg/kg/day boron equivalents, males and 0, 1.8, 4.0 or 11.6 mg/kg/day boron equivalents, females). One animal/sex/dose group was sacrificed at 12 months for interim evaluation. At 24 months, two control and high dose animals/sex were sacrificed and three low and mid dose
animals/sex were sacrific ed. The remaining control and high dose animals were continued on untreated diet for 3 months and were sacrificed at 27 months to evaluate recovery. Boron balance studies were also performed by determining boron in blood, urine and feces at several study intervals from control and high dose dogs. Tissue samples were also analyzed for boron at
the sacrifice intervals.

Clear treatment

- related effects were not observed. At 12 months slight focal atrophy of the testes was seen at 0.20%. At 24 months, one male had complete testicular atrophy but the second male was normal. There was slight testicular atrophy in the control and treated male in the recovery group. Because of the duration of the study, lack of significant atrophy at 12 months and small
numbe r of animals, the testicular atrophy at 24 months is noted, but of uncertain relationship to treatment. Boron balance studies indicated that it did not accumulate in tissues, with levels reaching steady state by 1

- 2 weeks. Boron was completely eliminated by 9 days after eliminating the test diet. The NOAEL is 0.20% (10.2 mg/kg/day boron equivalents). A
LOAEL was not achieved.

This chronic study in the dog is classified as acceptable/nonguideline and satisfies the guideline requirement for a chronic ora l study [OPPTS 870.4100, OECD 452] in the dog when considered together with MRIDs 00005624, a 38

- week dietary dog study and 00064203, a 90

- day dog study) , which together establish an effect level. The study was conducted prior to current guideline standar ds and is deficient in several respects (small numbers of animals at sacrifice times, incomplete clinical chemistry parameters and histopathology, etc.). However, it is considered acceptable for regulatory purposes in conjunction with the other studies.

A .4.5 Carcinogenicity

870.4200a Carcinogenicity Study

- rat

See 870.4100a (870.4300)

870.4200b Carcinogenicity (feeding)

- Mouse

In a n oral carcinogenicity study (MRID 41863101 )

, boric acid (technical, 99.7% a.i., lot no.
051479 ) was administered to 50 B6C3F1 mice/sex/dose in the diet at dose levels of 0, 2500 or 5000 ppm (equivalent to 0, 400

- 500 or 1100

- 1200 mg/kg bw/day boric acid, respectively; boronBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 86 of 99 equivalents 0, 66 or 192 mg/kg bw/day, males and 8 5 or 21 2 mg/kg bw/day , females ) for two

years. An interim sacrifice group was not included in the study. It is noted that the study authors stated that actual compound consumption may have been lower in this study due to spillage of test diets, which they estimated at about 48 and 96 mg/kg bw/day.

A t 2500 ppm, reduced survival of males was seen in the last weeks of the study (60% vs. 82%, controls); female survival was unaffected (control to high dose 66%, 66% and 74%, respectively). Splenic lymphoid depletion in males (controls to high dose 5/48, 1 1/49 and 25/48, respectively) was considered secondary to stress. At 5000 ppm, survival of males was reduced compared to controls during the second year of treatment (at termination, 44% at high dose vs. 82%, controls. Mean body weights showed decreases of about 11

- 17% in both sexes beginning at about week 32. Increases in testicular atrophy (control to high dose 3/49, 6/50 and 27/47) and interstitial cell hyperplasia (0/49, 0/50 and 7/47) were also observed. An increase in pulmonary hemorrhage in femal es (4%, 10%, 24%) was considered of uncertain relationship to treatment,
and was not observed in males. No treatment

- related effects on clinical signs of toxicity were reported. Clinical pathology, hematology, ophthalmologic and organ weight data were no t collected in this study. The LOAEL for males is 2500 ppm ( 66 mg/kg/day boron equivalents, based on decreased survival and increased splenic lymphoid depletion. A NOAEL for males was not identified. The LOAEL for females is 5000 ppm ( 2 12 mg/kg/day bor on equivalents), based on decreased body weight. The NOAEL is 2500 ppm ( 85 mg/kg/day boron equivalents).

At the doses tested, there was not a treatment related increase in tumor incidence wh en compared
to controls. A marginal increase in the incidenc e of hepatocellular carcinomas in low dose males (control to high dose overall rates 5/50, 12/50 and 8/49) and combined hepatocellular adenomas and carcinomas (control to high dose overall rates 14/50, 19/50 and 15/49) in treated males were
not considered treatment

- related because they were within historical control range and did not
show a dose

- response. An increased combined incidence of subcutaneous tumors (fibromas, sarcomas, fibrosarcomas, neurofibrosarcomas) in mid dose males (2/50, 10/50 and 2/150) was not considered treatment

- related because of the variability in spontaneous occurrence of these
tumors in historical controls and lack of a dose

- response. Dosing was considered adequate based

on decreased survival and decreased body weights in both sex es, along with splenic lymphoid depletion and testicular lesions in males.

