Skin Notation (SK) Profile

Atrazine

[CAS No. 1912-24-9]

Department of Health and Human Services

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 
ii

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Suggested Citation

NIOSH [20XX]. NIOSH skin notation profile: Atrazine. By Hudson NL, Dotson GS. Cincinnati, 

OH: U.S. Department of Health and Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication 

No. XXX

DHHS (NIOSH) Publication No. XXX
iii

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Foreword

As the largest organ of the body, the skin performs multiple critical functions, such as serving as 

the primary barrier to the external environment. For this reason, the skin is often exposed to 

potentially hazardous agents, including chemicals, which may contribute to the onset of a 

spectrum of adverse health effects ranging from localized damage (e.g., irritant contact 

dermatitis and corrosion) to induction of immune-mediated responses (e.g., allergic contact 

dermatitis and pulmonary responses), or systemic toxicity (e.g., neurotoxicity and hepatoxicity). 

Understanding the hazards related to skin contact with chemicals is a critical component of 

modern occupational safety and health programs. 

In 2009, the National Institute for Occupational Safety and Health (NIOSH) published 

Current Intelligence Bulletin (CIB) 61 – A Strategy for Assigning New NIOSH Skin Notations

[NIOSH 2009-147]. This document provides the scientific rationale and framework for the 

assignment of multiple hazard-specific skin notations (SK) that clearly distinguish between the 

systemic effects, direct (localized) effects, and immune-mediated responses caused by skin 

contact with chemicals. The key step within assignment of the hazard-specific SK is the 

determination of the hazard potential of the substance, or its potential for causing adverse health 

effects as a result of skin exposure. This determination entails a health hazard identification 

process that involves use of the following:

 Scientific data on the physicochemical properties of a chemical

 Data on human exposures and health effects

 Empirical data from in vivo and in vitro laboratory testing

 Computational techniques, including predictive algorithms and mathematical models that 

describe a selected process (e.g., skin permeation) by means of analytical or numerical 

methods. 

This Skin Notation Profile provides the SK assignments and supportive data for atrazine. In 

particular, this document evaluates and summarizes the literature describing the hazard potential 

of the substance and its assessment according to the scientific rationale and framework outlined 

in CIB 61. In meeting this objective, this Skin Notation Profile intends to inform the audience—

mostly occupational health practitioners, researchers, policy- and decision-makers, employers, 

and workers in potentially hazardous workplaces—so that improved risk-management practices 

may be developed to better protect workers from the risks of skin contact with the chemicals of 

interest.

John Howard, M.D.

Director

National Institute for Occupational Safety and Health

Centers for Disease Control and Prevention
iv

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Contents

Foreword.............................................................................................................................................................. iii

Abbreviations........................................................................................................................................................ v

Glossary............................................................................................................................................................... vii

Acknowledgments.............................................................................................................................................. viii

1.0 Introduction.....................................................................................................................................................1

1.1 General Substance Information ..........................................................................................................................1

1.2 Purpose ...............................................................................................................................................................1

1.3 Overview of SK Assignment.................................................................................................................................1

2.0 Systemic Toxicity from Skin Exposure (SK: SYS)................................................................................................2

3.0 Direct Effects on Skin (SK: DIR).........................................................................................................................4

4.0 Immune-mediated Responses (SK: SEN)...........................................................................................................5

5.0 Summary..........................................................................................................................................................5

References.............................................................................................................................................................7

Appendix: Calculation of the SI Ratio for Atrazine ............................................................................................... 10

Overview .................................................................................................................................................................10

Calculation ..............................................................................................................................................................12

Appendix References...............................................................................................................................................13
v

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agency determination or policy.

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

cm2squared centimeter(s)

cm/hr centimeter(s) per hour

cm/s centimeter(s) per second

DEREK Deductive Estimation of Risk from Existing Knowledge

DIR skin notation indicating the potential for direct effects to the skin following 

contact with a chemical

EC European Commission 

g gram(s)

g/L gram(s)/liter

GHS Globally Harmonized System for Classification and Labelling of Chemicals

GPMT guinea pig maximization test

hr hour(s)

