FLUORIDE ACTION NETWORK PESTICIDE PROJECT
Return to FAN's Pesticide Homepage
Return to Trifluralin Index Page
Trifluralin. US EPA IRIS profile. 1993.
Trifluralin
(CASRN: 1582-09-8)
U.S. Environmental Protection Agency
INTEGRATED RISK INFORMATION SYSTEM (IRIS)
Substance Name: Trifluralin
CASRN: 1582-09-8
Last Revised: 10/01/93
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups
composed of U.S. EPA scientists from several Program Offices. The
summaries presented in Sections I and II represent a consensus reached in
the review process. The other sections contain U.S. EPA information which
is specific to a particular EPA program and has been subject to review
procedures prescribed by that Program Office. The regulatory actions in
Section IV may not be based on the most current risk assessment, or may be
based on a current, but unreviewed, risk assessment, and may take into
account factors other than health effects (e.g., treatment technology).
When considering the use of regulatory action data for a particular
situation, note the date of the regulatory action, the date of the most
recent risk assessment relating to that action, and whether technological
factors were considered. Background information and explan-ations of the
methods used to derive the values given in IRIS are provided in the five
Background Documents in Service Code 5, which correspond to Sections I
through V of the chemical files.
Category (section) Status Last Revised
------------------------------------ ----------- --------
Oral RfD Assessment Available 07/01/89
Inhalation RfC Assessment empty
Carcinogenicity Assessment Available 10/01/93
Drinking Water Health Advisories empty
U.S. EPA Regulatory Actions Available 01/01/92
Supplementary Data empty
Trifluralin RfD-
--------------- REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) -----------
Substance Name: Trifluralin
CASRN: 1582-09-8
The Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis, but may not exist for
other toxic effects such as carcinogenicity. In general, the RfD is an
estimate (with uncertainty spanning perhaps an order of magnitude) of a
daily exposure to the human population (including sensitive subgroups) that
is likely to be without an appreciable risk of deleterious effects during a
lifetime. Please refer to the Oral RfD Background Document for an
elaboration of these concepts. RfDs can also be derived for the
noncarcinogenic health effects of compounds which are also carcinogens.
Therefore, it is essential to refer to other sources of information
concerning the carcinogenicity of this substance. If the U.S. EPA has
evaluated this substance for potential human carcinogenicity, a summary of
that evaluation will be contained in the Carcinogenicity Assessment Section
of this file when a review of that evaluation is completed.
--------------------- RfD ASSESSMENT SUMMARY TABLE -----------------
Crit. Dose: 0.75 mg/kg-day [Study 1 NOAEL(adj)]
UF: 100 MF: 1 RfD: 7.5E-3 mg/kg-day Confidence: High
Crit Effect: (1) Increased liver weights; increase in methemoglobin
--------------NOAEL -----------------(Study 1)--LOAEL --------------------
-Reported -30 ppm -150 ppm
- - -
-ADJ - 0.75 mg/kg-day - 3.75 mg/kg-day
- - -
-Study Type -12-Month Dog Feeding Study -12-Month Dog Feeding Study
- - -
-Reference -Hoechst Aktiengesellschaft, 1984a-Hoechst Aktiengesellschaft,
- - -1984a
---------------------------------------------------------------------------
1) Hoechst Aktiengesellschaft, 1984a
12-Month Dog Feeding Study
Critical Effect: Increased liver weights; increase in methemoglobin
Defined Dose Levels:
NOAEL= 30 ppm
NOAEL(ADJ)= 0.75 mg/kg-day
LOAEL= 150 ppm
LOAEL(ADJ)= 3.75 mg/kg-day
Conversion Factors: 1 ppm = 0.025 mg/kg/day (assumed dog food
consumption)
------------ DISCUSSION OF PRINCIPAL AND SUPPORTING STUDIES --------
Hoechst Aktiengesellschaft. 1984a. MRID No. 00151908. Available from EPA.
Write to FOI, EPA, Washington, DC 20460.
