2

Table of Contents

EXECUTIVE SUMMARY

................................ ................................ ................................ ... 3

I. BACKGROUND

................................ ................................ ................................ ................... 7

II. INERT INGREDIENT PROFILE

................................ ................................ ......................... 7

A. Summary of Uses

................................ ................................ ................................ ....... 7

B. Physical Chemical Properties

................................ ................................ .................... 7

III. HUMAN HEALTH ASSESSMENT

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

A. Summary of Toxicity Data

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

B. Toxicity Endpoint Selection

................................ ................................ .................... 15

C. Special Considerations for Infants and Children

................................ ..................... 16

IV. EXPOSURE ASSESSMENT

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

A. Dietary Exposure:

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

i. Acute exposure

................................ ................................ ................................ ..... 17 ii. Chronic exposure

................................ ................................ ................................ . 18 iii. Cancer exposure

................................ ................................ ................................ . 19

B. Residential (Non

- Occupational) Exposure:

................................ ............................. 19

i. From non

- dietary exposure.

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

V. AGGREGATE RISK ASSESSMENT

................................ ................................ ................ 23

i. Acute Dietary Risk.

................................ ................................ ............................... 23

ii. Ch ronic Dietary Risk.

................................ ................................ .......................... 23 iii. Aggregate Cancer Risk for U.S. Population.

................................ ...................... 23

iv. Short

- term Aggregate Risk.

................................ ................................ ................ 23

v. Intermediate

- Term Aggregate Risk.

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

VI. OCCUPATIONAL EXPOSURE/RISK PATHWAY

................................ .......................... 25

A. Occupational Handler Risk

................................ ................................ ...................... 25

B. Occupational Post

- Application Risk

................................ ................................ ........ 27

VII. CUMULATIVE EXPOSURE

................................ ................................ ............................. 27

VIII. ENVIRONMENTAL JUSTICE STATEMENT

................................ ................................ .. 28

IX. ENVIRONMENTAL FATE CONSIDERATIONS

................................ ............................ 28

X. ECOTOXICITY

................................ ................................ ................................ ................... 30

XI. RISK CHARACTERIZATION

................................ ................................ ........................... 31
REFERENCES

................................ ................................ ................................ ................................ 35

APPENDIX

................................ ................................ ................................ ................................ ...... 383

EXECUTIVE SUMMARY

Pyxis Regulatory Consulting Inc. on behalf of United Phosphorus, Inc. (630 Freedom Business Center, Suite 402, King of Prussia, PA 19406) is requesting that EPA establish an exemption from the requirement of a tolerance for diisopropanolamine. Diisopropanolamin e also referred to as DIPA or 1,1’

- iminodiproan

- 2

- ol (CAS Reg. No. 110

- 97

- 4) is already approved as an inert ingredient for non

- food use pesticide formulations. Pyxis Regulatory Consulting Inc. is
request ing that EPA establish a tolerance exemption for the use of diisopropanolamine as an inert ingredient (neutralizer or stabilizer) at no more than 10% in pesticide formulations applied to pre

and post

- harvest crops in accordance with 40 CFR 180.910.

Diisopropanolamine, which will be here by referred to as DIPA, is widely used as an emulsifier , st abilizer, surfactant , and in chemical intermediates. The major uses of DIPA are as a scavenger for carbon dioxide and hydrogen sulfide in the purification of natural gas, and as a pH adjuster or as an emulsifier or viscosity modifier in personal care products ( e.g., c osmetics, tanning solutions, soaps, and detergents).

The acute oral toxicity of DIPA is low. The acute oral LD 50 s in rats were > 2000 mg/kg bw. The acute dermal toxicity in rats and rabbits were > 80 00 mg/kg bw

. DIPA is an eye irritant based on a primary eye irritation study in rabbits (Tox Category I). DIPA is dermally irritating based on primary skin irritation study in rabbits (Tox Category II) with erythema after 24 hours and scaling after 8 days. DIPA is not a dermal sensitizer and no acute inhalation studies were available in the
database.

Two subchronic oral toxicity studies using DIPA on rats were available. In the 14

- day non

guideline toxicity study the No Observerable Adverse Effect Level ( NOAEL ) was 600 mg/kg/day in males and females based on decreased bodyweight gain and relative kidney weight increases

seen at 1200 mg/kg/day. In the 90

- day OECD 408 ( OCSPP 870.3100 ) guideline study the NOAEL was 100 mg/kg/day ( males ) based on increase d absolute and relative kidney weights at 500 mg/kg/day and 500 mg/kg/day for females based on increases in absolute and relative kidney weigh ts at 1000 mg/kg/day. There was also a 28

- day dermal toxicity study, OECD 410 (OCSPP 870.3200)

, with DIPA in which the NOAEL was at limit dose of 750 mg/kg/day for systemic
effects.

In a developmental toxicity study in rats, OECD 414 (OCSPP 870.3700) with DIPA, no observable effects were seen at the limit dose of 1000 mg/kg/day for both mater n al a nd developmental toxicity.

In a n in vitro mammalian cell gene mutation test (OECD 476 ; OCSPP 870.5300 ), two
bacterial reverse mutation test s (OECD 471 ; OCSPP 870.5100 ) and an in vitro mammalian chromosomal aberration test (OECD 473 ; OCSPP 870.5375) ), results for mutagenicity and genotoxicity were negative for DIPA

.

Ther e was a carcinogenicity study in rats dosed at 1% (~1000 mg/kg/day) DIPA for 94
weeks. No increase in incidence of tumors over controls was observed under the conditions of the study.4 No immunotoxicity or neurotoxicity studies on DIPA were available in the database. However, evidence of immunotoxicity or neurotoxicity was not observed in the submitted studies.

A dermal metabolism and dermal absorption study on DIPA were provid ed. Based on the study, i.v. administration of radioactive labeled DIPA rapidly decreased in plasma and was
undetectable at 18 and 24 hours. 96.8% was excreted in urine and none was detectable in the feces. Dermal administration portion of the study determ ined that ~20% was absorbed within 48 hours. Most of the radiolabeled DIPA was excreted in urine. The application site contained 49% of the applied DIPA. Little DIPA was observed in the feces. The total recovered dose was 69.2%. The absolute dermal absorpt ion was calculated to be 12%.

EPA has also determined that reliable data show the safety of infants and children would be adequately protec ted if the FQPA SF were reduced to 1X.

An a cute dietary risk assessment was not conducted because no endpoint o f concern following a single or few exposures was identified in the available studies. A chronic dietary exposure assessment was completed and performed using the Dietary Exposure Evaluation Model

DEEM

- FCID TM , Version 3.16. The chronic R eference Dose (cRfD ) of 100 mg/kg/day was
determined on the basis of the subchronic oral toxicity study in rats . The LOAEL of 500 mg/kg/day DIPA is based on changed in absolute and relative kidney weights seen in males. This

s tudy provided the lowest NOAE L in the database ( most sensitive endpoint) and will also provide the most protective limits for human effects. An UF of 100X (10

- fold for interspecies extrapolation and 10

- fold for intra species variability) was applied to the NOAEL of 100 mg/kg/day to derive the cRfD. Th e FQPA safety factor of 1X is applicable for chronic dietary risk

assessment. Therefore, the chronic population

- adjusted dose (cPAD) is 1.0 mg/kg/day. This endpoint of concern was also used for all inhalation exposure scenarios. A NOAEL of 750 mg/kg/day fr om the 28

- day dermal toxicity study s howed no systemic toxicity, therefore dermal exposure is not considered a concern and quantification of dermal risk is not necessary

. De rmal absorption was determined to be 12 % based on the dermal absorption study and i nhalation absorption was assumed to be 100%

.

Based on analyses of estimated dietary risks (I

- DEEM) for the general U.S. population and various population subgroups, the chronic dietary exposure estimates for DIPA are significantly below the Agency’s leve l of concern for all supported commodities. The chronic dietary exposure estimate for the highest exposed population subgroup, children 1

- 2 years old is 14.1% of the chronic population adjusted dose (cPAD) and 3.8% for the general population

.

The Agency’ s level of concern (LOC) for DIPA occupational and residential inhalation exposures is 100 [i.e., a margin of exposure (MOE) greater than 100 is not of concern to EPA ]. The LOC is based on a 10X uncertainty factor (UF) to account for interspecies extrapolation to humans from the animal test species and 10X UF to account for intra

- species sensitivity.

Short

- term aggregate exposure takes into account short

- term residential exposure plus chronic exposure to food and water (considered to be a backgrou nd exposure level). DIPA may be used as an inert ingredient in pesticide products that could result in short

- term residential exposure.5

The Agency has determined that it is appropriate to aggregate chronic exposure through food and
water with short

- term re sidential exposures. Using the exposure assumptions described in Section IV, EPA has calculated the combined short

- term aggregated food, water, and residential exposures.
The adult short

- term aggregate MOE was calculated to be 2600 for both males and femal es. Adult aggregate MOE combines average food and water exposure from the chronic dietary exposure with high end residential applicator exposure ( liquid hose end sprayer ). As the level of concern is for MOEs that are lower than 100, this MOE is not of conc ern. EPA has concluded the combined
short

- term aggregated food, water, and residential exposures results in an aggregate MOE of 680 for children. Children’s aggregate MOE combines average food and water exposure from the chronic dietary exposure with resid ential exposure associated with contact with threated lawns (hand

- to

- mouth). As the level of concern is for MOEs that are lower than 100, these MOEs are not
of concern.

Intermediate

- term aggregate exposure takes into account intermediate

- term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). DIPA may be used as an inert ingredient in pesticide products that could result in intermediate

term residential exposure. The Agency has determined that it is appropriate to aggregate chronic exposure through food and water with intermediate

- term residential exposures. Using the exposure assumptions described in section IV EPA has calculated the combined intermediate

- term aggregated food, water, and residential exposures. The adult intermediate

- term aggregate MOE
was calculated to be 2600 for both males and females. Adult aggregate MOE combines average food and water exposure from the chronic dietary exposure with high end residential applicator exposure ( liquid hose end sprayer ). As the level of concern is for MOEs that are lower than 100,
this MOE is not of concern. EPA has concluded the combined intermediate

- term aggregated food, water, and residential exposures results in an aggregate MOE of 690 for children. Children’s aggregate MOEs combine average food and water exposure from the chronic dietary exposure with residential exposure associated with contact with threated lawns (hand

- to

- mouth,). As the level of concern is for MOEs that are lower than 100, these MOEs are not of concern.

Occupational handler risks are not of concern for all scenarios. It is noted that this occupational handler assessment assumes that mixer/loader/applicators are not wear ing protective respirators when using open pour in support of aerial and groundboom application. The estimated

MOEs a re greater than 100 based on 100% inhalation absorption . Therefore, the estimated MOEs do not exceed the Agency’s level of concern. This assessment is considered to b e a screening level estimate, demonstrating that there are minimal potential risks to workers re

- entering fields treated with pesticides containing DIPA as inert ingredients. Therefore an occupational post application risk assessment was not performed.