IARC International Agency for Research on Cancer

IPCS International Program for Chemical Safety 

(IRR) subnotation of SK: DIR indicating the potential for a chemical to be a skin irritant 

following exposure to the skin

kaq coefficient in the watery epidermal layer

kp skin permeation coefficient 

kpol coefficient in the protein fraction of the stratum corneum

kpsc permeation coefficient in the lipid fraction of the stratum corneum 

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

LLNA local lymph node assay

LOAEL lowest-observed-adverse-effect level 

log KOW base-10 logarithm of a substance’s octanol–water partition

M molarity

m

3

cubic meter(s)

mg milligram(s)

mg/cm2/hr milligram(s) per square centimeter per hour

mg/kg milligram(s) per kilogram body weight

mg/m3 milligram(s) per cubic meter

mL milliliter(s)

mL/kg milliliter(s) per kilogram body weight

MW molecular weight

NIOSH National Institute for Occupational Safety and Health

NOAEL no-observed-adverse-effect level
vi

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

NTP National Toxicology Program

OEL occupational exposure limit

OSHA Occupational Safety and Health Administration

ppm parts per million

REL recommended exposure limit

RF retention factor 

SEN skin notation indicating the potential for immune-mediated reactions following 

exposure of the skin

SI ratio ratio of skin dose to inhalation dose

SK skin notation

SW solubility in water

SYS skin notation indicating the potential for systemic toxicity following exposure of 

the skin

USEPA United States Environmental Protection Agency

μg microgram(s)

μg/cm2 microgram(s) per square centimeter

μg/cm2/hr microgram(s) per square centimeter per hour

μL microliter(s)

μmol micromole(s)
vii

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Glossary 

Absorption—The transport of a chemical from the outer surface of the skin into both the skin 

and systemic circulation (including penetration, permeation, and resorption). 

Acute exposure—Contact with a chemical that occurs once or for only a short period of time. 

Cancer—Any one of a group of diseases that occurs when cells in the body become abnormal 

and grow or multiply out of control. 

Contaminant—A chemical that is (1) unintentionally present within a neat substance or mixture 

at a concentration less than 1.0% or (2) recognized as a potential carcinogen and present within a 

neat substance or mixture at a concentration less than 0.1%. 

Cutaneous (or percutaneous)—Referring to the skin (or through the skin). 

Dermal—Referring to the skin. 

Dermal contact—Contact with (touching) the skin. 

Direct effects—Localized, non-immune-mediated adverse health effects on the skin, including 

corrosion, primary irritation, changes in skin pigmentation, and reduction/disruption of the skin 

barrier integrity, occurring at or near the point of contact with chemicals. 

Immune-mediated responses—Responses mediated by the immune system, including allergic 

responses. 

Sensitization—A specific immune-mediated response that develops following exposure to a 

chemical, which, upon re-exposure, can lead to allergic contact dermatitis (ACD) or other 

immune-mediated diseases such as asthma, depending on the site and route of re-exposure. 

Substance—A chemical. 

Systemic effects—Systemic toxicity associated with skin absorption of chemicals after exposure 

of the skin.
viii

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Acknowledgments

This document was developed by the Education and Information Division (Paul Schulte, Ph.D., 

Director). G. Scott Dotson, Ph.D., was the project officer for this document, assisted in great part 

by Naomi Hudson, Dr.P.H., MPH, Clayton B’Hymer, Ph.D., and H. Fredrick Frasch, Ph.D. The 

basis for this document was a report (Toxicology Excellence for Risk Assessment [TERA]) 

contracted by NIOSH and prepared by Bernard Gadagbui, Ph.D., and Andrew Maier, Ph.D. 

For their contribution to the technical content and review of this document, special 

acknowledgment is given to the following NIOSH personnel:

Denver Field Office

Eric Esswein, M.Sc.

Division of Applied Research and Technology 

John Snawder, Ph.D.

Mark Toraason, Ph.D.

Division of Respiratory Disease Studies 

Gregory A. Day, Ph.D. 

Aleksander Stefaniak, Ph.D. 

Division of Surveillance, Hazard Evaluations, and Field Studies

Matt Dahm, M.Sc.

Todd Niemeier, M.Sc.

Aaron Sussell, Ph.D.

Loren Tapp, M.D. 

Education and Information Division 

Devin Baker, M.Ed.

Charles L. Geraci, Ph.D.

Thomas J. Lentz, Ph.D.

Richard Niemeier, Ph.D.

Ralph Zumwalde, M.Sc.

Health Effects Laboratory Division

Stacey Anderson, Ph.D.

Michael Luster, Ph.D. 

Anna Shvedova, Ph.D.

Paul Siegel, Ph.D.

Berran Yucesoy, Ph.D.
ix

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information quality guidelines. It has not been formally disseminated by the National Institute for 

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agency determination or policy.

National Personal Protective Technology Laboratory

Heinz Ahlers, J.D., M.Sc.