This carcinogenicity study in the mouse is classified as acceptable/guideline and satisfies the guideline requirement for a carcinogenicity study [O PPTS 870.4200b; OECD 451] in mice. Several study deficiencies are noted for this report, including lack of hematology and organ weight data. IT is noted that NTP carcinogenicity studies do not routinely assess clinical pathology and organ weights. However, MTDs were achieved for bo th sexes and the study is considered adequate for the purposes of assessing the carcinogenicity of boric acid in the mouse.

A.4.6 Mutagenicity

Gene MutationBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 87 of 99 Guideline 870.5100, Bacterial reverse gene mutation (Ames Assay)
MRID 42038901 Acceptable/guideline Tested at 10

- 2500 μg/plate boric acid
Negative for induction of mutagenic response in S. typhimurium strains TA1535, TA1537, TA1538, TA98 or TA100 in the presence or absence of S9 up to 2500 μg/plate. No cytotoxicity was observed.

Guideline 870.5300, Mammalian forward gene mutation, Mouse lymphoma L5178Y cell

MRID 42038902
Acceptable/guideline Tested at 1200

- 5000 μg/mL boric acid +/

- S9

Negative for induction of mutagenic response in two independently performed mouse L5178Y cell lymphoma forward mutation assays. Marginal cytotoxicity at 3500

- 5000 μg/mL.

Cytogenetics

Guideline 870.5385, in vivo micronucleus assay, Mouse
MRID 42038904 Acceptable/guideline Tested at 900, 1800 or 3500 mg/kg bw boric acid
Negative for induction of clastogenic response to the bone marrow of Swiss mice. No systemic toxicity or target cytotoxicity observed up to 3500 mg/kg bw.

Other Genotoxicity

870.5550

, Unscheduled DNA synthesis, in vivo Rat liver
MRID 42038903 Acceptable/guideline Tested at 5

– 5000 μg/mL boric acid
Negative for increased unscheduled DNA synthesis in cultured rat hepatocytes. Slightly increased percent cells in repair at ≥2500 μg/mL in repeat assay were considered secondary to increased cytotoxicity at those
dose levels.

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study

- Hen

Study not available

870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity (limit dose) study (MRID 48773701) , groups of ~7

- week

- old Sprague

Dawley [Crl:CD®(SD)] rats (10/sex/dose) were given a single oral (gavage) dose of boric acid ( supplied as 56.73% a.i. boron oxide

, L ot # 8C20) in 1% (w/v) aqueous carboxymethyl cellulose

at the limit dose of 2000 mg/kg bw (350 mg/kg bw boron equiv alents) and observed for 14 days. Dosing volume was 10 mL/kg bw. A group of control animals was administered vehicle only. Neurobehavioral assessment (functional observational battery (FOB) and motor activity testing)

w ere performed in 10 animals/sex/group pre

- test, on Day 1 at the estimated time of peak effect determined by plasma T max ( stated to be within 2

- 3 hours of dosing based on published data ), and on Days 7 and 14. Cholinesterase activity was not determined. At study termination, 5 animals/sex/group were euthanized and perfused in situ for neuropathological examination. All of the perfused animals were subjected to histopathological evaluation of brain and peripheral nervous system tissues.

No definitive, adverse effects of tre atment with the limit dose were noted. All rats survived to study termination, and n o treatment

- related clinical sig n s were noted. Body weight gain ofBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 88 of 99 treated males was reduced by 16% over Days 1

- 14 (p≤0.05), but was not accompanied by
decreases in absol ute body weight and was due in part to lower initial mean body weight

. F urthermore, f

eed consumption was not measured, so it is not known if treated male rats exhibited a concomitant decrease in feed consumption. Absolute body weight and body weight gain of treated female rats were comparable to that of controls.

Treatment with the limit dose did not result in neurotoxicity in male or female rats as assessed by functional observation battery (FOB), motor activity counts, gross necropsy, brain weight, o r neuropathological examination. Brain weights of male rats were slightly increased (8% above controls) in the treated group but this change was not associated with microscopic changes in the
brain and was therefore not considered a treatment

- related eff ect or an adverse change. Positive control studies demonstrated the ability of the testing laboratory to conduct neurotoxicity screening assessments.

Based on a lack of effects in this study, the N OAEL for male and female Sprague Dawley rats (neurotoxici ty and systemic toxicity) was ≥ 2000 mg/kg bw (350 mg/kg bw boron equivalents). A LOAEL was not established.

This neurotoxicity study is classified as acceptable (guideline) and satisfies the guideline requirement for an acute neurotoxicity study in rat s (870.6200 a ; OECD 424). Although only a single dose was evaluated, the test material was administered at the limit dose.