Ba sed on the ready biodegradability of DIPA in an OECD 301F (OCSPP 835.3110) guideline study

, 94% of DIPA was biodegraded in 28 days and 60% in 10 days

. In an Zahn

Wellens/EMPA Test, OECD 302B (OCSPP 835.3200) guideline study, 90

- 100% biodegraded in

7

- days, therefore effects of concern to nontarget aquatic species resulting from the use of DIPA as
an iner t ingredient are not expected . Acute toxicity st udies performed with DIPA on fish, invertebrates and algae showed that the compound was practically nontoxic. DIPA has a low potential for bioaccumulation based on the low Kow values and has an estimated Bioconcentration6

Factor ( BCF ) of 3. Diisopropanolamine (DIPA) is not expected to pose an environmental fate concern due to its biodegradability.

Based on studi es conducted with various species of fish ranging from 24 hour to 96 hour exposures, DIPA is considered to be practically nontoxic to freshwater species. Freshwater fish acute toxicity LC 50 s are > 100 mg/L. Studies conducted with Daphnia magna , DIPA is exp ected to be practically non

- toxic to aquatic invertebrates. Freshwater invertebrate acute toxicity EC 50 s are > 270 mg/L. DIPA is also not expected to be toxic to non

- target aquatic plants based on testing
with Scenedesmus subspicatus . The 72

- hour EC 50 was 270 mg/L (growth rate, nominal).

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 Ju stice in Minority Populations and Low

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

Taking into consideration all available inf ormation on DIPA , EPA concludes that there is a reasonable certainty that no harm to any population subgroup will result from aggreg ate exposure
to DIPA when considering residential, occupation al , dietary exposure and all other non

occupational sources of pesticide exposure for which there is reliable information. Therefore, the
establishment of an exemption from tolerance under 40 CFR 180.910 for residues of diisopropanolamine (CAS Reg. No. 110

- 97

- 4 ) when used as a pesticide inert ingredient at no more than 10% in formulations when applied to pre

- or post

- harvest crops can be considered assess ed as safe under section 408(q) of the FFDCA.7

I. BACKGROUND

Pyxis Regulatory Consulting Inc. on behalf of United Phosphorus, Inc . ( 630 Freedom Business Center, Suite 402, King of Prussia, PA 19406 ) is requesting that EPA establish an exemption for diisoprop anolamine non

- food use

. Diisopropanolamine also referred to as DIPA or 1,1’

- iminodiproan

- 2

- ol (CAS Reg. No. 110

- 97

- 4 ) is already approved as an inert ingredient for

non

- food use pesticide formulations

. Pyxis Regulatory Consulting Inc. request that EPA expa nd it to include use as an inert ingredient (neutralizer or stabilizer) at no more than 10% in pesticide
formulations in accordance with 40 CFR 180.9 10 which is applied to pre

- and post

- harvest crops

.

II. INERT INGREDIENT PROFILE

A. Summary of Uses
Diisopropanolamine, which will be here by referred to as DIPA, is widely used as an emulsifier, stabilizer, surfactant , and in chemical intermediates. The major uses of DIPA are as a scavenger for carbon dioxide and hydrogen sulfide in the purification of natural gas, and as a pH adjuster or as an emulsifier or viscosity modif ier in personal care products (e.g., c osmetics, tanning solutions, soaps, and detergents).

B. Physical Chemical Properties
Some of the physical and chemical characteristics of DIPA , alon g with its structure and nomenclature, are found in Table 1.

Table 1. P hysical and Chemical Properties of Diisopropanolamine (DIPA)

Parameter Value Source

Structure ChemIDplus

CAS # 110

- 97

- 4 ChemIDplus

Molecular Formula C 6 H 15 NO 2 ChemIDplus Molecular Weight (g/mol) 133.189 ChemIDplus

Common Names 1,1’

- iminodiproan

- 2

- ol; DIPA ChemIDplus

Color White (room temperature) Colorless (>44°C) Dow Technical Data Sheet

Physical State Solid (room temperature) Liquid (>44°C) Dow Technical Data Sheet

Odor Slight ammonia

- like Dow Technical Data Sheet

Flash Point 136°C (Setaflash closed cup) Dow MSDS pH 11 (1% aqueous solution) Dow MSDS8

Table 1. P hysical and Chemical Properties of Diisopropanolamine (DIPA)

Parameter Value Source Viscosity (dynamic) 86 cps (at 60°C) Dow MSDS Melting Point 42°C Dow Technical Data Sheet Boiling Point (°C) @ 19 hPa 249°C (at 1013 hPa) Dow Technical Data Sheet Specific Gravity 0.992 (at 40/4°C) Dow MSDS Liquid Density 8.27 lb/gal (at 25°C) Dow MSDS Dissociation Constant (pK
a ) pK a 9.1 (at 25°C) SIDS for Isopropanolamines

Octanol/water Partition Coefficient (K
ow ) Log K ow - 0.82 Dow MSDS

Soil organic carbon/water Partition coefficient (Koc) 1 (estimated) Dow MSDS

Solubility (at 25°C) 1200 g/100 g water 810 g/100 g acetone 9 g/100 g ethanol 670 g/100 g methanol DOW DIPA Product Safety

Assessment

Vapor Pressure 0.035 mm Hg (at 50°C) Dow MSDS

Henry's Law Constant 2.52E

- 11 atm*m3/mole (at 25°C)
estimated Dow MSDS

III. HUMAN HEALTH ASSESSMENT

A. Summary of Toxicity Data

Acute Oral Toxicity In an acute oral toxicity study, f emale rats were treated with a single 2000 mg/kg dose of
DIPA. The acute oral LD 50 in female rats was > 2000 mg/kg (BASF 1993)

.

In another acute oral toxicity study, the acute oral LD 50 in rats was reported as 6720 mg/kg (Union Carbide 1968)

.

In another acute oral toxicity study, the acute oral LD 50 in rats was reported to be approximately 6000 mg/kg (CASF 1965)

.

Dermal Toxicity In an acute dermal toxicity study, female Harlan

- Wistar rats were tested with undiluted
DIPA on intact skin. The dose site was covered and the test material was left in contact
with the test site for 4 hours. The LD 50 was calculated using the moving average method based on a 14 day observation period. The LD 50 wa s determined to be 16,000 mg/kg (Union Carbide 1974)

.

In another acute dermal toxicity study, four male rabbits per dose were treated with undiluted DIPA at dose levels of 4000, 8000 or 16000 mg/kg on clipped intact skin. The
test site was covered with an impervious sheet. All four rabbits died in the 16,000 mg/kg group and 2/4 died in the 8000 mg/kg group. There were no deaths in the 4000 mg/kg group. Gross pathology of decedents showed congestion of lungs, liver, spleen and kidneys, mottled livers and opaque stomachs. The LD 50 was 8000 mg/kg (RTECS 1979)

.9 Inhalation Toxicity

No inhalation studies available in the database.

Primary Eye Irritation In an unpublished primary eye irritation study summarized in DOW HPV summary, DIPA
was concluded to be an eye irritant when tested on rabbits (Huels 1985)

In another primary eye irritation study on rabbits with DIPA, burns of the mucous membranes of the eye and corneal opacity were reported. DIPA was concluded to be an eye
irritant (Burkackaja et al. 1986).

Primary Skin Irritation In an acute dermal irritation study, rabbits were tested with 80% DIPA rubbed with water. Distinct erythema was observed after 24 hours and scaling after 8 days. DIPA was
concluded to be irritating to rabbit’s skin (BASF 1965)

.

In another skin irritation study, undiluted DIPA was applied to intact rabbit skin for at least
4 hours under a semi

- occlusive dr essing. In another study, D IPA was applied to intact rabbit skin for an undefined prolonged period under an occlusive dressing. No skin irritation was observed after undiluted DIPA was applied to skin for 4 hours under a semi

occlusive patch; however, when it was applied under occlusive conditions for a “prolonged” period hyperemia and necrosi s or denaturation were observed (Huels 19 85)

.

Dermal Sensitization

In a dermal sensitization study, t he Buehler method was followed using guinea pigs. Ten male Hartley albino guinea pigs received three dermal applications of 0.4 ml of 50% DIPA in distilled water over a three week induction perio d. Two weeks after the last induction application, a challenge application of 0.4 ml of 50% DIPA was applied. The test site was evaluated for dermal irritation 24 and 48 hours after the challenge application. DIPA did not cause erythema 48 hours after appl ication of the challenge dose. It was concluded that under the conditions of the study, DIPA did not cause delayed contact hypersensitivity in guinea pigs (Dryzga 1987)

.

The results of the available acute toxicity s tudies are summarized in Table 2

.
Acute Toxicity

Table 2 . Acute Toxicity Profile of Diisopropanolamine (DIPA)

Study Type Results Toxicity Category
MRIDs # /Reference

Acute Oral

- rat LD 50 (female) = 2000 mg/kg bw III BASF 1993

LD 50 = 6720 mg/kg bw IV Union Carbide 1968

LD 50 ( fe male) = 6000 mg/kg bw IV BASF 1965

Acute Dermal

– rats/rabbits LD 50 (rats ) = 16000 mg/kg bw IV Union Carbide 1964

LD 50 (rabbits ) = 8000 mg/kg bw IV RTECS 1979

Acute Inhalation

- N/A N/A N/A N/A Eye irritant N/A Huels 198510

Table 2 . Acute Toxicity Profile of Diisopropanolamine (DIPA)

Study Type Results Toxicity Category
MRIDs # /Reference Primary Eye Irritation

- rabbit Eye irritant I Burkackaja et al. 1986

Primary Skin Irritation

- rabbit Erythema after 24 hours and scaling after 8 days. Irritating to
rabbit skin II BASF 1965

Undiluted DIPA under semi

occlusive patch no skin
irritation. Under occlusive conditions, hypermia and
necrosis observed. N/A Huels 1985

Dermal Sensitization Not a dermal sensitizer N/A Dryzga 1987

Subchronic Toxicity

- In a 14

- day subchronic oral toxicity study, groups of Fischer 344 rats (5/sex/group) were administered DIPA in their drinking water at levels of 0, 100, 300, 600, 1200 or 3000 mg/kg/day for 14 days. Rats were observed for clinical signs of toxicity twice per day. Rats were fasted pri or to sacrifice. Clinical chemistry parameters were measured. A complete necropsy was performed and brain, heart, liver, kidney, thymus and testes were weighed. The kidneys, liver and urinary bladder from all rats were examined microscopically. At 3000 mg/ kg/da y, two of five males died. B ody weight loss and markedly decreased food and water consumption were observed in both sexes. Histopathological examination of the kidneys of these animals revealed acute inflammation and degeneration in the kidneys and

ur inary bladder. These findings were slight in severity and probably due to decreased water consumption. At 1200 mg/kg/day, male and female rats had slightly decreased food and water consumption and decreased bodyweight gain in males. Kidney weights were
inc reased in both sexes and one male rat had kidney “alteration” similar to what was seen at 3000 mg/kg/day. The NOAEL was 600 mg/kg/day in both males and females based on the effects observed at 1200 mg/kg/day (McCollister et al. 1981)

.