Beagle dogs (6/sex/dose) were fed diets containing 0, 30, 150, or 750 ppm
(0, 0.75, 3.75, and 18.75 mg/kg/day) of trifluralin for 12 months. At 750
ppm (HDT; 18.75 mg/kg/day) there was a decreased weight gain in males and
females. There were some significant decreases in red blood cell parameters
in high-dose males and females. There was an increase in methemoglobin in
mid- and high-dose males and females. Total serum lipids, triglycerides,
and cholesterol were increased in high-dose males and females when compared
with controls. There were increases in liver weight in males receiving 150
and 750 ppm (3.75 and 18.75 mg/kg/day) and females receiving 750 ppm
trifluralin and increases in mean spleen weight in females receiving 750
ppm. There was no histologic findings that correlated with organ weight
changes. Based on the increases in liver weights and methemoglobin, the
LEL is 150 ppm (3.75 mg/kg/day) and the NOEL is 30 ppm (0.75 mg/kg/day).
------------------- UNCERTAINTY AND MODIFYING FACTORS ---------------
UNCERTAINTY FACTORS:
An uncertainty factor of 100 was used to account for the inter- and
intraspecies differences.
--------------------- ADDITIONAL COMMENTS / STUDIES -----------------
The previous RfD for trifluralin was established using a 3-month rat
feeding study (Eli Lilly & Co., 1985) with a Systemic LEL of 2.5 mg/kg/day
(lowest dose tested) based on increased alpha 1, alpha 2 and beta globulins
in the urine. The original data from this study was re-examined with regard
to total protein, alpha 1, alpha 2, and beta and gamma globulin. This
reexamina-tion concluded that an NOEL was established at 50 ppm (2.5
mg/kg/day) and an LEL at 200 ppm (10 mg/kg/day) based on evidence of
protein excretion (TP, alpha 1, alpha 2, and beta globulins). Therefore,
when the complete database for trifluralin is considered, the chronic dog
study is the appropriate study to establish the RfD.
Data Considered for Establishing the RfD
1) 1-Year Feeding - dog: Principal study - see previous description; core
grade guideline
2) 2-Year Feeding (oncogenic) - rat: Systemic NOEL=200 ppm (10 mg/kg/day);
Systemic LEL=800 ppm (40 mg/kg/day) (body weight changes); core grade
guideline (Hoechst Aktiengesellschaft, 1986a)
3) 2-Generation Reproduction - rat: Systemic NOEL=200 ppm (10 mg/kg/day);
Systemic LEL=630 ppm (31.5 mg/kg/day) (decreased body weight); Reproductive
NOEL=2000 ppm (100 mg/kg/day) (HDT); Reproductive LEL=none; core grade
minimum (Elanco Product Co., 1986)
4) 2-Generation Reproduction - rat: Reproductive NOEL=650 ppm (32.5
mg/kg/day); Reproductive LEL=2000 ppm (100 mg/kg/day) (HDT; reduced litter
size); Developmental NOEL=200 ppm (10 mg/kg/day); Developmental LEL=650 ppm
32.5 mg/kg/day) (increased weanling body weight); Parental NOEL=none;
Parental LEL=200 ppm (10 mg/kg/day) (LDT; increased kidney weights); At 650
ppm renal lesions of the proximal tubules and increased relative kidney
weights; core grade minimum (Hoechst Aktiengesellschaft, 1984b)
5) Teratology - rat: Maternal NOEL=225 mg/kg/day; Maternal LEL=475
mg/kg/day (decreased body weight and food consumption); Fetotoxic NOEL=475
mg/kg/day; Fetotoxic LEL=1000 mg/kg/day (decreased mean fetal body weight);
Teratogenic NOEL=1000 mg/kg/day (HDT); Teratogenic LEL=none; core grade
minimum (Elanco Product Co., 1984a)
6) Teratology - rabbit: Maternal NOEL=100 mg/kg/day; Maternal LEL=225
mg/kg/day (body weight loss); Fetotoxic NOEL=225 mg/kg/day; Fetotoxic
LEL=500 mg/kg/day (HDT; decreased fetal weight and increased number of
fetal runts); Teratogenic NOEL=500 mg/kg/day (HDT); Teratogenic LEL=none;
core grade minimum (Elanco Product Co., 1984b)
Other Data Reviewed:
1) Oncogenicity - mouse: Systemic NOEL=50 ppm (7.5 mg/kg/day); Systemic
LEL=200 ppm (30 mg/kg/day) (increased liver weight in males); At 800 ppm
(120 mg/kg/day) (HDT) an increase in liver weight in males and females was
observed; core grade supplementary (pending submission of historical
control data) (Hoechst Aktiengesellschaft, 1986b)
2) 6-Month Feeding - dog: NOEL=none; LEL=400 ppm (10 mg/kg/day) (LDT;
enlarged livers, discolored kidneys, corneal vascularization, hemolytic
anemia and increase alkaline phosphatase); core grade supplementary
