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. Chronic 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...................................................................................................................................... 38
3

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. 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. 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 preand 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, 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 modifier in personal care products (e.g., cosmetics, tanning 

solutions, soaps, and detergents). 

The acute oral toxicity of DIPA is low. The acute oral LD50s in rats were > 2000 mg/kg bw. 

The acute dermal toxicity in rats and rabbits were > 8000 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 nonguideline 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 increased 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 

weights 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 maternal and 

developmental toxicity. 

In an in vitro mammalian cell gene mutation test (OECD 476; OCSPP 870.5300), two 

bacterial reverse mutation tests (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. 

There 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 provided. 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 determined 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 absorption was calculated to be 12%. 

EPA has also determined that reliable data show the safety of infants and children would be 

adequately protected if the FQPA SF were reduced to 1X. 

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 completed and performed using the Dietary Exposure Evaluation Model 

DEEM-FCIDTM, Version 3.16. The chronic Reference 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 

study 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 interspecies 

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 quantification 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, 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 background 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 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 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 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.

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 intermediateterm 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 wearing protective 

respirators when using open pour in support of aerial and groundboom 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 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.

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 ZahnWellens/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 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 
6

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

concern due to its biodegradability. 

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 LC50s are > 100 mg/L. Studies conducted with Daphnia magna, DIPA is expected to 

be practically non-toxic to aquatic invertebrates. Freshwater invertebrate acute toxicity EC50s 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 EC50 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 Justice in Minority Populations and Low-Income Populations," 

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 aggregate exposure 

to DIPA when considering residential, occupational, 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 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 assessed 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 diisopropanolamine 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 expand it 

to include use as an inert ingredient (neutralizer or stabilizer) at no more than 10% in pesticide 

formulations in accordance with 40 CFR 180.910 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 modifier in personal care products 

(e.g., cosmetics, tanning solutions, soaps, and detergents). 

B. Physical Chemical Properties

Some of the physical and chemical characteristics of DIPA, along with its structure and 

nomenclature, are found in Table 1.

Table 1. Physical and Chemical Properties of Diisopropanolamine (DIPA)

Parameter Value Source

Structure ChemIDplus

CAS # 110-97-4 ChemIDplus

Molecular Formula C6H15NO2 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 MSDS
8

Table 1. Physical 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 (pKa) pKa 9.1 (at 25°C) SIDS for Isopropanolamines

Octanol/water Partition Coefficient 

(Kow)

Log Kow -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, female rats were treated with a single 2000 mg/kg dose of 

DIPA. The acute oral LD50 in female rats was > 2000 mg/kg (BASF 1993).

In another acute oral toxicity study, the acute oral LD50 in rats was reported as 6720 mg/kg

(Union Carbide 1968).

In another acute oral toxicity study, the acute oral LD50 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 LD50 was calculated using the moving average method 

based on a 14 day observation period. The LD50 was 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 LD50 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 dressing. In another study, DIPA 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 semiocclusive patch; however, when it was applied under occlusive conditions for a 

“prolonged” period hyperemia and necrosis or denaturation were observed (Huels 1985).

Dermal Sensitization

In a dermal sensitization study, the 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 period. 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 application 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 studies 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 LD50 (female) = 2000 mg/kg bw III BASF 1993

LD50 = 6720 mg/kg bw IV Union Carbide 1968

LD50 (female) = 6000 mg/kg bw IV BASF 1965

Acute Dermal –

rats/rabbits

LD50 (rats) = 16000 mg/kg bw IV Union Carbide 1964

LD50 (rabbits) = 8000 mg/kg bw IV RTECS 1979

Acute Inhalation - N/A N/A N/A N/A

Eye irritant N/A Huels 1985
10

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 semiocclusive 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 prior 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/day, two of five males died. Body 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 

urinary 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 

increased 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 subchronic 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 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 histopathological examinations of selected tissues were conducted. 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 statistically 

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 weights were statistically increased in 

male and female rats at 500 and 1000 mg/kg/day. In males, absolute kidney weights were 

also statistically 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 either macroscopic or 
11

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 days/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 

histopathological examination of selected tissues was conducted. There were no treatmentrelated effects on body weight, body weight gain or food consumption. Hematology, 

clinical chemistry and urinalysis parameters were unaffected by treatment. There were no 

findings 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 500 

mg/kg/day. Scabs were seen at the treatment site of one male at 500 mg/kg/day and two at 

750 mg/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 males and two females at 500 mg/kg/day. 