Angie Shepherd

For their contribution to the technical content and review of this document, special 

acknowledgment is given to the following CDC personnel:

Office of Surveillance, Epidemiology and Laboratory Services/Epidemiology and Analysis 

Program Office 

Barbara Landreth, M.A.

In addition, special appreciation is expressed to the following individuals for serving as 

independent, external reviewers and providing comments that contributed to the development or 

improvement of this document:

 G. Frank Gerberick, Ph.D., The Procter and Gamble Company, Cincinnati, OH

 Dori Germolec, Ph.D., National Toxicology Program, National Institute for 

Environmental Health Sciences, Research Triangle, NC

 Ben Hayes, M.D., Ph.D., Division of Dermatology, Vanderbilt School of Medicine, 

Nashville, TN 

 Jennifer Sahmel, M.Sc., CIH, ChemRisk, Boulder, CO

 James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, OH
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policy.

1.0 Introduction 

1.1 General Substance Information 

Chemical: Atrazine

CAS No: 1912-24-9

Molecular weight (MW): 215.7

Molecular formula: C8H14CIN5

Structural formula:

Synonyms: 2-Chloro-4-ethylamino-6-isopropylamino-s-triazine; 6-Chloro-N-ethyl-N'-(1-methylethyl)-

1,3,5-triazine-2,4-diamine

Uses: Atrazine is a herbicide; in 1997, an estimated 75 million pounds (34 million kilograms) of atrazine 

were used [ATSDR 2003].

1.2 Purpose 

This skin notation profile presents (1) a brief summary of epidemiological and toxicological data 

associated with skin contact with atrazine and (2) the rationale behind the hazard-specific skin notation 

(SK) assignment for atrazine. The SK assignment is based on the scientific rationale and logic outlined 

in the Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New NIOSH Skin Notations

[NIOSH 2009]. The summarized information and health hazard assessment are limited to an evaluation 

of the potential health effects of dermal exposure to atrazine. A literature search was conducted through 

February 2013 to identify information on atrazine, including but not limited to data relating to its 

toxicokinetics, acute toxicity, repeated-dose systemic toxicity, carcinogenicity, biological 

system/function–specific effects (including reproductive and developmental effects and 

immunotoxicity), irritation, and sensitization. Information was considered from studies of humans, 

animals, or appropriate modeling systems that are relevant to assessing the effects of dermal exposure to 

atrazine. 

1.3 Overview of SK Assignment

Atrazine may potentially be capable of causing adverse health effects following skin contact. A critical 

review has determined that the quantity and quality of the available data are insufficient to assign any of 
2

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the other skin notations so atrazine is assigned the SK notation ID(SK). Table 1 provides an overview of 

the critical effects and data used to develop the SK assignment for atrazine. 

Table 1. Summary of the SK Assignment for atrazine

Skin Notation Critical

Effect

Available

Data

ID(SK)-- --

2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

Toxicokinetic studies following dermal exposure to atrazine were identified. Limited dermal absorption 

of atrazine has been reported in humans. Buchholz et al. [1999] measured unabsorbed radioactivity and 

radioactivity excreted in urine and feces over a 7-day period following application of 0.167 milligrams 

(mg) or 1.98 mg of [14C]-atrazine to 25 square centimeters (cm2) of the forearms of 10 healthy male 

subjects for 24 hours [Buchholz et al. 1999]. These investigators reported dermal absorption of 0.3-5.1% 

(the percent excreted in urine and feces) of the applied dose [Buchholz et al. 1999]. In a study where 

atrazine exposure was evaluated in 6 workers by personal and biological monitoring, Catanacci et al. 

[1993] found that box cutters workers were exposed to atrazine primarily via dermal contact (4 of the 6 

workers) and that 1-2% of the exposure dose of atrazine and its metabolites were detected in the urine of 

these workers, indicating that atrazine has limited absorption in humans following dermal absorption. 

Evidence of limited absorption following dermal exposure to atrazine has been provided by an animal

study in vivo showing the presence of atrazine and its metabolites in the plasma, urine, and/or feces. In a 

skin penetration study conducted by Hall et al. [1988], approximately 3 to 10% of the applied dose (3 

micro curies [μCi] and 6 μCi of 14C labeled acetone in 100 and 200 μL of acetone for young and old 

rats, respectively) penetrated the clipped dorsal skin of young and adult rats. Ademola et al. [1993] 

conducted an in vitro study with human skin samples exposed to [14C]-atrazine. These investigators 

reported that 2.1-6.2% of the dose permeated the skin and 7.3-16.4% after the skin was dosed with 

atrazine for a 20-hour period. Brand and Mueller [2002] reported 4.47% to 8.67% was recovered when

solutions of 1:10 and 1:40 of atrazine in methanol was applied to skin of hairless mice for 24 hr. 

