# Skin Notation (SK) Profile

Dichlorvos

[CAS No. 62

- 73

- 7]

Department of Health and Human Services
Centers for Disease Control and Prevention National Institute for Occupational Safety and Healthii

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## Suggested Citation

NIOSH [20XX]. NIOSH skin notation profile: Dichlorvos (PCP). 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)

Publicati on No. XXX

DHHS (NIOSH) Publication No. XXXiii

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## 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 pote ntially 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., allerg ic 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 2 009, 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 respo nses 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 deter mination 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 test ing

 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 dichlorvos

. 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 ou tlined
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 im proved 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 Pr eventioniv

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- 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. 

## Contents

FOREWORD

................................ ................................ ................................ ................................ ............................ III

ABBREVIATIONS

................................ ................................ ................................ ................................ ..................... V

GLOSSARY

................................ ................................ ................................ ................................ ............................. VII

ACKNOWLEDGMENTS

................................ ................................ ................................ ................................ ..... VIII

1.0 INTRODUCTION

................................ ................................ ................................ ................................ ................. 1

1.1 G ENERAL S UBSTANCE I NFORMATION :

................................ ................................ ................................ ................. 1
1.2 P URPOSE

................................ ................................ ................................ ................................ .............................. 1
1.3 O VERVIEW OF SK A SSIGNMENT

................................ ................................ ................................ .......................... 2

2.0 SYSTEMIC TOXICIT Y FROM SKIN EXPOSURE (SK: SYS)

................................ ................................ ...... 2

3.0 DIRECT EFFECTS O N SKIN (SK: DIR)

................................ ................................ ................................ ........... 4

4.0 IMMUNE

- MEDIATED RESPONSES ( SK: SEN)

................................ ................................ ............................. 5

5.0 SUMMARY

................................ ................................ ................................ ................................ ............................ 5

REFERENCES

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

APPENDIX: CALCULATION OF THE S I RATIO FOR DICHLORV OS

................................ ........................ 10

O VERVIEW

................................ ................................ ................................ ................................ ............................... 10
C ALCULATION

................................ ................................ ................................ ................................ ......................... 12
A PPENDIX R EFEREN CES

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

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## Abbreviations

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

cm 2 squared centimeter(s)
cm/hour centimeter(s) per hour

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
GHS G lobally Harmonized System for Classification and Labelling of Chemicals
GPMT guinea pig maximization test
IARC International Agency for Research on Cancer (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 ps c permeation coefficient in the lipid fraction of the stratum corneum
LD 50 dose resulting in 50% mortality in the exposed population
LD Lo dermal lethal dose
LOAEL lowest

- observed

- adverse

- effect level log K OW base

- 10 logarithm of a substance’s octano l

– water partition

M molarity

m 3 cubic meter(s)

mg milligram(s) mg/cm 3 milligram(s) per cubic centimeter mg/kg milligram(s) per kilogram body weight mg/min milligram(s) per minute
MW molecular weight
NIOSH National Institute for Occupational Safety and Health
NOAEL no

- observed

- adverse

- effect level
NTP National Toxicology Program
OEL occupational exposure limit
OSHA Occupational Safety and Health Administration
REL recommended exposure limit
RF retention factor
SEN skin notation indicating the potential for immune

- mediated reactions following

exposure of the skinvi

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. 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 ski n USEPA United States Environmental Protection Agencyvii

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## 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 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 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, 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

- exposure, 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 after exposure
of the skin.viii

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## 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, Todd Neimeier, M.Sc., and Sudha Pandalai, M.D., 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 Clayton B’Hymer, Ph.D. 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, an d Field Studies Matt Dahm, 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.

Health Effects Laboratory Division Stacey Anderson, Ph.D. H. Fredrick Frasch, Ph.D. Vic Johnson, Ph.D. Michael Luster, 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 Protection Technology Laboratory Heinz Ahlers, 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 ex pressed 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, ChemRis k, Boulder, CO

 James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, OH1

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- 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: Dichlorvos
CAS No: 62

- 73

- 7 Molecular weight (

MW ): 221.0
Molecular formula: (CH 3 O) 2 P(O)OCH=CCl 2 Structural formula:

Synonyms: 2,2

- Dichlorovinyl dimethyl phosphate; Phosphoric acid, 2,2

- dichloroethenyl dimethyl ester; 2,2

- Dichloroethenyl phosphoric acid dimethyl ester; 2,2

- Dichlorovinyl dimethyl phosphoric acid ester;
DDVP

Uses: Dichlorvos is used primarily as a broad spectrum organophosphate pesticide [ATSDR 1997].