870.6200 Subchronic Neurotoxicity Screening Battery

Study not available

870.6300 Developmental Neurotoxicity Study

Study not available

A.4.8 Metabolism

870.7485 Metabolism

- Rat

Study not available

870.7600 Dermal Absorption

- Human

(1) In vivo

In a n in vivo dermal penetration stud y (MRID 48507005) 1.8 mL of enriched 10 B ( >99% purity )
5% boric acid in water (Lot No. BL

- EV

- 9 4

- 36 (BA)), 5% borax in water (Lot No. 1797

- 16), or 10% disodium o c taborate tetrahydrate in water (DOT, Lot No. 0797

- 17) was applied to the upper dorsal skin of 8 healthy male and female human volun teers/dose group between the ages of 22 and 50 years. Th e amount of test material applied was determined by weighing the dosing microsyringe prior to and after dosing. The test materials were applied to an area 30 x 30 cm andBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 89 of 99 were allowed to remain in contact with the skin for 24 hours before washing. T

- shirts were worn by the test subjects to protect the treated area and allow collec tion of residual test material following application. Subjects were asked to follow dietary restrictions during the test period, thereby avoiding certain foods known to contain h igher boron levels. Six days after the initial application, the skin was irritated with a 2% sodium lauryl sulfate (SLS) solution and the same
test materials re

- admin istered the following day. Urine was collected at 24

- hour intervals 4 days

pre

- treatmen t; following treatment with the test materials for 7 days; and for 7 days following

treatment after skin irrita tion with 2% sodium lauryl sulfate (SLS) for determination of 10 B

recovery. The urine, skin wash gauze, and T

- shirts were assayed by inductivel y coupled plasma

mass spectrometry for 10 B content and the determination of the 10 B/ 11 B ratio. The study was conducted in accordance with human studies’ ethical conduct guidelines.

Following dermal treatment of human v olunteers with 10 B enriched 5% Boric Acid, 5% Borax, or 10% DOT, very limited absorption occurred. Boric a cid absorption, as percent of admin is

tered dose

, was 0.226 ± 0.125 %, with flux and permeability constants calculated as 0.0094

μ g/cm 2 / hour and 1.9 × 10

- 7 cm/ hour , respectiv e l y. Borax, as percent of administered dose
absorb ed

, was 0.210 ± 0.194 % , with flux and permeability constant s calculated as 0.00875

μ g/cm 2 / hour and 1.8 × 10

- 7 cm/ hour , respective ly. DOT percent of administered dose absorbed
dose was 0.122 ± 0.108 % , with flux and permeability constants calculated as 0.010 μ g/cm 2 / hour
and 1.0 × 10

- 7 cm/ hour , respectively. Approximately 60% (49

- 64%) of the administered topical
dose was recovered after 24 hours in the T

- shirt covering the dosed skin and the skin washes.
Pr e

- treat ment of the skin with the irritant 2% sodium lauryl sulfate had essentially no effect on boron skin absorption for a ll three dosage forms; with 0.239 ± 0.174 % recovered after boric acid
treatment, 0.185 ± 0.219 % following borax treatment, and 0.107 ± 0.134 % following DOT

treatment. No skin irritation was noted following treatment with any of the test materials; trans

epidermal water loss was reportedly measured, but data were not provided

. The results show
that the in vivo dermal absorption of bor on was low and unaffected by mild skin irritation.

The percent of absorbed dose measured for the three test materials used in this study may be arbitrarily low since the amount of boron in soft tissues and bone were not determined. These cannot be readily determined in an in vivo human

- based study. The determina tion of percent of absorbed dose is also hampered by the moderate recovery of the ad ministered 10 B dose (49

– 64%) and lack of information regarding a bsorbable dose remaining in the skin. However these limitations are balanced somewhat by (1) the known rapid elimination of boron compounds and low retention in tissues following absorption (>90% by 3 days post

- dosing), which suggests that a significant l evel of radioactivity would not be retained in tissues; (2) the long (24 hr) exposure period, which would provide a higher absorption level compared to the standard 6

- 8 hr exposure; (3) collection of urine for 7 days following dosing, during which time mos t of the absorbable dose would be expected to have been absorbed and excreted. The low level of absorbed dose in the urine is also consistent with other published studies conducted in animals. Given the rapid excretion and low percent absorbed dose after 7 days, it seems unlikely that significantly more of the dose would be excreted at later times. Although recovery of total radioactivity was low, adjustment of the absorbed dose for the low recovery (i.e., 50%) would still give a low absorption value (<0 .5%). Therefore absorption is likely to be very low. T he composition of treatment groups by sex and age, individual or group transepidermal water loss (TEWL) measurements, individual or group skin irritation scores, and readily useable individual testBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 90 of 99 ma terial absorption data were not located in the study report. There fore, verifi cation of the reported results by repeat analysis were not possible. However, the value of repeat analysis is question able given the low percent of dose for each test materi al recovered.

This in vivo human study is considered Acceptable/Non

- guideline. Although the study has several limitations, including relatively low recovery of radioactivity and sampling of urine only

, it provides information regarding dermal absorption in humans and is consistent with published data indicating low or no dermal absorption of boric acid/borate salts across undamaged skin.