In a 90

- day subchron ic oral toxicity study (EPA OCSPP 870.3100/OECD 408) , groups of Fischer 344 rats (10/sex/group) were administered DIPA in their drinking water at levels of 0, 100, 500 or 1000 mg/kg/day for 13 weeks. An additional 10 rats/sex/group were used for a 4 week recovery group. Animals were monitored for clinical s igns, body weights and food consumption. Hematology, clinical chemistry, and urinalysis parameters were examined and ophthalmic examinations were conducted. Selected organ weights were recorded and histopathological examinations of selected tissues were co nducted. Body weight, body weight gain and food consumption were unaffected by treatment. Water consumption was lower at the high dose compared to control groups but was not statistically significant. Cholesterol, albumin and phosphorus levels were statist ically elevated in males at the high dose, but not in females. In addition, urine specific gravity was statistically higher in both sexes at the high dose which is likely related to decreased water consumption. Absolute and relative kidney weig hts were sta tistically increase d in male and female rats at 500 and 1000 mg/kg/day. In males, absolute kidney weights were
also statistic ally increased , 9.8% at 100 mg/kg/day , 16.2% at 500 mg/kg/day and 20.9% at 1000 mg/kg/day . No pathology findings were found upon ei ther macroscopic or11 microscopic examination of organs/tissues. Based on effects on absolute and relative kidney weights at 500 and 1000 mg/kg/day, the NOAEL for males is 100 mg/kg/day. The NOAEL for females was 500 mg/kg/day based on absolute and relative kidney weights observed at 1000 mg/kg/day (Johnson et al. 2007)

.

In a 28

- day dermal toxicity study (EPA OCSPP 870.3200/OECD 410) , DIPA was dermally applied to groups of Fischer 344 rats (5/sex/group) at dose levels of 0, 100, 500 or 750 mg/kg/day five day s/week for 4 weeks. The application site was clipped free of hair and covered with an occlusive wrap during the dosing period (6 hours) each day. The test material was made up in deionized water weekly. Skin reactions were graded and recorded
at the end of each week. Animals were monitored for clinical signs, body weights and food consumption. Hematology, clinical chemistry, and urinalysis parameters were examined and ophthalmic examinations were conducted. Selected organ weights were recorded and histopath ological examination of selected tissues was conducted. There were no treatment

related effects on body weight, body weight gain or food consumption. Hematology, clinical chemistry and urinalysis parameters were unaffected by treatment. There were no
findi ngs upon necropsy or microscopic examination of selected organs/tissues, except for skin changes. Erythema (graded very slight to slight) was noted for all five males and three females treated with 750 mg/kg/day and two males and two females treated with 5 00 mg/kg/day. Scabs were seen at the treatment site of one male at 500 mg/kg/day and two at
750 m g/kg /day and two females at 500 mg/kg/day and three at 750 mg/kg /day. Microscopically, slight hyperkeratosis of the treated site was seen in all rats at 750

mg /kg/day and very slight hyperkeratosis in two ma les and two females at 500 mg/kg /day. The NOAEL for systemic effects was the hig hest dose tested, 750 mg/kg/day (Johnson et al. 2007)

.

Developmental Toxicity

- In a developmental toxicity study (EPA OCSPP 87 0.3700/OECD 414), time

- mated Fischer

3 44 rats (25/sex/group) were administered DIPA by gavage on gestation days 6 through 20 at dose levels of 0, 100, 300 or 1000 mg/kg. Dams were monitored for clinical signs daily and body weight and food consumption peri odically. On gestation day 21, the dams were sacrificed, examined grossly and weights of liver, kidney and gravid uterus were recorded. The number of corpora lutea, uterine implantation, resorptions and live/dead fetuses were
determined. The fetuses were w eighed, sexed and examined for external findings. Approximately one

- half of the fetuses were examined for visceral and craniofacial alternations and the remaining fetuses were examined for sk eletal alterations. Treatment
with DIPA had no effect on body wei ght gain or food consumption during the dosing period, kidney or liver weights, gravid uterine weight, number of corpora lutea, implantations or resorptions, % pre

- and post

- implantation loss, mean fetal weight or males or females, fetal sex ratio or the n umber of viable fetuses. There were no statistically significant increases in abnormalities (external, visceral or skeletal) in any treatment group

c ompared to the control. Class II wavy ribs were observed in one fetus in the 300 mg/kg group. Hydroureter was observed in one fetus in the 100 mg/kg group and one fetus in the high dose group. However, they were within the normal range. The NOAEL was 1000 mg/kg for both mate rnal and developmental toxicity (Johnson et al. 2007)

.12 Mutagenicity and Genotoxicity

In an in vitro mammalian cell gene mutation test (EPA OCSPP 870.5300/OECD 476), DIPA was tested for its potential to induce gene mutations at the HGPRT locus of Chinese hamster ovary cells at concentrations of 0, 313, 625, 1250, 2500 and 5000 μg/ml with an d without metabolic activation. DIPA did not induce a mutagenic response un der the conditions of the study (Cifone, M. 1994)

.

In a bacterial reverse mutation test (EPA OCSPP 870.5100/OECD 471), DIPA was tested in the Ames Salmonella mutation assay in test er strains TA98, TA199, TA1535 and TA1537. Concentrations tested were 0, 100, 333, 667, 1000, 3330 and 5000 μg/plate both in the presence and absence of metabolic activation. DIPA was negative for inducting
mutations in all tester strains both with and wit hou t metabolic activation (Lawlor, T. 1994)

.

In a bacterial reverse mutation test (EPA OCSPP 870.5100/OECD 471), DIPA was tested in the Ames Salmonella preincubation assay using tester strains TA1535, TA1537, TA97
and TA100 with and without metabolic acti vation (S

- 9). A preliminary dose

- setting test
was conducted. The doses tested were 0, 33, 100, 333, 1000, 3333 and 10000μg/plate in the presence and absence of S

- 9. DIPA was negative in the Ames Salmonella preincubation assay both with and without metaboli c activation (Mortelmans et al. 1986)

.

In an in vitro mammalian chromosomal aberration test (OCSPP 870.5375/OECD 473), the clastogenic potential of DIPA was evaluated using rat lymphocytes. Cell treatment time was 4 hours in the presence and absence of me tabolic activation. The cultures were harvested 24 hours after cessation of treatment. Cultures treated with 0, 313, 625 and 1250 μg/ml in the presence of metabolic activation and cultures treated with 0, 1250, 2500 and 5000 μg/ml in the absence of metabol ic activation were selected for evaluation based on mitotic indices. Confirmatory assays were conducted with two harvest periods of 24 and 48 hours after treatment. Concentrations tested were 0, 313, 625 and 1250 μg/ml at 24 hours and 0 and 1250 μg/ml at 4 8 hours. No significant increase in abnormal cells was observed in any of the assays. The positive controls, cyclophosphamide and mitomycin C produced the expected responses. DIPA was considered negative for inducting chromosomal
aberrations in rat lymphoc ytes (Murli 1994).

Carcinogenicity In a carcinogenicity study, a g roup of 20 male Wistar rats was administered DIPA in the
diet at a concentration of 1% (~1000 mg/kg/day) for 94 weeks. Another group of 20 male rats received untreated diet for the same time period. At the end of the 94 week period, the rats were sacrificed by exsanguination under ether anesthesia and a complete necropsy was performed. Body weight, daily int ake of diet and water were recorded. All major organs, including the lung, heart, thymus, thyroid, salivary gland, esophagus, liver, stomach, duodenum, small and large intestines, pancreas, spleen, kidney, adrenal gland, pituitary, brain, testis, epididymi s, prostate, urinary bladder, skin containing the mammary gland and the nasal cavity were examined histologically. Mortality was unaffected by treatment. A total of 19 males rats survived in the control group and 16 in the treated group. Bodyweight, diet i ntake and water consumption were unaffected by treatment. The only tumors occurring in the DIPA treated group were 2 adrenal gland tumors13 (pheochromocytoma) and 6 tumors of the testes (Leydig cell). The control group had 4 pheochromocytomas and 9 Leydig ce ll tumors. DIPA did not increase the incidence of tumors at any site evaluated under the conditions of this study (Yamamoto et al. 1989)

.

Reproductive Toxicity No reproductive studies were available in the database for DIPA , however, no effects were observed on reproductive organs including histopathological examination in subchronic studies and also no effects on reproductive parameters in the developmental toxicity study
in rats at the limit dose.

Immunotoxicity
No i mmuno toxicity studies were available in the database for DIPA

. However, evidence of immunotoxicity was not observed in the submitted studies.

Neurotoxicity

No neurotoxicity studies were available in the database for DIPA

. However, evidence of neurotoxicity was not observed in the submitted studies.

Metabolism and Pharmacokinetics In a dermal metabolism and dermal absorption study (non

- guideline), 14 C

- labeled DIPA (>99.5% purity) with a specific activity of 75μCi/mg was administered to fem ale Fischer 344 rats (~10 weeks old) via an i.v. dose of 19 mg/kg (~5μCi) or 19.5 mg/kg (~19μCi) dermally to a shaved area on their backs. Four rats were used for each dosing regimen. Blood, urine, feces, expired air and tissues from the dermally dosed ani mals (liver, kidney, perirenal fat and skin) were collected and analyzed for levels of radioactivity. After i.v. administration, the radioactivity rapidly decreased in plasma and was undetectable at 18
and 24 hours. The half

- live of the rapid initial phase was 0.39 hour s . An average of 96.8%
of the r adioactivity was excreted in the urine with 71.3% eliminated within 6 hours and
93.1% within 12 hours. Greater than 99% of the excreted radioactivity was unchanged DIPA. No radioactivity was observed in the fece s. Following dermal application, ~10% of the dose was absorbed within 38 hours with a steady

- state penetration rate of ~0.2%/hour. Most of the applied radioactivity was excreted in the urine at a constant rate. The application site contained a large amount of radioactivity 49%. Little radioactivity ( <0.2% of the dose) was observed in the feces. DIPA did not accumulate in tissues with ~0.1% of the dose observed in liver and kidney. Dermally applied DIPA was not volatile and none of the applied radioactivity was found as CO 2 . Total recovery of the applied dose was 69.2% which is a reflection of the low recovery (48%) observed in one rat. The absolute dermal absorption of DIPA was concluded to be 12% (Saghir et al. 2007)14

Table 3 . Toxicology Profile of Diisopropanolamine (DIPA) Guideline No./ Study Type Doses Levels Results MRID No. (year)/References 14 Day oral toxicity

– rats (drinking water)

Non

- guideline 0, 100, 300, 600,

1200 or 3000 mg/kg/day NOAEL 600 mg/kg/day in males and

females

LOAEL 1200 mg/kg/day based on decreased food and water consumption, decreased body weight gain in males and relative kidney weights increased in both

sexes. McCollister et al.
1981

90 Day oral toxicity study

– rats (drinking water)

OCSPP 870.3100
OECD 408 0, 100, 5 00 or 1000 mg/kg/day NOAEL (males) 100 mg/kg/day

LOAEL (males) 500 mg/kg/day based on increase in absolute and relative kidney weight. Johnson et al. 2007