The NOAEL for systemic effects was the highest dose tested, 750 mg/kg/day (Johnson et 

al. 2007).

Developmental Toxicity -

In a developmental toxicity study (EPA OCSPP 870.3700/OECD 414), time-mated Fischer 

344 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 periodically. 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 weighed, 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 skeletal alterations. Treatment 

with DIPA had no effect on body weight 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 number of viable fetuses. There were no statistically 

significant increases in abnormalities (external, visceral or skeletal) in any treatment group 

compared 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 maternal 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 and 

without metabolic activation. DIPA did not induce a mutagenic response under 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 tester 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 without 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 activation (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 metabolic 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 metabolic 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 metabolic 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 48 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 lymphocytes (Murli 1994).

Carcinogenicity

In a carcinogenicity study, a group 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 intake 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, epididymis, 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 intake and water consumption were unaffected by treatment. The only 

tumors occurring in the DIPA treated group were 2 adrenal gland tumors 
13

(pheochromocytoma) and 6 tumors of the testes (Leydig cell). The control group had 4 

pheochromocytomas and 9 Leydig cell 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 immunotoxicity 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), 14C-labeled DIPA 

(>99.5% purity) with a specific activity of 75μCi/mg was administered to female 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 animals (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 hours. An average of 96.8% 

of the radioactivity 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 feces. 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 CO2. 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, 500 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

Johnson 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 1991
15

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. 

Application 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 available 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. 

Table 4. Summary of Toxicological 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 

UFA = 10 x

UFH = 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 

UFA = 10 x

UFH = 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

UFA= 10 x

UFH= 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

Table 4. Summary of Toxicological 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 at doses 

up to 750 mg/kg/day in a dermal toxicity study.

Inhalation short-term 

(1 to 30 days)

Oral study NOAEL= 100

mg/kg/day (inhalation 

absorption rate = 100%)

UFA = 10 x

UFH = 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)

Oral study NOAEL = 100

mg/kg/day (inhalation 

absorption rate = 100%)

UFA = 10 x

UFH = 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.

UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of 

the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study 

for long-term risk assessment. UFDB = 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 dose. 

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 completeness 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 concludes 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, developmental, 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 Agency 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 uncertainty 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 observed on reproductive organs including histopathological 
17

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 additional 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 level or higher 

residues and 100% crop treated information for all commodities. By using these screeninglevel assessments, chronic exposures/risks will not be underestimated.

Taking into consideration the available information, EPA concludes the additional 10X 

FQPA safety factor can be reduced to 1X.

IV. EXPOSURE ASSESSMENT

The petitioner has requested use of DIPA with a limitation of 10% maximum in pesticide 

formulation. The petitioner requested 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 constraints 

prohibit the Agency from 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 of 

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 methods of application and 

sites of application. 

It should be noted again, as indicated from the earlier 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 ingredient 

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 We 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 ingredient 

would be no higher than the highest established tolerance for an active ingredient on a 

given commodity. As to residue levels in food, no 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 insecticides, 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) Dietary 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 tolerance for a given commodity. Implicit in 

this assumption is that there would be similar rates of degradation (if any) between the 

active and inert ingredient 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 series of compounded 

conservatisms. First, assuming that the level of residue for an inert ingredient is equal to the 

level of residue for the active ingredient will overstate exposure. The concentration 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 different 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 assessment to account for the use limitations of the 

amount of DIPA that may be in formulations (no more than 10% 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 with 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 would 
19

be present at the level of the active ingredient in the highest tolerance for every commodity. 