(2) In vitro

In an in vitro skin permeability study (MRID 48549901) , human (cadaver) thigh skin was assessed over 24 hours following treatment with 10B

– enriched boric acid [0.05%, 0.5%, or 5% w/v; Batch No. BL

- EV

- 94

- 36(BA); 99.6% a.i.], Borax (5% w/v; Batch No. 1797

- 16; 100% a.i.), or disodium octaborate tetrahydrate [DOT ; 5% w/v; Batch No. 1797

- 17; 99.8% a.i.]. Boric acid (5%) was tested at 2 μl/cm2 and 1000 μl/cm2. The other two concentrations of boric acid, as well as Borax and DOT were tested at 1000 μl/cm2. The test materials were applied to the upper
side of the skin samples in flow

- through test cells. Receptor fluid was collected every 4 hours, the skin samples were washed, and the receptor fluid, washings, and skin samples were analyzed for the test materials. The skin samples were not tape

- stripped following washi ng to remove the
outer stratum corneum and were not included in the estimation of absorbed dose. It is noted that the study report did not indicate whether an assessment of skin integrity was performed.

The mean percent boric acid dose absorbed (present in the receptor fluid) at the three different concentrations did not vary markedly (0.28

– 1.20%). The 95% confidence intervals overlapped in every case. The mean rates of flux were 0.25, 0.58, and 14.58 μg/cm2/hr for the 0.05%, 0.5%,
and 5% boric acid co ncentrations, respectively. Flux did not vary strictly in proportion with the percent concentration of boric acid, but the permeability constants were relatively consistent across the concentration range tested. The 5% boric acid test using only a 2 μl/cm2 application rate, which mimicked conditions of an in vivo study with boric acid (MRID 48507005), resulted in 1.75% dose absorbed and a permeability constant that was two orders of magnitude lower than the constants observed in the 1000 μl/cm2 tests (“infi nite dose” tests). These results indicate that caution should be used when extrapolating in vitro studies conducted at infinite doses to in vivo
situations of finite doses. Most of the boric acid doses were recovered in the 24

- hour skin washings with 72. 4 ± 9.1%, 86.0 ± 5.9%, and 81.9 ± 2.9% for the 0.05, 0.5, and 5% concentrations, respectively, for the 1000 μl/cm2 tests. The permeability data obtained on 5% Borax and 10% DOT tested at 1000 μl/cm2 were similar to that obtained on 5% boric acid at 1000 μl /cm2 (0.41% and 0.19% of dose absorbed for Borax and DOT, respectively).

This in vitro skin permeability study using human (cadaver) skin is acceptable/nonguideline

, but does not satisfy the guideline requirement for a dermal penetration study (870.7600 ). The study provides useful supplemental information to the OCSPP 870.7600 requirement.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

– MouseBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 91 of 99 In an imm unotoxicity study (MRID# 48786601 ), Boric acid (56.37%, Lot No. 8C20) in carboxymethyl cellulose (10 mL/kg) was ad ministered to female B6C3F1mice (10/group) by gavage at 0 or 1000 mg/kg/day for 28 consecutive day s (0 or 175 boron equivalents)

. On study Day 25, a ll animals in all groups were immunized w ith a single intravenous injection of the antigen, sheep red blood cells 2 x10 8 SRBC/animal. Positi ve control group consisted of 10
females received 80 mg/kg of cyclophosph amide (CPH) in saline by intraperitoneal injection, 24
hours before sacrificed

. Ani mals were sacrificed on Day 29. All animals were evaluated for mortality, clinical signs, body weight changes and food consumption, spleen and thymus weights. A T

- cell dependent antibody response (TDAR) was assessed with an antibody plaque

forming cells (A FC) assay.

There were no effects of test substance treatment on mortality, body weight, clinical signs, food consumption, and spleen and thymus weights. There was a statistically significant decrease (p≤0.05) in the specific activity (AFC/1 0 6 live spleno cytes) and total activity (AFC/spleen) in the 1000 mg/kg group when compared to the vehicle control group.

In a follow

- up study ( MRID# 48798001 ), Boric acid (56.37%, Lot No. 8C20) in carboxymethyl cellulose (10 mL/kg) was ad ministered to female B6C3F1mice (10/group) by gavage at dose levels of 0, 250, 500, 750 or 1000 mg/kg/day (0, 43.8, 87.5, 131.3 or 175 mg/kg/day boron equivalents) for 28 consecutive day s. On study Day 25, a ll animals in all groups were
immunized with a s ingle intravenous injection of the antigen, sheep red blood cells 3 x10 8

SRBC/animal

. Positi ve control group consisted of 10 females received 80 mg/kg of cyclophosph amide (CPH) in saline by intraperitoneal injection, 24 hours before sacrificed.
Animals we re sacrificed on Day 29. All animals were evaluated for mortality, clinical signs, body weight changes and food consumption, spleen and thymus weights. TDAR was assessed
with an anti

- SRBC AFC assay.