28 Day dermal toxicity study

– rats
OCSPP 870.3200

OECD 410 0, 100, 500 or 750 mg/kg/day; 5 days/week for 4
weeks NOAEL 750 mg/kg/day for systemic

effects

. Johnson et al. 2007

Developmental Toxicity study

– rats (gavage)

OCSPP 870.3700

OECD 414 0, 100, 300 or 1000 mg/kg/day NOAEL 1000 mg/kg/day for both maternal

and developmental toxicity Joh nson et al. 2007

In vitro mammalian cell gene mutation test

– Chinese hamster ovary
cells

OCSPP 870.5300
OECD 476 0, 313, 625, 1250, 2500 and 5000 μg/ml
with and without
metabolic activation Negative Cifone 1994

Bacterial reverse
mutation test

OCSPP 870.5100

OECD 471 0, 100, 333, 667, 1000, 3330 and 5000 μg/plate with and
without metabolic
activation Negative Lawlor 1994

Bacterial reverse
mutation test
OCSPP 870.5100

OECD 471 0, 33, 100, 333, 1000, 3333, 10000 μg/plate
with and without
metabolic activation Negative Mortelmans et al.
1986

In vitro mammalian
chromosomal
aberration test

OCSPP 870.5375

OECD 473 0, 313, 625 and 1250 μg/ml at 24 hours and 0 and 1250 μg/ml at
48 hours Negative Murli 1994

Carcinogenicity in rats

Non

- guideline 1% (~1000 mg/kg/day) for 94
weeks No increase in incidence of tumors on

controls at any site evaluated under the conditions of this study. Yamamoto 1989
and 199115

Table 3 . Toxicology Profile of Diisopropanolamine (DIPA) Guideline No./ Study Type Doses Levels Results MRID No. (year)/References

Dermal Metabolism and Dermal Absorption study

Non

- guideline 19 mg/kg (~5μCi) i.v. 19.5 mg/kg (~19μCi) dermal application i.v. administration: radioactivity rapidly

decreased in plasma and undetectable at 18
and 24 hours.96.8% excreted in urine none
detectable in feces.
Dermal administration: ~20% was absorbed
within 48 hours. Most excreted in urine. Appli cation site contained 49%. Little was
observed in feces. Total recovered dose was 69.2%. Absolute dermal absorption was
12%. Saghir 2007

B. Toxicity Endpoint Selection

The 90

- day subchronic oral toxicity study in rats was selected for dietary and inhalation exposure scenarios (all durations) for this risk assessment. The NOAEL in this study was 100 mg/kg/day. The LOAEL was 500 mg/kg/day based on increases in absolute and relative kidney weights . The rationale for selecting this study for the dietary, oral and inhalation exposure scenario is based on the fact that this study provided the lowest and most conservative toxicity endpoint.

No dermal endpoint of concern was identified in the availabl e database since there was no systemic toxicity in the 28

- day dermal toxicity study at doses up to 750 mg/kg/day (the highest dose tested) and relatively low dermal absorption ( 12% ) . A default 100 % inhalation absorption will be used for inhalation exposure scenarios.

T able 4

. Summary of Toxic ological Doses and Endpoints of Diisopropanolamine (DIPA) for Use in Human
Health Risk Assessment Exposure/Scenario Point of Departure and Uncertainty/Safety Factors RfD, PAD, LOC
for Risk
Assessment Study and Toxicological
Effects

Acute dietary (General population including infants and children) An acute effect was not found in the database therefore an acute dietary assessment is
not necessary.

Chronic dietary (All populations) NOAEL= 100 mg/kg/day

UF A = 10 x UF H = 10 x FQPA SF = 1 x Chronic RfD =
100 mg/kg/day

cPAD = 1.0 mg/kg/day [ 90

- day oral toxicity

- rat ]

LOAEL = 500 mg/kg/day based

on increase in relative and absolute kidney weight

.

Incidental oral short

- term (1 to 30 days) NOAEL= 100 mg/kg/day

UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE =

100 [ [ 90

- day oral toxicity

- rat ]

LOAEL = 500 mg/kg/day based
on increase in relative and absolute kidney weight.

Incidental oral
intermediate

- term (1 to 6 months) NOAEL= 100 mg/kg/day

UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE =

100 [ 90

- day oral toxicity

- rat ]

LOAEL = 500 mg/kg/day based
on increase in relative and absolute kidney weight.16

T able 4

. Summary of Toxic ological Doses and Endpoints of Diisopropanolamine (DIPA) for Use in Human
Health Risk Assessment Exposure/Scenario Point of Departure and Uncertainty/Safety Factors RfD, PAD, LOC
for Risk
Assessment Study and Toxicological
Effects

Dermal short

- and
intermediate term Dermal exposure was not assessed because no systemic toxicity was identified a t doses
up to 750 mg/kg/day in a dermal toxicity study.

Inhalation short

- term (1 to 30 days) O ral study NOAEL= 100 mg/kg/day (inhalation absorption rate = 100%)

UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE =

100 [ 90

- day oral toxicity

- rat ]

LOAEL = 500 mg/kg/day based
on increase in relative and absolute kidney weight.

Inhalation (1 to 6 months) O ral study NOAEL = 100 mg/kg/day (inhalation absorption rate = 100%)

UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE =
100 [ 90

- day oral toxicity

- rat ]

LOAEL = 500 mg/kg/day based
on increase in relative and absolute kidney weight.

Cancer (Oral, dermal, inhalation) Based on the lack of increased incidence of tumor formation compared to controls in a carcinogenicity study and the lack of mutagenicity, DIPA is considered not likely to be carcinogenic.

UF A = extrapolation from a nimal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (i ntraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of data or other data deficiency. FQPA SF = Food Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference do se. MOE = margin of exposure. LOC = level of concern.

C. Special Considerations for Infants and Children
FFDCA, as amended by FQPA, directs the Agency to use an additional 10X safety factor (SF), to account for potential pre

- and postnatal toxicity and comp leteness of the data with respect to exposure and toxicity to infants and children. FQPA authorizes the Agency to modify the 10X FQPA SF only if reliable data demonstrate that the resulting level of exposure would be safe for infants and children. EPA conc ludes that the FQPA safety factor could be reduced to 1X for DIPA for the following reasons:

i. The toxicity database for DIPA contains the following acceptable studies: subchronic, developm ental , and chronic/carcinogenicity studies

, several mutagenicity
studies , and a dermal metabolism and absorption studies

. No repeated dose inhalation toxicity study is available in the database, however all inhalation MOEs, which are based
on the POD from the 90

- day oral toxicity study, are greater than 15,000. The Age ncy does not believe that any inhalation study would provide a POD so substantially different from
the POD in the 90

- day oral toxicity study to result in a risk of concern from inhalation exposure; therefore, there is no need to include an additional uncer tainty factor to account
for the lack of inhalation data.

ii. Maternal and developmental toxicity was not observed at the limit dose of 1000 mg/kg/day in rats. No reproductive studies were available in the database for DIPA, however, no effects were obser ved on reproductive organs including histopathological17 examination in subchronic studies and also no effects on reproductive parameters in the developmental toxicity study in rats at the limit dose

.

iii. There is no indication that DIPA is a neurotoxic chemical. Although no neurotoxicity studies were available in the database, no clinical signs of neurotoxicity were observed in the available subchronic and chronic studies. Therefore, there is no need for a developmental neurotoxicity study or additiona l UFs to account for neurotoxicity.

iv. There is no indication that DIPA is an immunotoxic chemical. Although no immunotoxicity studies were available in the database, no signs of immunotoxicity were observed in the available studies. Therefore, there is no need for a immunotoxicity study or additional UFs to account for immunotoxicity.

v. The dietary food exposure assessment utilizes proposed tolerance leve l or higher residues and 100% crop treated information for all commodities. By using these screening

level assessments, chronic exposures/risks will not be underestimated.

Taking into consideration the available information, EPA concludes the additional 10X FQPA safety factor can be reduc ed to 1X.

IV. EXPOSURE ASSESSMENT

The petitioner has requested use of DIPA with a limitation of 10% maximum in pesticide
formulation. The petitioner request ed the ability to use DIPA in any type of pesticide i.e., insecticide, fungicide or herbicide on any application site i.e., agricultural crops, livestock,
residential uses indoor and outdoor. The petitioner did not provide any exposure or risk assessments regarding human occupational or residential exposure. Resources con straints prohibit the Agency fro m conducting monographic, “all

- inclusive” assessments of exposure for all possible or imaginable combinations of methods of application to all possible application sites.

Therefore, the Agency has conducted a “screening

- level” assessment of a wide variety o f sites and use patterns in an effort to obtain a qualitative idea of the possible results of human exposures that might result from such combinations of method s of application and
site s of application.

It should be noted again, as indicated from the ea rlier discussion of toxicological properties, that the data and information regarding toxicological effects are limited. Thus the “screening

- level” assessment is based upon some conservative assumptions.

A. Dietary Exposure:

i. Acute exposure . No adverse effects attributable to a single exposure of DIPA were seen in the toxicity databases. Therefore, acute dietary risk assessment for DIPA is not required.18 ii. Chronic exposure

. The chronic dietary exposure assessment for this inert ingredie nt utilizes the Dietary Exposure Evaluation Model Food Commodity Intake Database (DEEM

- FCID), Version 3.16, EPA, which includes food consumption information from the U.S. Department of Agriculture’s national health and Nutrition Examination Survey,
“What W e Eat In America”, (NHANES/WWEIA) . This dietary survey was conducted from

2003 to 2008

. In the absence of actual residue data, the inert ingredient evaluation is based on a highly conservative model which assumes that the residue level of the inert ingredi ent would be no higher than the highest established tolerance for an active ingredient on a given commodity. As to residue levels in food, n o residue data were submitted for DIPA. In the absence of specific residue data, EPA has developed an approach which uses surrogate information to derive upper bound exposure estimates for the subject inert ingredient. Upper bound exposure estimates are based on the highest tolerance for a given commodity from a list of high

- use insecticide s, herbicides, and fungicides. A complete description of the general approach taken to assess inert ingredient risks in the absence of residue data is contained in the memorandum entitled “Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water) D ietary Exposure and Risk Assessments for the Inerts.” (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA

- HQ

- OPP

- 2008

- 0738.

In the dietary exposure assessment, the Agency assumed that the residue level of the inert ingredient would be no higher than the highest t olerance for a given commodity. Implicit in this assumption is that there would be similar rates of degradation (if any) between the active and inert ingredi ent and that the concentration of inert ingredient in the scenarios leading to these highest of tolerances would be no higher than the concentration of the active ingredient.

The Agency believes the assumptions used to estimate dietary exposures lead to an extremely conservative assessment of dietary risk due to a seri es of compounded
conservatisms. First, assuming that the level of residue for an inert ingredient is equal to the level of residue for the active ingre dient will overstate exposure. The c oncentration of active ingredients in agricultural products is generally at least 50 percent of the product and often can be much higher. Further, pesticide products rarely have a single inert ingredient; rather there is generally a combination of differen t inert ingredients used which additionally reduces the concentration of any single inert ingredient in the pesticide product
in relation to that of the active ingredient. In the case of DIPA , EPA made a specific adjustment to the dietary exposure assessme nt to account for the use limitations of the
amount of DIPA that may be in formulations (no more than 1 0% by weight in pesticide and
assumed that the DIPA is present at the maximum limitations rather than at equal quantities with the active ingredient.

