# 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 Healthii

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. 

## Disclaimer

Mention of any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health (NIOSH). In addition, citations to Web sites external to NIOSH do not constitute NIOSH endorsement of the sponsoring organization s or their programs or products. Furthermore, NIOSH is not responsible for the content of these Web sites.



## Ordering Information

To receive this document or information about other occupational safety and health topics,
contact NIOSH:

Telephone: 1

- 800

- CDC

- INFO (1

- 800

- 232

- 4636)
TTY: 1

- 888

- 232

- 6348
E

- mail: cdcinfo@cdc.gov Or visit the NIOSH Web site: www.cdc.gov/niosh

For a monthly update on news at NIOSH, subscribe to NIOSH eNews by visiting www.cdc.g ov/niosh/eNews

. 

## 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. XXXiii

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. 

## 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 system ic 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 H ealth (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 notation s (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 poten tial 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 propertie s 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

- manage ment 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 Preventioniv

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. 

## Content s

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 Referen ces

................................ ................................ ................................ ................................ ............... 13v

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. 

## Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists
ATSDR Agency for Toxic Substances and Disease Registry
CIB Current Intelligence Bulletin

cm 2 squared 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 G lobally 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 f or Chemical Safety (IRR) subnotation of SK: DIR indicating the potential for a chemical to be a skin irritant

following exposure to the skin
k aq coefficient in the watery epidermal layer
k p skin permeation coefficient
k pol coefficient in the protein fraction of the stratum corneum
k psc permeation coefficient in the lipid fraction of the stratum corneum
LD 50 d ose resulting in 50% mortality in the exposed population
LD Lo dermal lethal dose
LLNA local lymph node assay
LO AEL lowest

- observed

- adverse

- effect level log K OW base

- 10 logarithm of a substance’s octanol

– water partition

M molarity

m 3 cubic meter(s)

mg milligram(s) mg/cm 2 /hr milligram(s) per square centimeter per hour mg/kg milligram(s) per kilogram body weight mg/m 3 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 levelvi

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 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

exp osure of the skin
SI ratio ratio of skin dose to inhalation dose
SK skin notation
S W 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/cm 2 microgram(s) per square centimeter μg/cm 2 /hr microgram(s) per square centimeter per hour μL microliter(s) μmol micromole(s)vii

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. 

## 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% o r ( 2 ) recognized as a potential carcino gen 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 w ith (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, oc curring at or near the point of contact with chemicals.

Immune

- mediated responses

— Responses mediated by the immune system, in cluding allergic

responses.

Sensitization

— A specific immune

- mediated response that develops following ex posure to a chemical, which, upon re

- expo sure, can lead to allergic contact derma titis (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 a fter exposure
of the skin.viii

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. 

## 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

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. 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
Envi ronmental 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, OH1

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. 

## 1.0 Introduction

1.1 General Substance Information

Chemical: Atrazine
CAS No: 1912

- 24

- 9 Molecular weight (

MW ): 215.7
Molecular formula: C 8 H 14 CIN 5 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 NIO SH 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 informa tion 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
immunoto xicity), 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 poten tially 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 of2

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. the other skin notations so atrazine is assigned the SK notat ion 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
radioactivit y excreted in urine and feces over a 7

- day period following application of 0.167 milligrams (mg) or 1.98 mg of [ 14 C]

- atrazine to 25 square centimeters (cm 2 ) of the forearms of 10 healthy male subjects for 24 hours [Buchholz et al. 1999]. These investigator s 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] foun d 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 absor ption 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
ski n penetration study conducted by Hall et al. [1988], approximately 3 to 10% of the applied dose (3 micro curies [μCi] and 6 μCi of 14 C 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 [ 14 C]

- atrazine. These inve stigators 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 methano l 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
2 009]. 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 sk in 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

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. N o dermal lethal doses (LD Lo s) for humans have been identified. The report ed dermal LD 50 value in rats was greater than 2,500 mg/kg/day [Gaines and Linder 1986]. Because the reported acute dermal LD 50 values for rats are higher than the critical dermal LD 50 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 devel opmental 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 st udy, 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 handlin g 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
wit h 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

. I n 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 adeq uate 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 r outes 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 designatio ns of multiple governmental and nongovernmental organizations for atrazine.4

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. 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 fo r 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 a ssessment, 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 int egrity 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 wit h 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

- agri cultural 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 st ructure

- activity relationship model, Deductive Estimation of Risk from Existing Knowledge ( DEREK ) for Windows, predicted atrazine to be negative for skin irritation.5

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. The available information upon which to base the potential of atrazine to cause skin irr itation 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 o thers) with a pesticide series of 36 substances including 1% atrazine. The authors reported no allergic reaction to atrazine in any of the subjects patch

tested. 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, predi cted 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 pro longed 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 ca use 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 Chemical s, is Skin Sensitization Category 1 (Hazard statement: May cause an allergic skin reaction) [ European Parliament 2008].6

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. 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.7

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. 

## 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 Bio logical 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

- tr iazine (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, Gil man 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 determ ination of free atrazine in urine. Bull Environ Contam Toxicol 44 :1

- 7.8

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. *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://eur

lex.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 re viewed 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, h ttp://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 Healt h 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 da tabase, http://www.osha.gov/chemicaldata/chemResult.html?recNo=300. Accessed: 01

- 28

- 15.

*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, Wet zel 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, http://www.epa.gov/iris/subst/0209.htm. Accessed: 01

- 28

- 15.

† 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 S I 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 incor porating 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 c oefficient ( k p ) 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 k p for the substance to describe the transdermal penetration rate of the substance [NIOSH 2009]. Th e k p , 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 K

OW ). In this example, k p 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 k

p 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 ( k p )

where k

psc is the permeation coefficient in the lipid fraction of the stratum corneum, k pol is the coefficient in the protein fraction of the stratum corneum, and k aq is the coefficient in the watery epidermal layer. These components are individually estimated by

log k psc = −1.326 + 0.6097 × log K
ow − 0.1786 × MW 0.5

k pol = 0.0001519 × MW −0.5

k aq = 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 k p , the water solub ility ( S

W ) 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
centi meters [cm 2 ]).

Equation 2: Determination of Skin Dose

Skin dose = k

p × S
w × Exposed skin surface area × Exposure time

= k p (cm/hr) × S
w (mg/cm 3 ) × 360 cm 2 × 8 hr

The inhalation dose (in mg) is derived on the basis of the occupational exposure li mit (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 mete rs (m 3 ) 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/m 3 ) × 10 m 3 × 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

T able 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( k psc ) cm/hr 0.0044 Permeation coefficient of the protein fraction of the stratum corneum ( k

pol ) cm/hr 1.034 × 10 - 5 Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.1702 Molecular weight ( MW

) * amu 215.7 Base

- 10 logarithm of its octanol

– water partition coefficient (Log K

ow ) * None 2.61 Calculated skin permeation coefficient ( k p ) cm/hr 0.0043
Skin dose
Water solubility ( S w ) * mg/cm 3 0.0347 Calculated skin permeation coefficient ( k p ) cm/hr 0.0043 Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8
Calculated skin dose mg 0.4285
Inhalation Dose Occupational exposure limit (OEL) † mg/m 3 5

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 Inst itute 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?CA S=1912249 . Accessed: 01

- 28

- 15.