The potential of atrazine to pose a skin absorption hazard was also evaluated, with use of a predictive 

algorithm for estimating and evaluating the health hazards of dermal exposure to substances [NIOSH 

2009]. The evaluation method compares an estimated dose accumulated in the body from skin 

absorption and an estimated dose from respiratory absorption associated with a reference occupational 

exposure limit. On the basis of this algorithm, a ratio of the skin dose to the inhalation dose (SI ratio) of 

0.01 was calculated for atrazine. An SI ratio of ≥0.1 indicates that skin absorption may significantly 

contribute to the overall body burden of a substance [NIOSH 2009]; therefore, atrazine is not considered 

to be significantly absorbed through the skin following dermal exposure. Additional information on the 

SI ratio and the variables used in its calculation are included in the appendix. 
3

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No dermal lethal doses (LDLos) for humans have been identified. The reported dermal LD50 value in rats 

was greater than 2,500 mg/kg/day [Gaines and Linder 1986]. Because the reported acute dermal LD50

values for rats are higher than the critical dermal LD50 value of 2,000 mg/kg body weight that identifies 

chemical substances with the potential for acute dermal toxicity [NIOSH 2009], atrazine is not acutely 

toxic following dermal exposure. 

No repeat-dose, sub-chronic, or chronic studies following dermal exposure to atrazine were identified in 

humans or animals. 

No standard toxicity or specialty studies evaluating biological system/function specific effects 

(including reproductive and developmental effects and immunotoxicity) following dermal exposure to 

atrazine were identified in animals. Epidemiological studies were identified that evaluated the 

reproductive toxicity of atrazine. In eligible households in the Ontario Farm Family Health study, 

households with at least one member who worked on a farm, Arbuckle et al. [2001] found no increase in 

risk of spontaneous abortion following preconception or postconception exposure to atrazine; however 

only 20% of women in the cohort reported handling pesticides and the type of exposure and if women 

were directly or indirectly exposed to atrazine and the exposure group is unknown [Arbuckle et al. 

2001]. Using data from the same cohort, Curtis et al. [1999] reported that atrazine was not associated 

with any decrease in fecundity. However, an earlier study by Savitz et al. [1997] using the Ontario Farm 

Family health Study, found that the use of atrazine as a yard herbicide, but not as a crop herbicide, was 

associated with an increase in preterm delivery.In this study male farm activities were observed in 

relation to miscarriage and preterm delivery [Savitz et al. 1997]. The inconsistencies in these data, and 

the uncertainty of exposure data (route of exposure and direct vs. indirect exposure) prevent adequate 

evaluation of the potential for atrazine to cause reproductive or developmental toxicity following dermal 

exposure. 

Several case-control studies were located regarding cancer incidence and exposure of humans to atrazine 

[Burnmeister 1990; Cantor et al. 1992; Mills 1998]. Although these studies found correlation between 

atrazine use and some cancers (e.g., non-Hodgkin’s lymphoma, leukemia, soft-tissue sarcoma, brain 

cancer, prostate cancer, and testicular cancer), lack of information on the exposure routes precludes 

estimation of the contribution of the dermal route. No standard rodent cancer bioassays following 

dermal exposure were identified. No agency or organization has classified atrazine as a carcinogen. 

Table 2 summarizes carcinogenic designations of multiple governmental and nongovernmental 

organizations for atrazine. 
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Table 2. Summary of the carcinogenic designations*for atrazine by numerous governmental and 

nongovernmental organizations

Organization Carcinogenic designation 

NIOSH [2005] No designation

NTP [2014] No designation

USEPA [2014] No designation

European Parliament [2008] No GHS designation 

IARC [2012] Group 3: Not classifiable as to its carcinogenicity to humans

EC [2013]† No designation

ACGIH [2014] Group A3: Confirmed animal carcinogen with unknown 

relevance to humans

ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, 

Institute for Health and Consumer Protection; GHS = Globally Harmonized System for Classification and Labelling of 

Chemicals; IARC = International Agency for Research on Cancer; NIOSH = National Institute for Occupational Safety and 

Health; NTP = National Toxicology Program; USEPA = United States Environmental Protection Agency.

* The listed cancer designations were based on data from nondermal (such as oral or inhalation) exposure since studies using 

the dermal route of exposure were unavailable.

†Date accessed.