(Hoechst Aktiengesellschaft, 1981)
3) 3-Month Feeding - rat: NOEL=none; LEL=800 ppm (40 mg/kg/day) (LDT;
liver/body weight increases and pituitary/body weight decreases in all
doses); core grade minimum (Hoechst Aktiengesellschaft, 1980)
4) 3-Month Special Urinalysis Study - rat: NOEL=50 ppm (2.5 mg/kg/day);
LEL=200 ppm (10 mg/kg/day) [evidence of protein excretion (TP, alpha 1,
alpha 2, and beta globulins)]; core grade minimum (Eli Lilly & Co., 1985)
5) Teratology - rat: Maternal NOEL=100 mg/kg/day; Maternal LEL=500
mg/kg/day (decreased food consumption and increased liver and spleen
weights); Developmental NOEL=none; LEL=20 mg/kg/day (reduced skeletal
maturity and increased vascular fragility); core grade supplementary
(Hoechst Aktiengesellschaft, 1983)
6) Teratology - rabbit: Maternal and Developmental NOEL=60 mg/kg/day (HDT);
Maternal and Developmental LEL=none; core grade supplementary (Hoechst
Aktiengesellschaft, 1984e)
Data Gap(s): None
------------------------- CONFIDENCE IN THE RfD ---------------------
Study: High Data Base: High RfD: High
The critical study is of good quality and is given a high confidence
rating. Additional studies are supportive and of good quality; therefore,
the data base is given a high confidence rating. High confidence in the
RfD follows.
--------------------- EPA DOCUMENTATION AND REVIEW -----------------
Source Document: This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documention: Pesticide Registration Standard, June 1985;
Position Document 1/2/3, August 1979; Position Document 4, July 1982;
Pesticide Registration Files
Agency Work Group Review: 05/30/86, 02/18/87, 04/20/89
Verification Date: 04/20/89
----------------------------- EPA CONTACTS -------------------------
William Burnam / OPP -- (703)305-7491
George Ghali / OPP -- (703)305-7490
----------------------------- BIBLIOGRAPHY -------------------------
Elanco Product Company. 1984a. MRID No. 00152419. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Elanco Product Company. 1984b. MRID No. 00152421. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Elanco Product Company. 1986. MRID No. 00162543. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Eli Lilly and Company. 1985. MRID No. 00157156, 40138301. Available from
EPA. Write to FOI, EPA, Washington D.C. 20460.
Hoechst Aktiengesellschaft. 1980. MRID No. 00151906. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Hoechst Aktiengesellschaft. 1981. MRID No. 00151907. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Hoechst Aktiengesellschaft. 1983. MRID No. 00151899. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Hoechst Aktiengesellschaft. 1984a. MRID No. 00151908. Available from
EPA. Write to FOI, EPA, Washington D.C. 20460.
Hoechst Aktiengesellschaft. 1984b. MRID No. 00151901, 00151903.
Available from EPA. Write to FOI, EPA, Washington D.C. 20460.
Hoechst Aktiengesellschaft. 1984c. MRID No. 00151900. Available from
EPA. Write to FOI, EPA, Washington D.C. 20460.
Hoechst Aktiengesellschaft. 1986a. MRID No. 00153496, 00162456, 00162458.
Available from EPA. Write to FOI, EPA, Washington D.C. 20460.
Hoechst Aktiengesellschaft. 1986b. MRID No. 00158935. Available from
EPA. Write to FOI, EPA, Washington D.C. 20460.
--------------------------- REVISION HISTORY -----------------------
02/89 RfD Data: Oral RfD summary noted as pending change
05/89 RfD Data: Withdrawn; new RfD verified (in preparation)
07/89 RfD Data: Oral RfD summary replaced; RfD changed
Trifluralin RfC-
-------- REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) ----
Substance Name: Trifluralin
CASRN: 1582-09-8
Status: empty
Trifluralin CARCIN-
-------------- CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE ----------
Substance Name: Trifluralin
CASRN: 1582-09-8
The Carcinogenicity Assessment Section provides information on three
aspects of the carcinogenic risk assessment for the agent in question; the
U.S. EPA classification, and quantitative estimates of risk from oral
exposure and from inhalation exposure. The classification reflects a
weight-of-evidence judgment of the likelihood that the agent is a human
carcinogen. The quantitative risk estimates are presented in three ways.