Second, the conservatism of this methodology is compounded by EPA’s decision to assume that, for each commodity, the active ingredient which will serve as a guide to the potential level of inert ingredient residues is the active ingredient wit h the highest tolerance level. This assumption overstates residue values because it would be highly unlikely, given the high number of inert ingredients, that a single inert ingredient or class of ingredients would19 be present at the level of the active ingredient in th e highest tolerance for every commodity. Finally, a third compounding conservatism is EPA’s assumption that all foods contain the inert ingredient a t the highest tolerance level. In other words, EPA assumed 100 percent of
all foods are treated with the in ert ingredient at the rate and manner necessary to produce the highest residue legally poss ible for an active ingredient. In summary, EPA chose a very conservative method for estimating what level of inert residue could be on food, and then
use this method ology to choose the highest possible residue that could be found on food
and assumed that al l food contained this residue. No consideration was given to potential degradation between harvest and consumption even though monitoring data shows that
tolerance level residues are typically one to two orders of magnitude higher than actual
residues in food when distributed in commerce.

Accordingly, although sufficient information to quantify actual residue levels in food is not available, the compounding of thes e conservative assumptions will lead to a significant exaggeration of actual exposures. EPA does not believe that this approach underestimates exposure in the absence of residue data.

Table 5 . Summary of Chron ic Dietary Exposure and Risk of Diisopropanola mine (DIPA)

Population Subgroup cPAD (mg/kg/day) Chronic Exposure (mg/kg/day) %cPAD General U.S. Population

1.0 0.037869 3.8 % All Infants (<1 year old) 0.078886 7.9 %

Children 1

- 2 years old 0.141248 14.1 %

Children 3

- 5 years old 0.097127 9.7 %

Children 6

- 12 years old 0.050111 5.0 %

Youth 13

- 19 years old 0.026960 2.7 %

Adults 20

- 49 years old 0.028948 2.9 % Adults 50+ years old 0.030358 3.0 %

Females 13

- 49 years old 0.029267 2.9 %

Based on analyses of estimated dietary risks for the general U.S. population and various population subgroups, the chronic dietary exposure estimates for DIPA are significantly below the Agency’s level of concern for all supported commodities. The chronic dietary exposure estimate for the highest exposed population subgrou p, children 1

- 2 years old is

14.1 % of the chronic population adjusted dose (cPAD). The chronic dietary exposure estimate for the general U.S. population is 3.8% of the cPAD.

iii. Cancer exposure

. D IPA is not expected to be carcinogenic based on a carcinogenicity study which showed no increase in incidence of tumors

. Also all mutagenicity studies on DIPA were negative. Therefore, a cancer dietary exposure assessment is not necessary to
assess cancer risk.

B. Residential (Non

- Occupational) Exposure:

The screening

- level assessment was conducted using an Antimicrobials Division (AD) assessment tool developed to assess Amine Oxide (“ 900439 , (C10

- 16); C10

- C18

- Alkyldimethylamine oxides; Human Health Risk Assessment and Ecological Effects20 Assessment to Sup port Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations.” 22 SEPT 2009; Memorandum L. Austin to P. Shah; Reg. Div./OPP/EPA). The assessment tool uses standard assessment methodology developed b y the Antimicrobials Division and the Science Advisory Council for Exposure (EXPOSAC), Health Effects Division/O ffice of Pesticide Programs. The methodology can also be found in part at: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

.

In its simplest form, exposure is assessed as follows:

Unit Exposure * Amount applied/Unit * Units treated/day * absorption f actor ÷ Body Wt. (mg/lb handled) (lb applied/unit) (acres etc) kg

Inhalation and oral exposures are assumed to be 100%.

The result is an estimated average daily dose (ADD or “exposure”) expressed as mg material/kg bw/day. That value is used then to calculate the Margin of Exposure (MOE) (estimated meas ure of risk). An MOE is calculated by dividing the value of the average daily dose into the toxicological endpoint of concern (also expre ssed in mg material/kg bw/day). Typically, result ing MOEs ≥ 100 do not exceed the Agency’s level of concern. MOEs less than 100 typically exceed the Agency’s level of concern.

For the dietary and inhalation exposure assessment s the Agency uses the toxicol ogical endpoint of 10 0 mg/kg/day identified from the 90

- day oral toxicity study in rats based on absolute and relative kidney weights

.

Results of the screening

- level assessments are presented in the document

. Margins of

e xposure are presented as summarie s for residential “handlers” (non

- occupationally associated applicators) and for oc cupational pesticide handlers. Since lawn and turf uses may be involved, assessments of post

- application exposures to “ residents” were also

conducted. Estim ated exposure dos es as well as margins of exposure are presented for
inhalation and incidental oral exposure. Post

- application oral exposures (hand

- to

- mouth activity) are presented for toddlers (children ages 1

- 2 years), the highest exposed population.

i . From non

- dietary exposure. The term “residential exposure” is used in this document to

refer to non

- occupational, non

- dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). D IPA may be used as inert ingredients in pesticide products that are registered for specific uses that may result in
indoor or outdoor residential exposures. Possible route s of exposure are expected to be inhalation and dermal exposure as a result of contact with areas treated with DIPA

. However since there are no endpoints of concern for dermal toxicity, dermal exposure is not expected t o be of concern. A screening level residential exposure and risk assessment was completed

. The Agency conducted exposure assessments based on typical end

- use21 product application methods and labeled application rates. However no example product
labels were provided by the registrant and conservative assumptions for application rates
were used. T he Agency conducted an assessment to represent worse

- case residential exposure by assessing residential applicator and post

- application exposures and risk from

DIPA i n pesticide formulations.Table 6

. Residential Handler Short

- and Intermediate

- term Exposures and Risks for Diisopropanolamine

(DIPA) Inerts

Pesticide Type Exposure Scenario Application

Rate 1 Exposed Population

& Exposure
Duration 2 Inhalation Dose

(mg/kg/day) 3 Inhalation

MOE 4

Herbicide/ Fungicide Liquids/Low Pressure

Handwand

0.3 7 5 lb/day Short & Intermediate

Term 0.000014 7100000

Liquids/Hose End Sprayer Short & Intermediate

Term 0.000080 1300000

Liquids/Trigger Sprayer

- HG, IS,

C&C Short & Intermediate

Term 0.000009 11000000

Insecticide Liquids/Low Pressure

Handwand

0.125 lb/day Short & Intermediate

Term 0.000005 21000000

Liquids/Hose End Sprayer Short & Intermediate

Term 0.000027 3800000

Liquids/Trigger Sprayer

- HG, IS,

C&C Short & Intermediate

Term 0.000003 34000000

1 Application rates for DIPA are based on d efault values provided in the AD assessment tool

. 2 ST and IT indicate short

- or intermediate

- term exposure durations

3 Inhalation Daily Dose = Application rate * Quantity Tre ated (5 gallons) * Unit Exposure (Varies by exposure scenario) * Dermal Absorption Factor (100%) / Body Weight (80 kg)

4 MOE = PoD (NOAEL of 100 mg/kg/day for oral/inhalation )/ Daily dose (mg/kg/day)

Table 7. Residential Post

- A pplication Short

- and Intermediate

- term Exposures and Risks for Diisopropanolamine (DIPA) Inerts

Pesticide Type Exposure Scenario Application

Rate 1 Exposed Population &

Exposure Duration 2 Daily Dose (mg/kg/day) 3 MOE 4

Outdoor Products

Herbicide

Insecticide

Fungicide Hand

- to

- Mouth from

Treated Lawn

0.45 lb/day Child ST 0.00672828 15000

Child IT 0.0031959 31000 Object

- to

- Mouth
from Treated Lawn Child ST 0.00168207 59000 Child IT

Soil Ingestion Child ST 0 .0000225397 4400000 Child IT

1 Application rates for DIPA are based on default values provided in the AD assessment tool.

2 ST and IT indicate short

- or intermediate

- term exposure durations

3 Daily Dose is calculated differently for each exposure scenario. Refer to AD assessme nt tool for more details.

4 MOE = PoD ( NOAEL of 10 0 mg/kg/day)/ Daily dose (mg/kg/day)

EPA has calculated the residential applicator and post

- application exposures

. Three exposure scenarios, low pressure handwand , hose end sprayer and trigger sprayer were assessed for each pesticide type, herbicide, insecticide and fungicide in both short and long term scenarios. The inhalation MOEs ranged from 1,300,000 to 34,000,000 . As the level of concern is for MOEs that are lower than 100, these MOEs are not of concern.

There is no concern for post

- application exposure to adults because no dermal endpoints of
concern were identified. The post

- application child (hand

- to

- mouth) short

- term MOE was
calculated to be 1 5 ,00 0 from treated lawns

. The post

- application child (hand

- to

- mouth)
intermediate

- te rm MOE was calculated to be 31 ,000 from treated lawns . As the level of concern is for MOEs that are lower than 100, these MOEs are not of concern.23

V. AGGREGATE RISK ASSESSMENT

EPA determines whether acute and chronic pesticide exposures are safe by comparing aggregate exposure estimates to the acute population adjusted dose ( aPAD ) and chronic population adjusted dose ( cPAD ). The aPAD and c PAD represent the highest safe exposures, taking into account all app ropriate safety factors (SFs). EPA calculates the aPAD and cPAD by dividing the POD (i.e. toxicological endpoint) by all applicable UFs. For linear cancer risks, EPA calculates the probab ility of additional cancer cases given the estimated aggregate exposure. Short

- , intermediate

- , and chronic

- term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the MOE called for by the product of all a pplicable UFs is not exceeded.

i. Acute Dietary Risk.
An acute aggregate risk assessment takes into account exposure estimates from acute dietary consumption of food and drinking water using the exposure assu mptions discussed
in S ection IV for acute exposure. However there was no hazard attributable to a single exposure seen in the toxicity database fo r DIPA ; therefore there is no concern for an acute dietary risk and an acute aggregate risk assessment was not conducted

.

ii. Chroni c Dietary Risk.
A chronic aggregate risk assessment takes into account exposure estimates from chronic dietary consumption of food and drinking water using the exp osure assumptions discussed
in S ection IV from chronic exposure. The chronic analysis was ba sed on a 90

- day oral toxicity study with a NOAEL of 100 mg/kg/day based on increases in both relative and absolute kidney weight. The chronic dietary exposure f ro m food and water to DIPA is 3.8% of the cPAD for the U.S. population and 14.1% for children 1

- 2 yrs old, the most highly exposed population subgroup.

iii. Aggregate Cancer Risk for U.S. Population.
The Agency has not identified any concerns for carcinogenicity relating to DIPA ; therefore,

a cancer dietary exposure assessment was not performed and an aggregate risk assessment
is not a concern

.

iv. Short

- term Aggregate Risk

. Short

- term aggregate exposure takes into account short

- term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). DIPA

may be used as an inert ingredient in pesticide products that could result in short

- term residential exposure. The Agency has determined that it is appropriate to aggregate chronic exposure through food and water with short

- term residential exposures. Using t he exp osure assumptions described in S ection IV, EPA has calculated the combined short

- term aggregated food, water, and residential exposures. The adult short

- term aggregate MOE
was calculated to be 2600 for both males and females. Adult aggregate MOE comb ines average food and water exposure from the chronic dietary exposure with high end24 residential applicator exposure ( liquid hose end sprayer )

. As the level of concern is for MOEs that are lower than 100, this MOE is not of concern. EPA has concluded the

c ombined short

- term aggregated food, water, and residential exposures results in an aggregate MOE of 680 for children. Children’s aggregate MOE combines average food and water exposure from the chronic dietary exposure with residential exposure associated with contact with threated lawns (hand

- to

- mouth). As the level of concern is for MOEs that are lower than 100, these MOEs are not of concern.