Taken together, information from human evidence, systemic toxicity studies, and toxicokinetic data are 

insufficient to demonstrate that atrazine is absorbed through the skin is systemically available or toxic. 

Therefore, on the basis of the data for this assessment, atrazine is not assigned the SK: SYS notation. 

3.0 Direct Effects on Skin (SK: DIR)

No human or animal in vivo studies on corrosivity of atrazine or in vitro tests for corrosivity using 

human or animal skin models or in vitro tests of skin integrity using cadaver skin were identified. 

However, the limited data identified demonstrate that atrazine is not a skin irritant in humans. A case 

report exists of a farmer who was diagnosed with acute contact dermatitis (painful erythematous 

eruptions with blistering and swelling) on his hands and forearms in the afternoon after applying 

atrazine to crops in the morning and cleaning the plugged nozzles of the spray rig several times with his 

bare hands earlier in the day [Schlicher and Beat 1972]. Because the farmer also applied a second 

pesticide in the afternoon of the same day, it was not possible to determine whether the dermatitis was 

caused by atrazine. Lisi et al. [1987] patch tested 384 subjects (including agricultural, ex-agricultural, 

and non-agricultural workers) with a pesticide series of 36 substances including 1% atrazine, which 

produced no skin irritation in any of the subjects patch-tested. No studies that evaluated the dermal 

irritation potential of atrazine in animals were available. The structure-activity relationship model, 

Deductive Estimation of Risk from Existing Knowledge (DEREK) for Windows, predicted atrazine to be 

negative for skin irritation.
5

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The available information upon which to base the potential of atrazine to cause skin irritation in humans 

is insufficient for adequate evaluation. Therefore, on the basis of the data for this assessment, atrazine is 

not assigned the SK: DIR (IRR) notation.

4.0 Immune-mediated Responses (SK: SEN)

There is insufficient information available to conclude that atrazine is a skin sensitizer based on 

occupational exposure experience. Lisi et al. [1987] conducted human patch testing on 384 subjects 

(including agricultural and ex-agricultural workers and others) with a pesticide series of 36 substances 

including 1% atrazine. The authors reported no allergic reaction to atrazine in any of the subjects patchtested. In other human patch tests, a 0.5% w/v suspension in water of an atrazine formulation did not 

cause skin sensitization on repeated application to 50 humans [Shelanski and Gittes 1965]. No studies 

that evaluated the potential for atrazine to cause skin sensitization were identified. The structure activity 

relationship model, DEREK for Windows, predicted atrazine to be positive for skin sensitization.

Atrazine does not appear to be a skin sensitizer based on a limited number of studies identified in 

humans. Predictive tests (guinea pig maximization tests, Buehler tests, murine local lymph node assays,

mouse ear swelling tests, etc) in animals were identified. Therefore, on the basis of the data for this 

assessment, atrazine is not assigned the SK: SEN notation.

5.0 Summary

The available data in both humans and animals indicate that atrazine is poorly absorbed through the 

skin. Although acute dermal toxicity studies identified suggested that atrazine has low toxicity, absence 

of reliable repeat-dose studies preclude adequate evaluation of the potential of atrazine to be 

systemically toxic following prolonged dermal exposure. No data were identified that demonstrated that 

atrazine was corrosive to the skin. Limited data precluded identifying if the substance was a skin irritant. 

The available information upon which to base the potential of atrazine to cause skin sensitization in 

humans is insufficient for adequate evaluation. Additionally, sensitization predictive tests in animals 

were not available for review. Therefore, on the basis of these assessments, atrazine is assigned a skin 

notation of ID(SK). 

Table 3 summarizes the skin hazard designations for atrazine previously issued by NIOSH and other 

organizations. The equivalent dermal designation for atrazine, according to the Global Harmonization 

System (GHS) of Classification and Labelling of Chemicals, is Skin Sensitization Category 1 (Hazard 

statement: May cause an allergic skin reaction) [European Parliament 2008]. 
6

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Table 3. Summary of previous skin hazard designations for atrazine

Organization Skin hazard designation 

NIOSH [2005] No designation

OSHA [2015]* No designation

ACGIH [2014] No designation; no sufficient data were available

EC [2013]* R43: May cause sensitization by skin contact

ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, 

Institute for Health and Consumer Protection; NIOSH = National Institute for Occupational Safety and Health; OSHA = 

Occupational Safety and Health Administration.

*Date Accessed.
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References

Note: Asterisks (*) denote sources cited in text; daggers (†) denote additional resources.