There were no effects of test substance treatment on m ortality, clinical signs, body weight, food consumption, and spleen and thymus weights.

The systemic toxicity NOAEL is 1000 mg/kg/day (175 mg/kg/day boron equivalents); the LOAEL was not established, tested at the Limit Dose.

There were no statistically significant differences of thymus and spleen weights in treated groups when compared to the vehicle control group in both studies. The anti

- SRBC antibody p laque

forming cell data showed decreases in the specific activity (AFC/ 10 6 live splenocytes) and tot al activity (AFC/spleen) with statistical significances observed in the 500, 750, and 1000 mg/kg

groups. A high inter

- individual variability was noted in all the treatment groups as well as in the control group. Evaluation of individual a nimal data of this study show ed a dose

- dependent
decrease of anti

- SRBC AFC response

. It is to be noted that the total viable cells in the spleen of treated groups were lower than the vehicle control group and the cell viability was low in the treated groups as well as in th e vehicle control group. Animals in the positive cont rol group
showed marked decreases in the anti

- SRBC AFC response. The positive control group confirmed the validity of the immunotoxicity assay.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 92 of 99 The Natural Killer (NK) cells activity was not evaluated in both studies. Under the HED guidance, a NK cells activity assay is not needed if a suppression of TDAR was established.

Under conditions of this study, the immunotoxicity NOAEL is 250 mg/kg/day (43.8mg/kg/day boron equivalents); the LOAEL is 500 mg/kg/ day (87.5 mg/kg/day boron equivalents), based on decreases of anti

- SRBC AFC response s

.

T he s e immunotoxicity studies are classified acceptable / guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in mice.Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 93 of 99 A ppendix B : Chemical Identity and Physical/Chemical Properties

T able B.1 Nomenclature of Boric Acid and its Sodium Salts

Common

name B oric acid Sodium
tetraborate decahydrate Sodium

tetraborate pentahydrate Sodium

tetraborate anhydrous Disodium

octaborate tetrahydrate Disodium

octaborate anhydrous Sodium

metaborate

Empirical
Formula H3BO3 Na2B4O710H20 Na2B4O75H20 Na2B4O7 Na2B8O 13 4H20 Na2B8O 13 NaBO2

Other

names orthoboric

acid

, boracid
acid borax

decahydrate, borax 10 mol,
disodium
tetraborate decahydrate,
sodium borate decahydrate,
sodium pyroborate
10H20 , sodium
biborate 10H20 disodium

tetraborate pentahydrate,
borax pentahydrate,
sodium borate pentahydrate,
sodium biborate 5H20,
sodium pyroborate
5H20 borax

(anhydrous),
sodium
borate (anhydrous),
sodium
biborate (anhydrous),
sodium pyroborate (anhydrous) sodium

octaborate tetrahydrate Boron

sodium
oxide Boric acid,

sodium
salt

PC Code 011001 011102 011110 and
011111 011112 01110 3 01110 7 011104

CAS Registry
Number 10043

- 35

-

3 1303

- 96

- 4 11130

- 12

- 4 or
12179

- 04

- 3 1330

- 43

- 4 12008

- 41

- 2

, 12280

- 03

- 4 12008

- 41

-

2 15293

- 77

-

3 , 7775

- 19

- 1

Table B .2 Physical/Chemical Properties of Boric acid and its Sodium Salts

Chemical Molecular

weight (g/mole) Physical

state Melting

point Solubility

in water pH Density/ Specific Gravity Vapor

Pressure Estimated

Octanol/
Water
Partition
Coefficient

Boric Acid 61.9 Solid crystalline powder 171 o C 5.6 g/100mL 5.1

(1% solution
at 20 o C) 1.51 at

20 o C
oC < 10

- 4

torr at 20 o C 0.175

Sodium
tetraborate decahydrate 381.87 crystalline powder 75 o C 4.70 g/100
mL at
20 o C 9.2

(1% solution
at 20 o C) 1.73 < 10

- 6

torr 0.175

Sodium
tetraborate pentahydrate 291.35 milky white
alkaline salt < 200 o C 3.59% at
20 o C 9.2

(1% solution
at 20 o C) 1.82 < 10

- 6

torr No data

Sodium
tetraborate anhydrous 201.27 Solid crystalline

or amorphous 742 o C 2.56 g/100
mL at
20 o C No data 2.37 < 10

- 6

torr No data

Disodium
octaborate tetrahydrate 412.31 Powder 815 o C 9.5% at
20 o C 8.5

(1% solution
at 23 o C) 25

- 35

lbs/ft3 < 10

- 6

torr No dataBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 94 of 99 Table B .2 Physical/Chemical Properties of Boric acid and its Sodium Salts

Chemical Molecular

weight (g/mole) Physical

state Melting

point Solubility

in water pH Density/ Specific Gravity Vapor

Pressure Estimated

Octanol/
Water
Partition
Coefficient
Disodium
octaborate anhydrous 340.31 Solid rods No data No data No data 1.8 g/mL at
20 o C < 10