Table 8. Short

- Term Aggregate Risk Calculations for Diisopropanolamine (DIPA)

Population PoD

mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average

Food &

Water Exposure 3 mg/kg/day Residential

Exposure 4 mg/kg/day Aggregate
MOE (food and residential) 5

Adult 100 100 1.0 0.037869 0. 0 00080 2600

Child 100 100 1.0 0.141248 0.00672828 680

1 The LOC (Level of Concern) is based on the standard inter

- , intra

- species uncertainty factors totaling 1 00.

2 Maximum Allowable Exposure (mg/kg/day) = PoD (Point of Departure)/LOC.

3 Average Food & Water Exposure = Chronic Dietary Exposure Table 5

. 4 Residential Exposure = Adult worse case scenarios for [Inhalation Handler Exposure + Post App. Exposure ].

5 Aggregate MOE = [PoD/ (Avg Food & Water Exposure + Residential Exposure)].

v. Intermediate

- Term Aggregate Risk.

Intermediate

- term aggregate exp osure takes into account intermediate

- term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). DIPA may be used as an inert ingredient in pesticide products that could result in
intermediate

- term res idential exposure. The Agency has determined that it is appropriate to aggregate chronic exposure through food and water with intermediate

- term residential exposures. Using the exposure assumptions described in section IV EPA has calculated the
combined in termediate

- term aggregated food, water, and residential exposures. The adult
intermediate

- term aggregate MOE was calculated to be 2600 for both males and females. Adult aggregate MOE combines average food and water exposure from the chronic dietary exposure with high end residential applicator exposure ( liquid hose end sprayer ). As the level of concern is for MOEs that are lower than 100, this MOE is not of concern. EPA has
concluded the combined intermediate

- term aggregated food, water, and resident ial exposures results in an aggregate MOE of 690 for children. Children’s aggregate MOEs combine average food and water exposure from the chronic dietary exposure with residential exposure associated with contact with threated lawns (hand

- to

- mouth,). As th e level of concern is for MOEs that are lower than 100, these MOEs are not of concern.

Table 9

. Intermediate

- Term Aggregate Risk Calculations for Diisopropanolamine (DIPA)

Population PoD

mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average

Food &

Water Exposure 3 Residential

Exposure 4 mg/kg/day Aggregate
MOE (food and residential) 525 mg/kg/day

Adult 100 100 1.0 0.037869 0. 0 00080 2600

Toddler 100 100 1.0 0.141248 0.0031959 690

1 The LOC (Level of Concern) is based on the standard inter

- , intra

- species uncertainty factors totaling 1 00.

2 Maximum Allowable Exposure (mg/kg/day) = PoD (Point of Departure)/LOC.

3 Average Food & Water Exposure = Chronic Dietary Exposure Table 5

. 4 Residential Exposure = Adult worse case scenarios for [Inhalation Handler Exposure + Post App. Exposure ].

5 Aggregate MOE = [PoD/ (Avg Food & Water Exposure + Residential Exposure)].

VI. O CCUPATIONAL EXPOSURE/RISK PATHWAY

The representative occupational scenarios selected by the Agency for assessment are

eva luated based on likely maximum application rates for products which may contain the inert ingredient for the short

- term exposure assessment, and average application rates for products likely
to contain the inert ingredient for the intermediate

- and long

- te rm exposure durations. Active ingredient application rates are corrected for the maximum amount of inert ingredient likely to be in the final formulations to determine exposure and risk from exposure to the inert ingredient by fungi cide/insecticide or herb icide.

The Agency traditionally considers a level of concern (LOC) for these risk assessments to be an MOE of 100 based on the standard 10X inter and 10X intra species extrapolation safety
factors.

A. Occupational Handler Risk

Exposure Scenarios Dermal and inhalation exposure are estimated using the Pesticide Handlers Exposure Database (PHED) and Outdoor Residential Exposure Task Force (ORETF) data. The analytical techniques are those developed by the Science Policy Council on Exposure (ExpoSAC), Heath Effects Division, Office of Pesticide Programs, US Environmental Protection Agency. The quantitative exposure/risk assessment developed for occupational handlers to support the requested exemption for the inert ingredient based on scenarios to

repres ent t he highest potential exposure.

The algorithm used to estimate exposure is: U.E. * AR * Units Treated/day * absorption factor ÷ body weight.

UE Unit Exposure in mg of materi al per lb of material handled. Unit Exposures

are derived in the Pesticide H andlers Exposure Database (PHED) and are recently summarized in the “Occupation Pesticide Handler Unit Exposure Surrogate Reference Table” US EPA Office of Pesticide Programs, March 2012 (unpublished)

AR Application Rate in lbs of material per unit (acres ) . In this case taken from

Herbicide Occupational Handler Inert Exposure Calculator and an additional26 10% limitation in formulation was applied to these values based on the proposed pesticide limitation listed in the petition

.

Units Treated/day

- - In th is case acres treated per day taken from the Antimicrobials

Division (AD) assessment tool developed to assess Amine Oxide (“ 900439

, (C10

- 16); C10

- C18

- Alkyldimethylamine oxides; Human Health Risk Assessment and Ecological Effects Assessment to Support Prop osed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations.” 22 SEPT 2009

AF Absorption factor

- - 100% default for inhalation routes of exposure

BW Body Weight

- - 80 kg f or combined adults in the U.S. Taken from “Use of New Human Body Weight Data as Presented in the EPA’s Exposure F actors Handbook: 2011 Edition” HED “HotSheet” No. 31. Although due to
software limitations of the assessment tool , the calculations provided be low
used the older default 70 kg.

In this case occupational exposures are presented for aerial applicators, ground applicators and for mixer/loaders preparing and applying liquid formulations diluted for use in applications. These are the occupational ac tivities believed to be associated with the highest

exposures use patterns

. The occupation exposure assessment utilized the baseline values for highest exposure herbicide, insecticide and fungicide. Only the herbicide data is provided below because it prov ided the lowest and most conservative MOEs. Also because no endpoint of concern was identified for dermal toxicity, only inhalation exposure of the
scenarios are assessed.

Table 10. Summary of Exposure & Risk to Occupational Handlers From Diisopropanolamine (DIPA)

Scenario Unit

Exposure 1 mg inert/lb
handled Application

Rate 1

lb inert/unit Units

Treated 1 Avg. Daily

Exposure 2 mg inert/kg bw/day MOE 3

Herbicide Mixer/Loaders Liquids: Aerial / Chemigation Inhalation: No respirator
0.0012 1.04 lb ai/A

(Corn) 1200 A/day Inhalation: No respirator
0.02139 Inhalation:

4700

Liquids: Airblast Inhalation: No respirator

0.0012 0.72 lb ai/A

(Nut Trees) 40 A/day Inhalation: No respirator
0.00049 Inhalation:

200000

Liquids: Groundboom Inhalation: No respirator

0.0012 1.04 lb ai/A

(Corn) 200 A/day Inhalation: No respirator

0.00357 Inhalation:

28000

Herbicide Applicator Liquid: Airblast Inhalation: Open Cab

0.0045 0. 16 lb ai/A

(Nut Trees) 40 A/day Inhalation: Open Cab

0.00041 Inhalation:

240000

Liquid: Groundboom Inhalation: Open Cab

0. 000 74 1.04 lb ai/A

(Corn) 200 A/day Inhalation: Open Cab

0.00220 Inhalation:

45000

Herbicide Mixer/Loader/Applicator27 1. Default values are taken from Antimicrobials Division (AD) assessment tool d eveloped to assess Amine Oxide (“ 900439 , (C10

- 16); C10

- C18

- Alkyldimethylamine oxides

2. Average Daily Ex posure = Unit Exposure * Application Rate (includes limitation 10%) * Units Treated * Absorption Rate÷ 7 0 kg Body Weight

3. MOE = Margin of Exposure = N OAEL  ADE. Inhalation NOAEL = 100 mg/kg bw/day.

The inhalation absorption was default at 100%. The inhalation toxicity was also assumed to be equivalent to oral toxicity (NOAEL 100 mg/kg/day)

. Risks were calculated using the

MOE approach, which is a ratio of the exposure to the toxicological PoD. Occupational
handler risks are not of concern. The Agency’s level of concern for inhalation and der mal exposure is for MOEs <100. The lowest estimated combined MOE was 4,700 , based on

li quid aerial/chemigation with no respirator, maximum application rate on corn and treating 1200 A/day. Therefore, the estimated occupational MOEs are not of concern.

B. Occup ational Post

- A pplication Risk

Exposure Scenarios RD uses the term post

- application t o describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also ref erred to

as re

- entry exposure). Such exposures may occur when workers enter previously treated areas to perform job fu nctions, including activities related to crop production, such as

sc outing 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 ty pe of pesticide application, and the che mical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure. Inhalation exposures are not typicall y calculated for occupational post

- application scenarios because inhalation exposures generally account for a negligible percentage of the overall body burden for most pesticide
chemicals.

This assessment is considered to be a screening level estimate, demonstrating that there are minimal potential risks to workers re

- entering fields treated with pesticides containing

DIPA as inert ingredients. Therefore an occupational post application risk assessment was not performed.

VII. C UMULATIVE EXP OSURE

Cumulative effects from substances with a common mechanism of toxicity . Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

EPA has not found DIPA to share a common mechanism of toxicity wi th any other
substan ces, and that DIPA do es not appear to produce a toxic metabolite produced by other Liquid: Low Pressure
handwand Inhalation:

No r espirator

0.030 0. 72

lb ai/A 5 A/day Inhalation: No respirator

0.00154 Inhalation:

6500028

substances. For the purposes of this tolerance action, therefore, EPA has assumed that DIPA does

not have a common mechanism of toxicity with other substances

. For informati on regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative

.

VIII. E NVIRONMENTAL JUSTICE STATEMENT

Potentia l 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," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

.

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, R D estimates risks to population subgroups from pesticide exposures that are based on patt erns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under CSFII and 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 country. Additionally, OPP is able to assess dietary exposure to smaller, spec ialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, 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 b ystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups

IX. E NVIRONMENTAL FATE CONSIDERATIONS

DIPA is not expected to persist in soil or water in the environment. DIPA is also expected to degrade fairly rapi dly based on the biodegradation studies summarized below. Significant residues of DIPA are not expected to persist on treated crops due to the hydrophilic nature of the compound. DIPA is expected to distribute mainly to soil (~62%) and water (~38%) compart ments based on level III fugacity model. DIPA is not expected to be found in the air (<0.1%) or sediment (<0.1%). DIPA will remain in the water compartment and not be found in sediments. DIPA has a low potential for bioaccumulation based on the low Kow val ues and has an estimated bioconcentration factor ( BCF ) of 3 (TOXNET, 2006).