Finally, a third compounding conservatism is EPA’s assumption that all foods contain the 

inert ingredient at the highest tolerance level. In other words, EPA assumed 100 percent of 

all foods are treated with the inert ingredient at the rate and manner necessary to produce 

the highest residue legally possible 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 methodology to choose the highest possible residue that could be found on food 

and assumed that all 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 these 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 Chronic Dietary Exposure and Risk of Diisopropanolamine (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 subgroup, 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. DIPA 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 Effects 
20

Assessment to Support 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 by the Antimicrobials Division and the Science Advisory Council 

for Exposure (EXPOSAC), Health Effects Division/Office 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 factor ÷ 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 measure of risk). An MOE is calculated by dividing the value of the average 

daily dose into the toxicological endpoint of concern (also expressed in mg material/kg 

bw/day). Typically, resulting 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 assessments the Agency uses the toxicological 

endpoint of 100 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 

exposure are presented as summaries for residential “handlers” (non-occupationally 

associated applicators) and for occupational pesticide handlers. Since lawn and turf uses 

may be involved, assessments of post-application exposures to “residents” were also 

conducted. Estimated exposure doses 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). DIPA 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 routes 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 to be of concern. A screening level residential exposure and risk assessment 

was completed. The Agency conducted exposure assessments based on typical end-use 
21

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. The Agency conducted an assessment to represent worse-case residential 

exposure by assessing residential applicator and post-application exposures and risk from 

DIPA in pesticide formulations. 
Table 6. Residential Handler Short- and Intermediate-term Exposures and Risks for Diisopropanolamine

(DIPA) Inerts

Pesticide 

Type

Exposure Scenario Application 

Rate1

Exposed Population 

& Exposure 

Duration2

Inhalation Dose 

(mg/kg/day)3

Inhalation 

MOE4

Herbicide/

Fungicide

Liquids/Low Pressure 

Handwand

0.375 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 default 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 Treated (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-Application Short- and Intermediate-term Exposures and Risks for 

Diisopropanolamine (DIPA) Inerts

Pesticide 

Type

Exposure Scenario Application 

Rate1

Exposed Population & 

Exposure Duration2

Daily Dose 

(mg/kg/day)3

MOE4

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 assessment tool for more details.

4 MOE = PoD ( NOAEL of 100 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 15,000 from treated lawns. The post-application child (hand-to-mouth)

intermediate-term 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 cPAD represent the highest safe 

exposures, taking into account all appropriate 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 probability 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 applicable 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 assumptions discussed 

in Section IV for acute exposure. However there was no hazard attributable to a single 

exposure seen in the toxicity database for DIPA; therefore there is no concern for an acute 

dietary risk and an acute aggregate risk assessment was not conducted.

ii. Chronic Dietary Risk. 

A chronic aggregate risk assessment takes into account exposure estimates from chronic 

dietary consumption of food and drinking water using the exposure assumptions discussed 

in Section IV from chronic exposure. The chronic analysis was based 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 from 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 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 
24

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 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 LOC1

Max

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure3

mg/kg/day

Residential 

Exposure4

mg/kg/day

Aggregate 

MOE

(food and

residential)5

Adult 100 100 1.0 0.037869 0.000080 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 100.

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 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.

Table 9. Intermediate-Term Aggregate Risk Calculations for Diisopropanolamine (DIPA)

Population

PoD

mg/kg/day LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure3

Residential 

Exposure4

mg/kg/day

Aggregate 

MOE

(food and

residential)5
25

mg/kg/day

Adult 100 100 1.0 0.037869 0.000080 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 100.

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. OCCUPATIONAL EXPOSURE/RISK PATHWAY

The representative occupational scenarios selected by the Agency for assessment are

evaluated 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-term 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 

fungicide/insecticide or herbicide. 