*ACGIH (American Conference of Governmental Industrial Hygienists) [2014]. Atrazine. In: TLVs and 

BEIs: Based on the documentation of Threshold Limit Values for chemical substances and physical 

agents and Biological Exposure Indices. Cincinnati, OH: American Conference of Governmental 

Industrial Hygienists.

*Ademola JI, Sedik LE, Wester RC, Maibach HI [1993]. In vitro percutaneous absorption and 

metabolism in man of 2-chloro-4-ethylamino-6-isopropylamine-s-triazine (atrazine). Arch Toxicol 

67:85-91.

*Arbuckle TE, Zhiqiu L, Mery LS [2001]. An exploratory analysis of the effect of pesticide exposure on 

the risk of spontaneous abortion in an Ontario farm population. Environ Health Perspect 109(8):851-

857.

*ATSDR [2003]. Toxicological profile for atrazine. In: Toxicological profile information sheet, 

http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=338&tid=59. Accessed: 01-28-15.

*Brand RM, Mueller C [2002]. Transdermal penetration of atrazine, alachlor, and trifluralin: effect of 

formulation. Toxicol Sci. 68(1): 18-23.

†Brown LM, Burmeister LF, Everett GD, Blair A [1993]. Pesticide exposures and multiple myeloma in 

Iowa men. Cancer Causes and Control 4:153-156.

*Buchholz BA, Fultz E, Haack KW, Vogel JS, Gilman SD, Gee SJ, Hammock BD, Hui X, Wester RC, 

Maibach HI [1999]. HPLC-accelerator MS measurement of atrazine metabolites in human urine after 

dermal exposure. Anal Chem 71:3519-3525.

*Burnmeister LF [1990]. Cancer in Iowa farmers: Recent results. Am J Ind Med 18:295-301.

*Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown LM, Schuman L, Dick FR [1992]. 

Pesticides and other agricultural risk factors for non-Hodgkin's lymphoma among men in Iowa and 

Minnesota. Cancer Res 52:2447-2455.

*Catenacci G, Barbieri F, Bersani M, Ferioli A, Cottica D, Maroni M [1993]. Biological monitoring of 

human exposure to atrazine. Toxicol Lett 69:217-222.

†Catenacci G, Maroni M, Cottica D, Pozzoli L [1990]. Assessment of human exposure to atrazine 

through the determination of free atrazine in urine. Bull Environ Contam Toxicol 44:1-7.
8

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information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

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policy.

*Curtis KM, Savitz DA, Weinberg CR, Arbuckle TE [1999]. The effect of pesticide exposure on time to 

pregnancy. Epidemiology 10:112-117.

*EC (European Commission) [2011]. Atrazine. In: EINICS (European Inventory of Existing 

Commercial Chemical Substances), http://esis.jrc.ec.europa.eu/. Accessed: 05-10-13. 

*European Parliament, Council of the European Union [2008]. Regulation (EC) No 1272/2008 of the 

European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging 

of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and 

amending Regulation (EC) No 1907/2006. OJEU, Off J Eur Union L353:1–1355, http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:EN:PDF. Accessed: 01-28-15. 

*Gaines TB, Linder RE [1986]. Acute toxicity of pesticides in adult and weaning rats. Fundam Appl 

Toxicol 7:299-308.

*Hall LL, Fisher HL, Sumler MR, Monroe RJ, Chernoff N, Shah PA [1988]. Dose response of skin 

absorption in young and adult rats. Philadelphia, PA: American Society for Testing and Materials 

(ASTM), 177-194.

*IARC (International Agency for Research on Cancer) [2012]. Agents reviewed by the IARC 

monographs. In: IARC monographs on the evaluation of carcinogenic risks to humans, 

http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed: 01-28-15.

†Innes JRM, Ulland BM, Valerio MG, Petrucelli L, Fishbein L, Hart ER, Pallotta AJ, Bates RR, Falk 

HL, Gart JJ, Klein M, Mitchell I, Peters J [1969]. Bioassay of pesticides and industrial chemicals for 

tumorigenicity in mice: A preliminary study. J Natl Cancer Inst 42(16):1101-1114.

*Lisi P, Caraffini S, Assalve D [1987]. Irritation and sensitization potential of pesticides. Contact 

Dermatitis 17:212-218

*Mills PK [1998]. Correlation analysis of pesticide use data and cancer incidence rates in California 

Counties. Arch Environ Health 53(6):410-413.

*NIOSH [2005]. NIOSH pocket guide to chemical hazards. Cincinnati, OH: U.S. Department of Health 

and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational 

Safety and Health, DHHS (NIOSH) Publication No. 2005-149, http://www.cdc.gov/niosh/npg/. 