The slope factor is the result of application of a low-dose extrapolation
procedure and is presented as the risk per mg/kg/day. The unit risk is the
quantitative estimate in terms of either risk per ug/L drinking water or
risk per ug/cu.m air breathed. The third form in which risk is presented
is a drinking water or air concentration providing cancer risks of 1 in
10,000, 1 in 100,000 or 1 in 1,000,000. The Carcinogen Assessment
Background Document provides details on the rationale and methods used to
derive the carcinogenicity values found in IRIS. Users are referred to the
Oral RfD and Inhalation RfC Sections for information on long-term toxic
effects other than carcinogenicity.
-------- EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY ----
WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification: C; possible human carcinogen
BASIS
Classification is based on the induction of urinary tract tumors (renal
pelvis carcinomas and urinary bladder papillomas) and thyroid tumors
(adenomas/carcinomas combined) in one animal species (F344 rats) in one
study. Trifluralin is structurally similar to ethalfluralin, a carcinogen
in the rat.
HUMAN CARCINOGENICITY DATA
None.
ANIMAL CARCINOGENICITY DATA
Limited. A chronic bioassay of trifluralin was performed in F344 rats in
which 60 animals/sex received dietary doses of 0, 813, 3250 and 6500 ppm
for 2 years (Emmerson et al., 1980). Statistically significant (p<0.05)
increases in the incidences of bladder papillomas and renal pelvis
carcinomas were found at the highest dose level tested in female and male
rats, respectively. In addition, a significant (p<0.05) increase in the
incidence of follicular cell tumors of the thyroid gland (adenomas plus
carcinomas combined) occurred at the highest dose tested in male rats. All
of the previous increased tumor incidences exceeded historical incidences
for similar tumors in other studies performed at the test laboratory.
Four other rodent chronic bioassays of trifluralin in the diet have been
performed. These included a 2-year study in Sprague-Dawley rats (0, 200,
1000 and 2000 ppm) (Eli Lilly, 1966), a 78-week study in Osborne-Mendel
rats (0, 3250 and 6500 ppm) (NCI, 1978a), a 78-week study in B6C3F1 mice
(0, 2375 and 5000 ppm) (NCI, 1978b) and a 2-year study in B6C3F1 mice (0,
563, 2250 and 4500 ppm) (Eli Lilly, 1980). Trifluralin did not produce
statistically significant increases in tumors in any of these studies.
SUPPORTING DATA FOR CARCINOGENICITY
Trifluralin is structurally related to ethalfluralin, which is oncogenic,
producing mammary gland fibroadenomas in female F344 rats. In addition,
both trifluralin and ethalfluralin produce a common urinary metabolite in
rats that produces nonneoplastic renal pathology, including bladder
calculi.
There was no evidence of mutagenicity for trifluralin in rat dominant
lethal, L5178Y mouse lymphoma, Salmonella typhimurium, Saccharomyces
cerevisiae, and DNA repair assays, nor did it induce sister chromatid
exchange in Chinese hamster ovary cells.
----- QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE -
Slope Factor: 7.7E-3 per mg/(kg/day)
Unit Risk: 2.2E-7 per ug/liter
Extrapolation Method: linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
E-4 (1 in 10,000) 5E+2 ug/liter
E-5 (1 in 100,000) 5E+1 ug/liter
E-6 (1 in 1,000,000) 5E+0 ug/liter
---------- DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) ------
Tumor Type: combined renal pelvis carcinomas, urinary bladder
papillomas and/or thyroid adenomas and carcinomas
Test Animals: rat/F344, male
Route: diet
Administered Human Equivalent Tumor
Dose (ppm) Dose (mg/kg)/day Incidence
------------ ---------------- ---------
0 0 5/60
813 5.1 5/60
3250 21.9 9/60
6500 46.5 17/60
--------- ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) -----
Incidence data were based on observation of at least one tumor at any of
the indicated sites.