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 

represent the 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 material per lb of material handled. Unit Exposures 

are derived in the Pesticide Handlers 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 additional 
26

10% limitation in formulation was applied to these values based on the 

proposed pesticide limitation listed in the petition. 

Units Treated/day - - In this 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 Proposed 

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 for combined adults in the U.S. Taken from “Use of 

New Human Body Weight Data as Presented in the EPA’s Exposure Factors 

Handbook: 2011 Edition” HED “HotSheet” No. 31. Although due to 

software limitations of the assessment tool, the calculations provided below

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 activities 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 provided 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 

Exposure1

mg inert/lb 

handled

Application 

Rate1

lb inert/unit

Units 

Treated1

Avg. Daily 

Exposure2

mg inert/kg bw/day

MOE3

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

0.00074

1.04 lb ai/A

(Corn)

200 A/day Inhalation:

Open Cab

0.00220

Inhalation:

45000

Herbicide Mixer/Loader/Applicator
27

1. Default values are taken from Antimicrobials Division (AD) assessment tool developed to assess Amine Oxide (“900439, (C10-

16); C10-C18-Alkyldimethylamine oxides

2. Average Daily Exposure = Unit Exposure * Application Rate (includes limitation 10%) * Units Treated * Absorption Rate÷ 70 kg 

Body Weight

3. MOE = Margin of Exposure = NOAEL  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 dermal 

exposure is for MOEs <100. The lowest estimated combined MOE was 4,700, based on 

liquid 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. Occupational Post-Application Risk

Exposure Scenarios

RD uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to 

as re-entry exposure). Such exposures may occur when workers enter previously treated 

areas to perform job functions, including activities related to crop production, such as 

scouting for pests or harvesting. Post-application exposure levels vary over time and 

depend on such things as the type of activity, the nature of the crop or target that was 

treated, the type of pesticide application, and the chemical’s degradation 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 typically 

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. CUMULATIVE EXPOSURE

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 with any other 

substances, and that DIPA does not appear to produce a toxic metabolite produced by other 

Liquid: Low Pressure 

handwand

Inhalation:

No respirator

0.030

0.72

lb ai/A

5 A/day Inhalation:

No respirator

0.00154

Inhalation:

65000
28

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 information regarding EPA's 

efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the 

cumulative effects of such chemicals, see EPA's website at 

http://www.epa.gov/pesticides/cumulative.

VIII. ENVIRONMENTAL JUSTICE STATEMENT 

Potential areas of environmental justice concerns, to the extent possible, were considered in 

this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal 

Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," 

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, RD estimates risks 

to population subgroups from pesticide exposures that are based on patterns 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, specialized 

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 bystanders and farm workers as well as lifestyle and traditional 

dietary patterns among specific subgroups

IX. ENVIRONMENTAL FATE CONSIDERATIONS

DIPA is not expected to persist in soil or water in the environment. DIPA is also expected 

to degrade fairly rapidly 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%) compartments 

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 values 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) NH3 added. After brief agitation a sample was removed for determining 
29

dissolved organic carbon (DOC), nitrate nitrogen (NO2) and nitrite nitrogen (NO3). 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 agitation. Every 4 hours, gas phase oxygen and carbondioxide 

were measured. On day 28, the aqueous phases were sampled for final DOC, NO2 and NO3

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 

Health Association, American Water Works Association and Water Environment Federation, 1992 

method for examination of water and wastewater, 18th edition, activated sludge from Bay City MI 

West Bay County 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 14C-DIPA concentrations of 0.5 and 5.2 mg/L with a final concentration of ~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 14CO2 were collected and analyzed for 14C 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 sites (Tittabawassee and Chippewa Rivers, Central 

MI). Vessels were dosed with 14C-DIPA and sampled to determine concentrations of DIPA, 

degradation products, and 14CO2. 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 levels. 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 biodegradability: 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 Dow HPV 2004, BASF 

Quadrol HPV 

Photodegradation (t1/2, 

days)