Accessed: 01-28-15. 

*NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin notations. 

Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 

2009-147, http://www.cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. Accessed: 01-28-15. 
9

This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

*NTP [2014]. Report on Carcinogens. Thirteenth Edition; U.S. Department of Health and Human 

Services, Public Health Service. National Toxicology Program, 

http://ntp.niehs.nih.gov/pubhealth/roc/roc13/index.html. Accessed: 01-28-15.

*Occupational Safety and Health Administration (OSHA) [ND]. Atrazine. In: OSHA occupational 

chemical database, http://www.osha.gov/chemicaldata/chemResult.html?recNo=300. Accessed: 01-28-

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*Savitz DA, Arbuckle T, Kaczor D, Curtis KM [1997]. Male pesticide exposure and pregnancy 

outcome. Am J Epidemiol 146(12):1025-1036.

*Schlicher JE, Beat VB [1972]. Dermititis resulting from herbicide use – a case study. J Iowa Med Soc 

62: 419-420.

*Shelanski MV, Gittes HR [1965]. Atrazine 80W: Repeated Insult Patch Test. Geigy Chemical Corp. 

Lab: Industrial Biology Laboratories Inc. Study no. IBL 2430.

*Stevens JT, Breckenridge CB, Wetzel LT, Gillis JH, Luempert LG, Eldridge JC [1994]. Hypothesis for 

mammary tumorigenesis in Sprague-Dawley rats exposed to certain triazine herbicides. J Toxicol 

Environ Health 43:139-153.

*Stevens JT, Breckenridge CB, Wetzel L, Thakur AK, Lui C, Werner C, Luempert LG, Eldridge JC 

[1999]. A risk characterization for atrazine: Oncogenicity profile. J Toxicol Environ Health 56:69-109.

*USEPA [2014]. Integrated Risk Information System. In: Integrated Risk Information System, 

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†van der Merwe D, Riviere JE [2005]. Effects of vehicles and sodium lauryl sulphate on xenobiotic 

permeability and stratum corneum partitioning in porcine skin. Toxicol. 206: 325–335.

†Wetzel LT, Luempert LG, Breckenridge CB, Tisdel MO, Stevens, JT [1994]. Chronic effects of 

atrazine on estrus and mammary tumor formation in female Sprague-Dawley and Fischer-344 rats. J 

Toxicol Environ Health 43:169-182.

†WHO (World Health Organization) [1996]. WHO/FAO Data Sheets on Pesticides No. 82 Atrazine. 

World Health Organization, http://www.inchem.org/documents/pds/pds/pest82_e.htm. Accessed: 01-11-

11.
10

This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Appendix: Calculation of the SI Ratio for Atrazine

This appendix presents an overview of the SI ratio and a summary of the calculation of the SI ratio for 

atrazine. Although the SI ratio is considered in the determination of a substance’s hazard potential 

following skin contact, it is intended only to serve as supportive data during the assignment of the 

NIOSH SK. An in-depth discussion on the rationale and calculation of the SI ratio can be found in 

Appendix B of the Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New NIOSH Skin 

Notations [NIOSH 2009]. 

Overview 

The SI ratio is a predictive algorithm for estimating and evaluating the health hazards of skin exposure 

to substances. The algorithm is designed to evaluate the potential for a substance to penetrate the skin 

and induce systemic toxicity [NIOSH 2009]. The goals for incorporating this algorithm into the 

proposed strategy for assigning SYS notation are as follows:

(1) Provide an alternative method to evaluate substances for which no clinical reports or animal 

toxicity studies exist or for which empirical data are insufficient to determine systemic effects.

(2) Use the algorithm evaluation results to determine whether a substance poses a skin absorption 

hazard and should be labeled with the SYS notation.

The algorithm evaluation includes three steps:

(1) determining a skin permeation coefficient (kp) for the substance of interest,

(2) estimating substance uptake by the skin and respiratory absorption routes, and 

(3) evaluating whether the substance poses a skin exposure hazard.

The algorithm is flexible in the data requirement and can operate entirely on the basis of the 

physicochemical properties of a substance and the relevant exposure parameters. Thus, the algorithm is 

independent of the need for biologic data. Alternatively, it can function with both the physicochemical 

properties and the experimentally determined permeation coefficient when such data are available and 

appropriate for use.