- 6

torr No data

Sodium
metaborate 65.82 Solid white pieces or powder 966 o C Soluble,
no value reported 11.82 (6%

solution) 51

- 61

lb/ft3 < 10

- 6

torr No data

Sources: U.S. EPA (1993), NIOSH (2001)Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 95 of 99 A ppendix C : Use Pattern Summary

Table C .1. Summary of Registered Use Directions for Boric Acid and its Sodium Salts

Application Type/Equip/etc. Formulation

[Representative EPA Reg. No.] Maximum Application Rate 1 PPE/Work Attire, REI,
Retreatment

Grass/Turf (Homes, Parks, Golf courses), Ant mounds, Building Perimeters

Broadcast application
via:

 Tractor

- drawn spreader

 Hand dispersal

 Belly grinder

 Cup/Spoon

 Push

- type rotary spreader Granule (insecticide)

EPA Reg. No. 19713

- 522 (Drexel Borxel)

5% boric acid Product rate 4 lb product/1000 ft 2

 Retreatment not specified

 PPE: eyewear/goggles, long sleeve shirt, long pants, waterproof gloves,
shoes/socks

 REI not specified Active ingredient rate 0.2 lb boric acid/1000 ft 2

9 lb boric acid/acre

Boron equivalent rate 1.5 lb boron/acre

0.035 lb boron/1000 ft 2

Golf Course Turf and Agricultural Food/Feed Crops (alfalfa, cane berries, bush berries, coffee, cacao, pome fruit, stone fruit, citrus, herbs, tree nuts, peanuts, strawberry, tobacco, Brassica leafy vegetables, bulb vegetables, corn, cucurbit, fruiting vegetables, leafy vegetables, except Brassica, legumes, root and tuber vegetables, soybean, cotton, herbs, avocado, kava, banana, guava, papaya, pineapple, watermelon and grasses) and Golf Course Turf

Broadcast application
via:

 Groundboom

sprayer

 Airblast sprayer

 Chemigation
and aerial application is prohibited Liquid concentrate (insecticide)

EPA Re g. No. 72662

- 3 (Prev

- Am Ultra)

0.99% sodium tetraborohydrate decahydrate (STD) Product rate 100 fl oz/100 gal soln

25 gal soln/acre

 Minimum retreatment is 7 days.

 PPE: eyewear/goggles, long sleeve shirt, long pants, waterproof gloves,
shoes/socks

 REI: 12 hours Active ingredient rate 0.00065 lb STD/gal soln

(product rate * 8.34 lb/gal soln * 0.99% ai)

0.016 lb STD/acre (0.00065 lb STD/gal soln * 25 gal soln/acre)

Boron equivalent rate 0.0018 lb boron/acre

Home gardens, lawns, greenhouses, ornamentals, shrubs

Broadcast application via hand sprayers (e.g., hose

- end sprayers, handwand sprayers) Liquid concentrate

(insecticide)

EPA Reg. No. 72662

- 5 (Prev

- Gard)

0.99% sodium tetraborohydrate decahydrate (STD) Product rate 1 fl oz. product/gal soln.

1 gal soln/1000 ft 2

 Spray every 7

- 10 days or as frequently as every 4 days

 PPE: eyewear/goggles, long sleeve shirt, long pants, waterproof gloves,
shoes/socks

 REI: 12 hours Active ingredient rate 0.00065 lb STD/gal

soln/1000 ft 2 (product rate * 8.34 lb/gal soln * 0.99% ai)

0.03 lb STD/acre

Boron equivalent rate 0.000073 lb boron/gal

soln/1000 ft 2

0.003 lb boron/acre

Tree StumpsBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 96 of 99 Table C .1. Summary of Registered Use Directions for Boric Acid and its Sodium Salts

Application Type/Equip/etc. Formulation

[Representative EPA Reg. No.] Maximum Application Rate 1 PPE/Work Attire, REI,
Retreatment

Application via
shaker can or hand

sprayers Dust/powder

(fungicide)

EPA Reg. No. 2935

- 501 ( Sporax)

100% sodium tetraborohydrate decahydrate (STD) Product rate 1 lb/50 ft 2 stump surface (equiv. 250 six inch stumps)

1 lb/gal soln/50 ft 2 stump surface (assume 1 gallon water dilution)  Spray every 7

- 10 days or as frequently as every 4 days

 PPE: eyewear/goggles, long sleeve shirt, long pants (or coveralls), waterproof gloves,
shoes/socks

 REI: 48 hours Active ingredient rate 1 lb STD/gal soln/50 ft 2

(product rate * 100% ai)

Boron equivalent rate 0.11 lb boron/gal soln/50
ft 2

0.0023 lb boron/gal
soln/ft 2

Indoor Crack

- and

- crevice (Residential, Commercial, Recreational) and Sewers

Application via shaker can, bulb dusters, power
dusters Dust (insecticide)

EPA Reg. No. 56

- 73 (Eaton’s Answer)