Absorbs light > 290 nm and direct photodegradation is 

possible. The predicted t1/2 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 2004
30

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. ECOTOXICITY

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 LC50s are > 100 mg/L. Studies conducted with Daphnia magna, DIPA is 

expected to be practically non-toxic to aquatic invertebrates. Freshwater invertebrate acute 

toxicity EC50s 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 EC50 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 studies 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 LC50 (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 observable 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 LC50 (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 Health Association (APHA) Standard Methods for the 

Examination of Water and Wastewater, Method No. 231. The LC50 (24-hr) was 1100 mg/L 

(Birdie et al. 1971).
31

In a 48-hour static acute toxicity study on Leuciscus idus with DIPA, the static LC50 (48-hr) 

was 1000 mg/L (Huels AG).

In a 96-hour static acute toxicity study on Leuciscus idus with DIPA, the NOAEC was 460 

mg/L. The static LC50 (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, the 24-hour EC50

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 EC50

was 2777.7 mg/L (nominal concentration). 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 EC50 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 LC50 >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 LC50 1100 Practically nontoxic Birdie et al. 1971

Leuciscus idus 48-hour LC50 1000 Practically nontoxic Huels AG

Leuciscus idus 96-hour 

NOAEC/LC50

460

1000-2200

Practically nontoxic BASF AG 1982

Invertebrate Daphnia magna 

Straus

24-hour EC50 353.8 (nominal) Practically nontoxic BASF AG

Daphnia magna 

Straus

48-hour EC50 277.7 (nominal) Practically nontoxic BASF AG

Plant Scenedesmus 

subspicatus

72-hour EC50 270 mg/L 

(growth rate, 

nominal)

Practically nontoxic BASF AG

XI. RISK CHARACTERIZATION 
32

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. 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. 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 preand post-harvest crops in accordance with 40 CFR 180.910. 

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 modifier in 

personal care products (e.g., cosmetics, 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 completed and performed using the Dietary Exposure Evaluation Model 

DEEM-FCIDTM, Version 3.16. The chronic Reference 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 

study 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 interspecies 

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 quantification 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, 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 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 
33

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 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 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.

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 intermediateterm 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 wearing protective 

respirators when using open pour in support of aerial and groundboom 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 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.

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 ZahnWellens/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 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 LC50s are > 100 mg/L. Studies conducted with Daphnia magna, DIPA is expected to 

be practically non-toxic to aquatic invertebrates. Freshwater invertebrate acute toxicity EC50s 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 EC50 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 Justice in Minority Populations and Low-Income Populations," 

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 aggregate exposure 

to DIPA when considering residential, occupational, 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 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 assessed as 

safe under section 408(q) of the FFDCA.
35

REFERENCES

Alexander, H.C. and 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 for DIPA and TIPA.

BASF AG, Department of Ecology; unpublished study; (1132/87) unpublished study as

summarized in Dow HPV summary and test plan for DIPA and TIPA.

BASF AG, 1981. Department of Ecology; unpublished study as a summarized in the Dow HPV 

summary and test plan for 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 study 345-351 as summarized in Dow

HPV summary and test plan DIPA and TIPA.

BASF AG, Department of Toxicology (1993) unpublished study (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 DIPA 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

Dryzga, M. (1987) Dow unpublished study as summarized in DOW HPV summary and test plan 

DIPA and TIPA.

Goodwin, P.A. and West, R.J. 1998. Evaluation of Ready Biodegradability of 

Monoisopropanolamine, Diisopropanolamine and Triisopropanolamine Using the OECD Method 

301F; Manometric Respirometry Test. R&D Report of The Down Chemical Company. 

Unpublished study as summarized in the Dow HPV summary and test plan for DIPA and TIPA.

Huels AG, (1985) unpublished study as summarized in DOW HPV summary and test plan DIPA 

and TIPA and SIAM 29, 20-22, October 2009.

Huels AG, Department of Biology and Toxicology. Unpublished results (Nr. 99), 12,03.199 as 

summarized in Dow HPV summary and test plan for DIPA and TIPA.