The first step in the evaluation is to determine the kp for the substance to describe the transdermal 

penetration rate of the substance [NIOSH 2009]. The kp, which represents the overall diffusion of the 

substance through the stratum corneum and into the blood capillaries of the dermis, is estimated from 

the compound’s molecular weight (MW) and base-10 logarithm of its octanol–water partition coefficient 

(log KOW). In this example, kp is determined for a substance with use of Equation 1. A self-consistent set 

of units must be used, such as centimeters per hour (cm/hr), outlined in Table A1. Other model-based 

estimates of kp may also be used [NIOSH 2009].
11

This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Equation 1: Calculation of Skin Permeation Coefficient (kp)

psc pol aq

p

k k k

k

1 1

1







where kpsc is the permeation coefficient in the lipid fraction of the stratum corneum, kpol is the coefficient 

in the protein fraction of the stratum corneum, and kaq is the coefficient in the watery epidermal layer.

These components are individually estimated by

log kpsc = −1.326 + 0.6097 × log Kow − 0.1786 × MW0.5

kpol = 0.0001519 × MW−0.5

kaq = 2.5 × MW−0.5

The second step is to calculate the biologic mass uptake of the substance from skin absorption (skin 

dose) and inhalation (inhalation dose) during the same period of exposure. The skin dose is calculated as 

a mathematical product of the kp, the water solubility (SW) of the substance, the exposed skin surface 

area, and the duration of exposure. Its units are milligrams (mg). Assume that the skin exposure 

continues for 8 hours to unprotected skin on the palms of both hands (a surface area of 360 squared 

centimeters [cm2]). 

Equation 2: Determination of Skin Dose

Skin dose = kp × Sw × Exposed skin surface area × Exposure time

 = kp(cm/hr) × Sw (mg/cm3) × 360 cm2× 8 hr

The inhalation dose (in mg) is derived on the basis of the occupational exposure limit (OEL) of the 

substance—if the OEL is developed to prevent the occurrence of systemic effects rather than 

sensory/irritant effects or direct effects on the respiratory tract. Assume a continuous exposure of 8 

hours, an inhalation volume of 10 cubic meters (m3) inhaled air in 8 hours, and a factor of 75% for 

retention of the airborne substance in the lungs during respiration (retention factor, or RF).

Equation 3: Determination of Inhalation Dose

Inhalation dose = OEL × Inhalation volume × RF

 = OEL (mg/m3) × 10 m3× 0.75

The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of 

skin dose to inhalation dose (the SI ratio). This ratio quantitatively indicates (1) the significance of 

dermal absorption as a route of occupational exposure to the substance and (2) the contribution of 

dermal uptake to systemic toxicity. If a substance has an SI ratio greater than or equal to 0.1, it is 

considered a skin absorption hazard.
12

This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Calculation 

Table A1 summarizes the data applied in the previously described equations to determine the SI ratio for 

atrazine. The calculated SI ratio was 0.0114. On the basis of these results, atrazine is not predicted to 

represent a skin absorption hazard.

Table A1. Summary of Data used to Calculate the SI Ratio for Atrazine 

Variables Used in Calculation Units Value 

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(kpsc) cm/hr 0.0044

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol) cm/hr 1.034 × 10-5

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.1702

Molecular weight (MW)

*

amu 215.7

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

* None 2.61

Calculated skin permeation coefficient (kp) cm/hr 0.0043

Skin dose

Water solubility (Sw)

* mg/cm3

0.0347

Calculated skin permeation coefficient (kp) cm/hr 0.0043

Estimated skin surface area (palms of hand) cm2360

Exposure time hr 8

Calculated skin dose mg 0.4285

Inhalation Dose

Occupational exposure limit (OEL)† mg/m35

Inhalation volume m

3

10

Retention factor (RF) None 0.75

Inhalation dose mg 37.5

Skin dose–to–inhalation dose (SI) ratio None 0.0114

*

Variables identified from SRC [ND].

†

The OEL used in calculation of the SI ratio for atrazine was the NIOSH recommended exposure limit (REL) 

[NIOSH 2005].
13

This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Appendix References 

NIOSH [2005]. NIOSH pocket guide to chemical hazards. Cincinnati, OH: U.S. Department of Health 

and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational 

Safety and Health, DHHS (NIOSH) Publication No. 2005–149, http://www.cdc.gov/niosh/npg/. 

Accessed: 01-28-15. 

4.

NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin notations. 

Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 

2009-147, http://www.cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. Accessed: 01-28-15.

SRC [2009]. Interactive PhysProp database demo, 

http://esc.syrres.com/fatepointer/webprop.asp?CAS=1912249. Accessed: 01-28-15.