The unit risk should not be used if the water concentration exceeds 5E+4
ug/L, since above this concentration the slope factor may differ from that
stated.
------- DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) ---
Tumors were induced at different sites in F344 rats of one or both sexes.
An adequate number of animals was observed in a lifetime study.
-- QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE -
No Data Available
--------------------- EPA DOCUMENTATION AND REVIEW -----------------
Source Document: U.S. EPA. 1982. Trifluralin (TREFLAN) Position Document
4. Office of Pesticides and Toxic Substances, Washington, DC. July 1982.
U.S. EPA. 1986. Toxicology Branch Peer Review Committee Memorandum on
Trifluralin, April 11.
The Toxicology Branch Peer Review Committee reviewed data on trifluralin.
Agency Work Group Review: 05/13/87, 06/03/87, 06/24/87
Verification Date: 06/24/87
--------------- EPA CONTACTS (CARCINOGENICITY ASSESSMENT) -----------
Elizabeth A. Doyle / OPP -- (703)308-2722
----------------------------- BIBLIOGRAPHY -------------------------
Eli Lilly Company. 1966. Rat oncogenicity study of trifluralin. (Cited
in U.S. EPA, 1986)
Eli Lilly Company. 1980. Mouse oncogenicity study of trifluralin. (Cited
in U.S. EPA, 1986)
Emmerson, J.L., E.C. Pierce, J.P. McGrath, et al. 1980. The chronic
toxicity of compound 36352 (trifluralin) given as a compound of the diet to
the Fischer 344 rats for two years. Studies R-87 and R-97 (unpublished
study received September 18, 1980 under 1471-35; submitted by Elanco
Products Co., Division of Eli Lilly and Co., Indianapolis, IN).
NCI (National Cancer Institute). 1978a. Rat oncogenicity study of
trifluralin. (Cited in U.S. EPA, 1986)
NCI (National Cancer Institute). 1978b. Mouse oncogenicity study of
trifluralin. (Cited in U.S. EPA, 1986)
U.S. EPA. 1982. Trifluralin (TREFLAN) Position Document 4. Office of
Pesticides and Toxic Substances, Washington, DC, July.
U.S. EPA. 1986. Toxicology Branch Peer Review Committee Memorandum on
Trifluralin, April 11.
--------------------------- REVISION HISTORY -----------------------
08/88 Ca Data: Carcinogen summary on-line
10/93 Ca Contact: Primary contact changed; secondary's phone no. changed
Trifluralin DWHA-
---------------------- DRINKING WATER HEALTH ADVISORIES ------------------
Substance Name: Trifluralin
CASRN: 1582-09-8
Status: empty
Trifluralin Regs-
------------------------- U.S. EPA REGULATORY ACTIONS ---------------------
Substance Name: Trifluralin
CASRN: 1582-09-8
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in the
Oral RfD, Inhalation RfC and Carcinogen Assessment Sections, as this may
explain inconsistencies. Also note that some regulatory actions consider
factors not related to health risk, such as technical or economic
feasibility. Such considerations are indicated for each action. In
addition, not all of the regulatory actions listed in this section involve
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background
information on each regulatory action in the Regulatory Action Background
Document.
------ FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTCIDE ACT (FIFRA) --
Pesticide Active Ingredient Registration Standard
Status: Issued 1987
Reference: Trifluralin Pesticide Registration Standard. April, 1987
(NTIS No. PB87-201935).
Contact: Registration Branch / OPP / (703)305-5447
Pesticide Active Ingredient Special Review
Action: Final Regulatory Decision - PD 4
Year: 1982
Econ/Tech?: No, does not consider economic or technical feasibility
Reference: 47 FR 33777 (08/04/82) [NTIS# PB82-263252]
Contact: Special Review Branch / OPP / (703)308-8010
Summary of Regulatory Actions: Registration allowed to continue if total
N-nitrosamine contamination is kept below 0.5 ppm for technical products,
and below a figure based on trifluralin content for formulated products.
Criterion of concern: oncogenicity and mutagenicity.
--------------------------- REVISION HISTORY -----------------------
01/92 Reg Data: Regulatory Action section on-line
Trifluralin Suppl-
----------------------------- SUPPLEMENTARY DATA -------------------------
Substance Name: Trifluralin
CASRN: 1582-09-8
Status: empty