In a biodegradation (aerobic) study with activated sludge following OECD Guideline 301F (OCSPP 835.3110) Ready Biodegradation Manometric Respirometry, a special one

- liter reaction vessel containing 500 mL of the inoculated mineral medium had 52.6 mg DIPA/ theoretical oxygen demand ( ThOD ) NH 3 added. After brief agitation a sample was removed for determining29

dissolved organic carbon (DOC), nitrate nitrogen (NO 2 ) and nitrite nitrogen (NO 3 ). The vessels were connected to the respirometer, purged with air, and the headspace volume of each vessel was determined by the respirometer system. During the 28

- day period, vessels were maintained in the dark at 22±1°C under continuous agi tation. Every 4 hours, gas phase oxygen and carbondioxide were measured. On day 28, the aqueous phases were sampled for final DOC, NO 2 and NO 3 concentrations. Solution pH levels were monitored at day 0 and day 28. DIPA degraded in the presence of activated sludge with an average of 94% biodegradation based on oxygen consumption after 28 days. DIPA is considered biodegradable because more than 60% biodegradation occurred within 10 days of study initiation (Dow HPV 2004)

.

In another biodegradation (aerobic) study with activated sludge following American Public

H ealth Association, American Water Works Association and Water Environment Federation , 199 2 method for examination of water and wastewater, 18 th edition, activated sludge from Bay City MI West Bay Coun ty Wastewater Treatment Plant was used to investigate the biodegradation of DIPA as the sole supplement of carbon and nitrogen. Vessels contained 1000 mg/L liquid suspended
solids and 14 C

- DIPA concentrations of 0.5 and 5.2 mg/L with a final concentration o f ~0.1μCi/mL radioactivity in solution. Studies were conducted in duplicate. Sampling occurred periodically to determine the presence of DIPA and degradation products. At each sampling point, traps containing base for collecting 14 CO 2 were collected and an alyzed for 14 C and traps were replenished with fresh base solutions. Additional samples were prepared to determine potential for

N

- nitrosamine formation from degradation of DIPA. Vessels contained 4.7mg/L non

- radiolabelled DIPA in the same activated sludge matrix. Samples were analyzed using differential pulse polarogrpahic analysis. A final set of samples were prepared using soil (Tappan loamy sand from Bay County MI) and sediments/water from two sit es (Tittabawassee and Chippewa R ivers, Central MI). Vesse ls were dosed with 14 C

- DIPA and sampled to determine concentrations of DIPA, degradation products, and 14 CO 2 . The half

- life for mineralization in the loamy sand soil was 1.6 days and in the activated sludge was <72 to < 120 hours from 0.5 mg/L and 5.2 mg/L DIPA, respectively. No N

- nitrosamines at levels greater than 100 μg/L formed from DIPA biodegradation in the presence of activated sludge. Two degradation products from the biodegredation of DIPA on soil and water/sediment formed transiently and at low le vels. These degradates were tentatively
identified as 1

- (2

- hydroxypropylamino)

- 2

- propanone and 1

- amino

- 2

- propanol (Dow HPV 2004)

.

In a third biodegradation study with activated sludge following OECD Guideline 302B (OCSPP 835.3200) , Inherent biodegradabili ty: Modified Zahn

- Wellens Test, 90

- 100% degredation of DIPA was observed after 7 days in an aerobic assay (Dow HPV 2004)

.

Table 11 . Summary of Environmental Fate Studies for Diisopropanolamine (DIPA) Study Results Reference

Bioaccumulation Based on Kow , not expected to bioaccumulate TOXNET 2006 Hydrolysis Stable at pH 5

- 9 D ow HPV 2004, BASF Quadrol HPV Photodegradation (t 1/2 , days) Absorbs light > 290 nm and direct photodegradation is possible. The predicted t 1/2 is 1.262 hours. Dow HPV 2004

Biodegradation Biodegradable; 94% degradation within 28 days Dow HPV 2004

100% within 72

- 120 hours in presence of activated sludge (OECD 301F ; OCSPP 835.3110 ) Dow HPV 2004

>90% degradation after 7 days in aerobic assay (OECD

302B ; OCSPP 835.3200 ) Dow HPV 200430

Aerobic Soil
Metabolism t1/2 = 1.6 days in loamy sand Dow HPV 2004

Aerobic Sediment/Water Study T1/2 = 5.1 days surface water Dow HPV 2004

MacKay Fugacity
Model <0.003% air
99.98% water
0.014% soil
0.0001% sediment Dow HPV 2004

X. E COTOXICITY

Based on studies conducted with various species of fish ranging from 24 hour to 96 hour exposures, DIPA is considered to be practically nontoxic to freshwater species. Freshwater fish acute toxicity LC 50 s are > 100 mg/L. Studies conducted with Daphnia magn a , DIPA is expected to be practically non

- toxic to aquatic invertebrates. Freshwater invertebrate acute toxicity EC 50 s are > 270 mg/L. DIPA is also not expected to be toxic to non

- target aquatic plants based on testing with Scenedesmus subspicatus . The 72

- hour EC 50 was 270 mg/L (growth rate, nominal).

Fish Acute Toxicity

In a 24

- hour static acute toxicity study on ten fish ( Cyprinus auratus ) were exposed to DIPA in separate stu dies at 20°C and pH 7 or pH 9. Tank water was aerated throughout the test period. Tap water was used as the source of water. Analytical monitoring of test
material concentrations was carried out before and after exposure. The LC 5 0 (24

- hr) was >5000 mg/L at pH 7.0 and 1100 mg/L at pH 9.0 (Birdie et al. 1979)

.

In a 24

- hour static acute toxicity study on ten fish ( Carassius auratus ) were exposed to DIPA in separate studies at 20°C and pH 7 or pH 10.2. Tank water was aerated throughout the test period. Tap water was used as source of water. Oxygen content was not allowed to drop below 6 mg/L during the exposure period. Analytical monitoring of test material concentrations was carried out before and after exposure. The median tolerance limit (TLm) was >5000 mg/L at pH 7.0 (precipitate formed)

. The median tolerance limit (TLm)
was 500

- 5000 mg/L at pH 10.2 (precipitate formed) (Birdie et al. 1973)

.

In a 96

- hour static acute toxicity study on fathead minnows ( Pimephales promelas Rafinesque ), were exposed to DIPA in dechlorinated Lake Huron water . The NOAEC was > 100 mg/L. No mortality or observa ble toxic effects were observed (Alexander et al. 1975)

.

In a 96

- hour static acute toxicity study (OECD 203) on Brachydanio rerio , the tropical freshwater minnow was exposed to DIPA. The LC 50 (96

- hr) was ≥ 1000

– 2200 mg/L( nominal). THE NOEC was 460 mg/L (BASF 1984)

.

In a 24

- hour static acute toxicity study on Carassius auratus with DIPA in water at pH 9.7

. Method used was American Public H ealth Association (APHA) Standard Methods for the
Examination of Water and Wastewater, Method No. 231. T he LC 50 (24

- hr) was 1100 mg/L (Birdie et al. 1971)

.31 In a 48

- hour static acute toxicity study on Leuciscus idus with DIPA, t he static LC 50 (48

- hr) was 1000 mg/L (Huels AG)

.

In a 96

- hour static acute toxicity study on Leuciscus idus with DIPA, t he NOAEC was 460 mg/L. The static LC 50 (96

- hour) was 1000

- 2200 mg/L (BASF AG 1982)

.

Aquatic Invertebrate Toxicity

In a 24

- hour acute toxicity study on Daphnia magna Straus with DIPA, t he 24

- hour EC 50 was 353.8 mg/L (nominal concentration). The test water was pH 7.9 (BASF AG)

.

In a 48

- hour acute toxicity study on Daphnia magna Straus with DIPA, the 48

- hour EC 50 was 2777.7 mg/L (nominal concentrat ion). The test water was pH 7.9 (BASF AG)

.

Aquatic Plant Toxicity

In a 72

- hour aquatic plant toxicity study on Scenedesmus subspicatus with DIPA, the 72

- hour EC 50 was 270 mg/L (growth rate, nominal) (BASF AG)

.

Table 12

. Summary of Aquatic Ecological Toxicity Studies for Diisopropanolamine (DIPA)

Species Study Results (mg/L) Tox. Category Reference

Fish Cyprinus auratus 24

- hour LC 50 >5000 Practically nontoxic Birdie et al. 1979

Carassius auratus 24

- hour TLm >5000 at pH 7.0
500

- 5000 at pH

10.2 N/A Birdie et al. 1973

Pimephales promelas Rafinesque (Fathead minnow) 96

- hour

NOAEC >100 Practically nontoxic Alexander et al.
1975

Brachydanio rerio (tropical
freshwater minnow) 96

- hour

NOEC 460 Practically nontoxic BASF 1984

Carassius auratus 24

- hour LC 50 1100 Practically nontoxic Birdie et al. 1971

Leuciscus idus 48

- hour LC 50 1000 Practically nontoxic Huels AG

Leuciscus idus 96

- hour

NOAEC/LC 50 460

1000

- 2200 Practically nontoxic BASF AG 1982

Invertebrate Daphnia magna

Straus 24

- hour EC 50 353.8 (nominal) Practically nontoxic BASF AG

Daphnia magna

Straus 48

- hour EC 50 277.7 (nominal) Practically nontoxic BASF AG

Plant Scenedesmus

subspicatus 72

- hour EC50 270 mg/L (growth rate, nominal) Practically nontoxic BASF AG

XI. R ISK CHARACTERIZATION32 Pyxis Regulatory Consulting Inc. on behalf of United Phosphorus, Inc. (630 Freedom Business Center, Suite 402, King of Prussia, PA 19406) is requesting that EPA establish an exemption from the requirement of a tolerance for diisopropanolamine. Diisopropanolamin e also referred to as DIPA or 1,1’

- iminodiproan

- 2

- ol (CAS Reg. No. 110

- 97

- 4) is already approved as an inert ingredient for non

- food use pesticide formulations. Pyxis Regulatory Consulting Inc. is requesting that EPA establish a tolerance exemption for the use of diisopropanolamine as an inert ingredient (neutralizer or stabilizer) at no more than 10% in pesticide formulations applied to pre

and post

- harvest crops in accordance with 40 CFR 180.910.

DIPA is widely used as an emulsifier , st abilizer, surfac tant , and in chemical intermediates. The major uses of DIPA are as a scavenger for carbon dioxide and hydrogen sulfide in the purification of natural gas, and as a pH adjuster or as an emulsifier or viscosity modifier in personal care products ( e.g., c osme tics, tanning solutions, soaps, and detergents).