Johnson, K., Dryzga, M., Brooks, K., et al. (2007) Repeated dose toxicity and developmental 

toxicity diisopropanolamine to rats. Food Chem. Toxicol. 45:1838-1845.

Lawlor, T. (1994) Dow Chemical unpublished study as summarized in Dow HPV summary and 

test plan DIPA and TIPA.

McCollister, S. et al. (1981) Dow Chemical unpublished study as summarize din DOW HPV 

summary and test plan DIPA and TIPA.

Mortelmans, K., Haworth, S., Lawlor, T., et al. (1986) Salmonella mutagenicity tests. II. Results 

from the testing of 270 chemicals. Environ. Mutagen. 8(Suppl 7):1-119.

Murli, H. (1994) Dow Chemical unpublished study as summarized in Dow HPV summary and test 

plan DIPA and TIPA.

RTECS, update 9607: Ain Shams Medical Journal, 20:23 (1979) as summarized in DOW HPV 

summary and test plan DIPA and TIPA.

Saghir, S., Frantz, S., Spence, M., et al. (2007) Pharmacokinetics and bioavailability of 

diisopropanolamine (DIPA) in rats following intravenous or dermal application. Food nad 

Chemical Toxicology 45:2047-2056

SIDS. Initial Assessment Profile for Isopropanolamine Category. Oct 20-22, 2009. 

http://webnet.oecd.org.Hpv/UI/handler.axd?id=92bff26c-f369-4369-87f2-4132c5bbec28. 

The Dow Chemical Company. Product Safety Assessment. Dow Diisopropanolamine. March 22, 

2010. http://www.dow.com/amines/prod/iso-dipa.htm. 

The Dow Chemical Company Technical Data Sheet for DIPA. 

http://www.dow.com/amines/prod/isodipa.htm. 
37

The Dow Chemical Company MSDS for DIPA. 

http://www.dow.com/webapps/msds/msdsearch.aspx.

The Dow Chemical Company. Isopropanolamines Physical properties. Undated. 

http://msdssearch.dow.com/PublishedLiteratureDowCOM/dh_0044/0901b803800446fd.pdf?filepa

th=amines/pdfs/noreg/111-01325.pdf&fromPage=GetDoc.

The Dow Cheimcal Company. HPV Robust Summaries for DIPA and TIPA. Dow 

Diisopropanolamine. December 2, 2004. 

http://www.epa.gov/hpv/pubs/summaries/isoproac/c15719tp.pdf.

TOXNET. Toxicology Data Network. National Library of Medicine. Diisopropanolamine. January 

12, 2006. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~y3xeFV:1.

Union Carbide (1974): Unpublished report prepared by the Chemical Hygiene Fellowship. 

Toxicity and irritation assay results of some food, drug and cosmetic product chemicals. Special 

report No. 37-77. Cited in BIBRA, Toxicity Profile – Diisopropanolamine, 1st ed. (1991) 

Union Carbide Data Sheet Isopropanolamines (1968) as summarized in DOW HPV summary and 

test plan DIPA and TIPA.

West, R.J. 1998. Biodegradation of Diisopropanolamine in Activated Sludge, Soil and River 

Water/Sediments. R&D Report of The Dow Chemical Company. Unpublished study as 

summarized in the Dow HPV summary and test plan for DIPA and TIPA. 

Yamamoto, K. Nakajima, A. Eimoto, H., et al. (1989) Carcinogenic activity of endogenously 

synthesized N-nitrosobis(2-hydroxypropyl)amine in rats administered bis (20hydroxypropyl)amine and sodium nitrite. Carcinogenesis 10:1607-1611

Yamamoto, K. (1991) Endogenously synthesized N-nitroso bis(2hydroxypropyl)amine and its 

carcinogenic potential in rats. J. Nara. Med. Ass. 42:134-152.
38

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/kg 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 0.097127 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%

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