99% boric acid Product rate 20 oz container

12 oz/190 ft 2

 No retreatment, PPE, or REI specified Active ingredient rate 19.8 oz boric acid/20 oz
container

11.9 oz boric acid/190 ft 2

Boron equivalent rate 0.22 lb boron/20 oz
container

0.00068 lb boron/ft 2

30 lb boron/acre

Application via hand dispersal Granule (insecticide)

EPA Reg. No. 64405

- 2 (Redzone Bait)

5% boric acid Product rate 2 lb/1000 ft 2

 PPE: eyewear/goggles, long sleeve shirt, long pants, waterproof gloves,
shoes/socks

 REI: 4 hours

 No retreatment specified Active ingredient rate 0.1 lb boric acid/1000 ft 2

Boron equivalent rate 0.017 lb boron/1000 ft 2

0.76 lb boron/acre

Structural Building/House Components (wall/cabinet voids, soffits, attic space, crawl spaces)

Application via bulb and power dusters Dust/Wettable Powder

(insecticide/fungicide)

EPA Reg. No. 64405

- 8 (Nibor Borate)

98% disodium octaborate tetrahydrate (DOT) Product rate 0.5 oz/ft 2

1.5 lb/gal water

 PPE: eyewear/goggles, long sleeve shirt, long pants, waterproof gloves,
shoes/s ocks, respirator in confined spaces

 REI: 48 hours

 No retreatment specified Active ingredient rate 0.49 oz DOT/ft 2

1.47 lb DOT/ gal soln

Boron equivalent rate 0.21 lb boron/lb product

0.1 oz boron/ft 2

0.0065 lb boron/ft 2

0. 31 lb boron/ gal solnBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 97 of 99 Table C .1. Summary of Registered Use Directions for Boric Acid and its Sodium Salts

Application Type/Equip/etc. Formulation

[Representative EPA Reg. No.] Maximum Application Rate 1 PPE/Work Attire, REI,
Retreatment

Application via hand sprayers (backpack, handgun, airless

sprayers, brush/rollers) Liquid concentrate

(insecticide/fungicide)

EPA Reg. No. 83465

- 1 (GB

- 40)

40% disodium octaborate tetrahydrate (DOT) Product rate 1 gallon product per 1 gallon water = 1 gal prod/2 gal soln (1 gallon product = 11.5

lbs)  PPE: eyewear/goggles,

long sleeve shirt, long pants, chemical resistant gloves, shoes/socks, respirator in confined

spaces

 REI: 48 hours

 No retreatment specified Active ingredient rate 2.3 lb DOT/gal soln

(product rate * 40% ai)

Boron equivalent rate 0.32 lb boron/gal soln

Poultry House, Soil/Manure, Garbage/Municipal Dumps

Application via bulb and power dusters and via hand sprayers Dust/Wettable Powder (insecticide)

EPA Reg. No. 1624

- 11 (Polybor 3)

98% disodium octaborate tetrahydrate (DOT) Product rate 5 lb/100 ft 2

2 lb/gal water

3 gal soln/100 ft 2  PPE: eyewear/goggles, long sleeve shirt, long pants, chemical resistant gloves, shoes/socks, respirator under certain
conditions

 REI not specified

 No retreatment specified Active ingredient rate 4.9 lb DOT/100 ft 2

0.65 lb DOT/gal soln

Boron equivalent rate 1 lb boron/100 ft 2

0.14 lb boron/gal soln

448 lb boron/acre Indoor Residential Carpets, Rugs, Upholstery

Application via hand

sprayers RTU Solution

(insecticide)

EPA Reg. No. 64405

- 6 (RTU Flea Spray)

8.5% disodium octaborate tetrahydrate (DOT) Product rate 1 gal/750 ft 2

 No retreatment, PPE, or REI specified Active ingredient rate 0.71 lb DOT/gal soln

(1 gal prod * 8.34 lb/gal * 8.5% ai)

0.00095 lb DOT/ft 2

Boron equivalent rate 0.15 lb boron/gal soln

0.0002 lb boron/ft 2

Application via hand

sprayers Dust/Wettable powder

(insecticide)

EPA Reg. No. 67419

- 1 (Ecology Works)

98% disodium
octaborate tetrahydrate (DOT) Product rate 1 cup/0.5 gal water

1 cup/100 ft 2

 Reapply every 8 weeks

 No PPE or REI specified Active ingredient rate 0.86 lb DOT/gal soln

(1 cup * 200 grams/cup * 1 lb/454 grams * 98% ai)

0.0043 lb DOT/ft 2

Boron equivalent rate 0.18 lb boron/gal soln

0 .0009 lb boron/ft 2

Bed Bug Treatments (Mattresses, Bed Frames, Floorboards, Baseboards, Carpets, Walls)Boric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 98 of 99 Table C .1. Summary of Registered Use Directions for Boric Acid and its Sodium Salts

Application Type/Equip/etc. Formulation

[Representative EPA Reg. No.] Maximum Application Rate 1 PPE/Work Attire, REI,
Retreatment