An acute dietary risk assessment was not conducted because no endpoint of concern following a single or few exposures was identified in the available studies. A chronic dietary
exposure assessment was com pleted and performed using the Dietary Exposure Evaluation Model

DEEM

- FCID TM , Version 3.16. The chronic R eference Dose (cRfD) of 100 mg/kg/day was
determined on the basis of the subchronic oral toxicity study in rats . The LOAEL of 500 mg/kg/day DIPA is ba sed on changed in absolute and relative kidney weights seen in males. This

s tudy provided the lowest NOAEL in the database (most sensitive endpoint) and will also provide the most protective limits for human effects. An UF of 100X (10

- fold for interspecie s extrapolation and 10

- fold for intra species variability) was applied to the NOAEL of 100 mg/kg/day to derive the cRfD. The FQPA safety factor of 1X is applicable for chronic dietary risk

assessment. Therefore, the chronic population

- adjusted dose (cPAD) is 1.0 mg/kg/day. This endpoint of concern was also used for all inhalation exposure scenarios. A NOAEL of 750 mg/kg/day from the 28

- day dermal toxicity study showed no systemic toxicity, therefore dermal exposure is not considered a concern and quantific ation of dermal risk is not necessary. Dermal absorption was determined to be 12% based on the dermal absorption study and inhalation absorption was assumed to be 100%.

Based on analyses of estimated dietary risks (I

- DEEM) for the general U.S. population and various population subgroups, the chronic dietary exposure estimates for DIPA are significantly below the Agency’s level of concern for all supported commodities. The chronic dietary exposure estimate for the highest exposed population subgroup, child ren 1

- 2 years old is 14.1% of the chronic population adjusted dose (cPAD) and 3.8% for the general population.

The Agency’s level of concern (LOC) for DIPA occupational and residential inhalation exposures is 100 [i.e., a margin of exposure (MOE) greater than 100 is not of concern to EPA ]. The LOC is based on a 10X uncertainty factor (UF) to account for interspecies extrapolation to humans from the animal test species and 10X UF to account for intra

- species sensitivity.

Short

- term aggregate exposure tak es into account short

- term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). DIPA may be used as an inert ingredient in pesticide products that could result in short

- term residential exposure. The Agency has determined that it is appropriate to aggregate chronic exposure through food and33

water with short

- term residential exposures. Using the exposure assumptions described in Section IV, EPA has calculated the combined short

- term aggregated food, water, and residential exposures.
The adult short

- term aggregate MOE was calculated to be 2600 for both males and females. Adult
aggregate MOE combines average food and water exposure from the chronic dietary exposure with high end residential applicator exposure (liquid hose end sprayer). As the level of concern is for MOEs that are lower than 100, this MOE is not of concern. EPA has conclud ed the combined
short

- term aggregated food, water, and residential exposures results in an aggregate MOE of 680 for children. Children’s aggregate MOE combines average food and water exposure from the chronic dietary exposure with residential exposure asso ciated with contact with threated lawns (hand

- to

- mouth). As the level of concern is for MOEs that are lower than 100, these MOEs are not
of concern.

Intermediate

- term aggregate exposure takes into account intermediate

- term residential exposure plus chroni c exposure to food and water (considered to be a background exposure level). DIPA may be used as an inert ingredient in pesticide products that could result in intermediate

term residential exposure. The Agency has determined that it is appropriate to aggr egate chronic exposure through food and water with intermediate

- term residential exposures. Using the exposure assumptions described in section IV EPA has calculated the combined intermediate

- term aggregated food, water, and residential exposures. The adul t intermediate

- term aggregate MOE was calculated to be 2600 for both males and females. Adult aggregate MOE combines average food and water exposure from the chronic dietary exposure with high end residential applicator exposure (liquid hose end sprayer). As the level of concern is for MOEs that are lower than 100,
this MOE is not of concern. EPA has concluded the combined intermediate

- term aggregated food, water, and residential exposures results in an aggregate MOE of 690 for children. Children’s
aggregat e MOEs combine average food and water exposure from the chronic dietary exposure with residential exposure associated with contact with threated lawns (hand

- to

- mouth,). As the level of concern is for MOEs that are lower than 100, these MOEs are not of conc ern.

Occupational handler risks are not of concern for all scenarios. It is noted that this occupational handler assessment assumes that mixer/loader/applicators are not wearing protective respirators when using open pour in support of aerial and ground boom application. The estimated MOEs are greater than 100 based on 100% inhalation absorption. Therefore, the estimated MOEs do not exceed the Agency’s level of concern. This assessment is considered to be a screening level estimate, demonstrating that the re are minimal potential risks to workers re

- entering fields treated with pesticides containing DIPA as inert ingredients. Therefore an occupational post application risk assessment was not performed.

Based on the ready biodegradability of DIPA in an OECD 301F (OCSPP 835.3110) guideline study, 94% of DIPA was biodegraded in 28 days and 60% in 10 days. In an Zahn

Wellens/EMPA Test, OECD 302B (OCSPP 835.3200) guideline study, 90

- 100% biodegraded in

7

- days, therefore effects of concern to nontarget aquatic sp ecies resulting from the use of DIPA as an inert ingredient are not expected. Acute toxicity studies performed with DIPA on fish, invertebrates and algae showed that the compound was practically nontoxic. DIPA has a low potential for bioaccumulation based on the low Kow values and has an estimated Bioconcentration Factor (BCF) of 3. Diisopropanolamine (DIPA) is not expected to pose an environmental fate concern due to its biodegradability.34 Based on studies conducted with various species of fish ranging from 24 hour to 96 hour exposures, DIPA is considered to be practically nontoxic to freshwater species. Freshwater fish acute toxicity LC 50 s are > 100 mg/L. Studies conducted with Daphnia magna , DIPA is expected to be practically non

- toxic to aquatic inver tebrates. Freshwater invertebrate acute toxicity EC 50 s are > 270 mg/L. DIPA is also not expected to be toxic to non

- target aquatic plants based on testing
with Scenedesmus subspicatus . The 72

- hour EC 50 was 270 mg/L (growth rate, nominal).

Potential area s 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 Popul ations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

Taking into consideration all available information on DIPA , EPA concludes that there is a reasonable certainty that no harm to any population subgroup will result from aggreg ate exposure
to DIPA when considering residential, occupation al , dietary exposure and all other nonoccupational sources of pesticide exposure for which there is reliable information. Therefore, the establishment of an exemption from tolerance under 40 CFR 180.910 for r esidues of diisopropanolamine (CAS Reg. No. 110

- 97

- 4 ) when used as a pesticide inert ingredient at no more
than 10% in formulations when applied to pre

- or post

- harvest crops can be considered assessed as safe under section 408(q) of the FFDCA.35

REFERENCES

Alexander, H.C. an d Batchelder, T.L. (1975). The Pollution Evaluation of Compounds. R&D Report of The Dow Chemical Company, unpublished study as summarized in Dow HPV summary and test plan for DIPA and TIPA.

BASF AG, Department of Biology and Toxicology . Unpublished results (87/269), 19.10.1987 as summarized in Dow HPV summary and test plan for DIPA and TIPA.

BASF AG, Department of Ecology; unpublished study (1092/88) unpublished study as
summarized in Dow HPV summary and test plan f or DIPA and TIPA.

B ASF AG, Department of Ecology; unpublished study; (1132/87) unpublished study as
summarized in Dow HPV summary and test plan f or DIPA and TIPA.

BASF AG, 1981. Department of Ecology; unpublished study as a summarized in the Dow HPV summary and test plan fo r DIPA and TIPA.

BASF AG, 1984. Department of Ecology; unpublished study (17F0414/915114,30.01.1995, unpublished study as summarized in Dow HPV summary and test plan for DIPA and TIPA.

BASF AG, Department of Toxicology (1965) unpublished st udy 345

- 351 a s summarized in Dow HPV summary and test plan DIPA and TIPA.

BASF AG, Department of Toxicology (1993) unpublished stu dy (91/414) as summarized in Dow HPV summary and test plan DIPA and TIPA.

Birdie, A.L., Wolff, C.J.M. and Winter, M. (1973). Determination of Acute Toxicity to Fish of Shell Chemicals. Koninklijke/Shell

- Laboratorium, Amsterdam. EPA/OTS, Doc #FYI

- OTS

- 0794

- 1002 unpublished study as summarized in Dow HPV summary and test plan for D IPA and TIPA.

Birdie, A.L., Wolff, C.J.M. and Winter, M. (1979). The Acute Toxicity of Some Petrochemicals to Goldfish. Koninklijke/Shell

- Laboratorium, Amsterdam (Shell Research B.V.), The Netherlands. Water Research, Vol. 13, pp 623

- 626 as summarized in Dow HPV Summary and test plan for
DIPA and TIPA.

Birdie, A.L. et al, Water Res. 13, 623

- 626, 1979 and TSCT, OTS84003A, Doc I.D. 878210129, 8DS, 01.03.1973, Shell Oil Co. as summarized in Dow HPV summary and test plan for DIPA and

TIPA.

Burkackaja, E. et al. (1986) Gig. Tr. Prof. Zabol. 7:46

- 48 as summarized in DOW HPV summary and test plan DIPA and TIPA.

Cifone, M. (1994) Dow Chemical unpublished study as summarized in Dow HPV summary and test plan DIPA and TIPA.36

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APPENDIX

US EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Chronic analysis for DIISOPROPANOLAMINE NHANES 2003

- 2008 2

- day
Residue file name: E: \ DEEM \ Diisopropanolamine \

Diisopropanolamine Limit 10%.R08 Adjustment factor #2 used. Analysis Date 04

- 22

- 2014/11:05:04 Residue file dated: 04

- 22

- 2014/11:03:23 Reference dose (RfD, Chronic) = 1 mg/k g bw/day COMMENT 1: Inert 57 active ingredients + drinking water (100ppb)

======================================================================

=========

Total exposure by population subgroup

-------------------------------------------- -----------------------------------

Total Exposure

----------------------------------- Population mg/kg Percent of Subgroup body wt/day Rfd

-------------------------------------- ------------- ---------------- Total US Population 0.037869 3.8% Hispanic 0.041352 4.1%

Non

- Hisp

- White 0.037160 3.7%

Non

- Hisp

- Black 0.035190 3.5%

Non

- Hisp

- Other 0.044671 4.5% Nursing Infants 0.049641 5.0%

Non

- Nursing Infants 0.091947 9.2%
Female 13+ PREG 0.033048 3.3%
Children 1

- 6 0.109335 10.9%
Children 7

- 12 0.045482 4.5%
Male 13

- 19 0.026752 2.7%
Female 13

- 19/NP 0.027186 2.7%
Male 20+ 0.028199 2.8%
Female 20+/NP 0.030632 3.1%
Seniors 55+ 0.030537 3.1%
All Infants 0.078886 7.9%
Female 13

- 50 0.029281 2.9%
Children 1

- 2 0.141248 14.1%
Children 3

- 5 0.0 97127 9.7%
Children 6

- 12 0.050111 5.0%
Youth 13

- 19 0.026960 2.7%
Adults 20

- 49 0.028948 2.9%
Adults 50

- 99 0.030358 3.0%
Female 13

- 49 0.029267 2.9%

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