Application via hand

sprayers RTU Solution

(insecticide)

EPA Reg. No. 64405

- 6 (RTU Flea Spray)

8.5% disodium octaborate tetrahydrate (DOT) Product rate 5 ounces/ft 2

 No retreatment, PPE, or REI specified Active ingredient rate 0.71 lb DOT/gal soln

(1 gal prod * 8.34 lb/gal * 8.5% ai)

0.028 lb DOT/ft 2

Boron equivalent rate 0.15 lb boron/gal soln

0.0058 lb boron/ft 2

Industrial Areas, Lots, Fence Lines, Runways and Underneath Asphalt, Wood Decks, Bleachers Broadcast application
via:

 Tractor

- drawn spreader

 Hand dispersal

 Belly grinder

 Cup/Spoon

 Push

- type rotary spreader

 Backpack Granule (herbicide)

EPA Reg. No. 33560

- 46 (Barespot)

49% sodium metaborate Product rate 3 lb product/100 ft 2

 PPE: eyewear/goggles, coveralls over long sleeve shirt and long pants, chemical resistant gloves, shoes/socks

 REI not specified

 No retreatment specified Active ingredient rate 1.5 lb sodium

metaborate/100 ft 2

653 lb sodium
metaborate/acre

Boron equivalent rate 105 lb boron/acre

Swimming Pools

Pour

- in Solid/Tablet

(antimicrobial)

EPA Reg. No. 1258

- 1276 (Endure)

100% sodium tetraborate pentahydrate Product rate 2 lb/1000 gallons water

 PPE: eyewear/goggles

 REI not applicable

 No retreatment specified Active ingredient rate 2 lb sodium tetraborate

pentahydrate/1000 gallons water

Boron equivalent rate 0.3 lb boron/1000

gallons (35 mg/L)

Materials Preservatives (Paints, Gypboard Coatings, Inks and Dyes)

Pour

- in Solid/Powder

(preservative)

EPA Reg. No. 1624

- 130 (Optibor Guard)

100% Boric acid Product rate 8% by weight of finished product

 PPE: not specified

 REI not applicable

 No retreatment specified Active ingredient rate 8% boric acid by weight

of finished product

Boron equivalent rate 1.4% boron by weight of

finished product

Wood Preservative (Pre

- construction/Lumber)

Pressure Treatment Emulsifiable

concentrate (preservative)

EPA Reg. No. 3008

- 120 (ORD

- 1302)

25% Disodium octaborate tetrahydrate Product rate 25% DOT in solution

 PPE: not specified

 REI not applicable

 No retreatment specified Active ingredient rate 25% DOT in solution

Boron equivalent rate 5.25% in solutionBoric Acid/Salts of Boric Acid Draft Risk Assessment DP No. D418384

Page 99 of 99 Table C .1. Summary of Registered Use Directions for Boric Acid and its Sodium Salts

Application Type/Equip/etc. Formulation

[Representative EPA Reg. No.] Maximum Application Rate 1 PPE/Work Attire, REI,
Retreatment

Dip Diffusion Solid/Powder (preservative)

EPA Reg. No. 74940

- 1 (Preservabalance)

99% Disodium octaborate tetrahydrate Product rate 280 lbs/100 gallons
solution

 PPE: not specified

 REI not applicable

 No retreatment specified Active ingredient rate 280 lbs DOT/100 gallons
solution

Boron equivalent rate 59 lb boron/100 gallons
solution

Sapstain Treatment Solution (preservative)

EPA Reg. No. 60061

- 122 (Timbertreat ICA

20)

20% Boric acid Product rate 20% boric acid solution  PPE: waterproof gloves, eye protection, long

sleeved shirt, long pants,
chemical

- resistant footwear, dust/mist respirator, chemical resistant apron

 REI not applicable

 No retreatment specified Active ingredient rate 20% boric acid solution

Boron equivalent rate 3.5 % boron solution

Remedial Wood Treatment (On

- site spray)

Manually pressurized
handwand Ready

- to

- use Solution

(antimicrobial)

EPA Reg. No. 19713

- 286 (Lum

- Bor)

98% Disodium octaborate tetrahydrate (DOT) Product rate 25% solution  PPE: waterproof gloves, eye protection, long

sleeved shirt, long pants, shoes, dust/mist respirator

 REI not applicable

 No retreatment specified Active ingredient rate 25% DOT solution (2.5

lb DOT/gallon solution)

Boron equivalent rate 0.525 lb boron/gallon
solution

T rowel or brush Ready

- to

- use Solution (antimicrobial)

EPA Reg. No. 83933

- 2 (Bioguard TriBor Paste)

45% Sodium tetraborate pentahydrate, 10%
boric acid Product rate 45% STP, 10% boric
acid

 PPE: not specified

 REI not applicable

 No retreatment specified Active ingredient rate 45% STP, 10% boric
acid

Boron equivalent rate 0.85 lb boron/gallon
solution