### 1.2 Purpose

This skin notation profile presents ( 1 ) a brief summary of epidemiological and toxicological data associated with skin contact with dichlorvos and ( 2 ) the rationale behind the hazard

- specific skin notation (SK) assignment for dichlorvos. 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 effect s of dermal exposure to dichlorvos. A literature search was conducted through February 2013 to identify information on dichlorvos, including but not limited to data relating to its toxicokinetics, acute toxicity, repeated

- dose systemic toxicity, carcinogen icity

, 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 re levant to assessing the effects of dermal exposure to dichlorvos.2

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. 

### 1.3 Overview of SK Assignment
Dichlorvos is potentially capable of causing numerous adverse health effects following skin contact. A
critical review of available data has resulted in the f ollowing SK assignment for dichlorvos: SK: SYS

DIR (IRR)

- SEN . Table 1 provides an overview of the critical effects and data used to develop the SK assignment for dichlorvos.

Table 1. Summary of the SK Assignment for Dichlorvos

Skin Notation Critical Effect Available Data
SK: SYS Histopathological changes in male

reproductive system, lungs, liver, lymphatic glands, thymus, and heart; neurotoxicity; inhibition of cholinesterase activity Sufficient animal data

SK: DIR (IRR) Skin irritation Sufficient human and
animal data
SK: SEN Skin allergy, photoallergy Sufficient human and
animal data



## 2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

Quantitative estimates of dermal absorption in humans were not identified, but the potential for significant dermal absorption is indicated by cases of systemic effects including neurotoxicity resulting from cholinesterase (ChE) activity inhibition after a single episode of dermal exposure [Bisby and Simpson 1975; Mathias 1983] and cholinesterase inhibition

- assoc iated symptoms following dermal exposures in animals [Durham et al. 1957; Gajewski and Katkiewicz 1981; Tos

- Luty et al.1994]. An animal study was identified that reported skin penetration of dichlorvos. Tos

- Luty et al. [1994] applied 0.3%, 0.62%, and 1.5% of dichlorvos in ethanol to the tails of rats for 4 hours. The highest penetration of dichlorvos in the rat tail skin (2.91% absorbed) was at the lowest concentration (0.3%), and 2.02% and 2.23% absorbed reported for concentrations of 0.62% and 1.5% dichol orvos, respectively [Tos

- Luty et al. 1994]. The potential of dichlorvos 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 dos e to the inhalation dose (SI ratio) of 2.55 was calculated for dichlorvos. An SI ratio of ≥0.1 indicates that skin absorption may significantly contribute to the overall body burden of a substance [NIOSH 2009]; therefore, dichlorvos is considered
to be abs orbed through the skin following dermal exposure. Additional information on the SI ratio and
the variables used in its calculation are included in the appendix

.

No quantitative estimates of the lethal dermal dose (LD Lo ) in humans have been identified. In animals,
dermal LD 50 values (the dose resulting in 50% mortality in the exposed animals) were influenced by the3

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. purity of dichlorvos tested, the vehicle used, and condition of the skin. LD 50 values for rats were reported to range from 75 milligrams per ki logram body weight (mg/kg) to 107 mg/kg [Gaines 1969; Durham et al. 1957]. Gajewski and Katkiewicz [1981] reported an LD 50 in a negative logarithm of 3.49 mols/kg in rats. Because the reported acute dermal LD 50 values for experimental animals are all lower
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], dichlorvos is considered systemically toxic by the
dermal route.

Dermal application of dichlorvo s to several animal species, including the monkey and rat, over a few days, resulted in significant inhibition of brain, erythrocyte, or serum ChE activity [Durham et al. 1957; Moriearty et al. 1993 ]. Symptoms of neurotoxicity have been reported within 20 minutes in monkeys after single or repeated dermal exposure to doses of dichlorvos in xylene at doses as low as 50 mg/kg or in rats topically exposed to 75 mg/kg [Durham et al. 1957]. These studies indicate that dichlorvos is a potent cholinesterase (ChE) inhibitor, significantly reducing blood plasma, red blood cell and brain ChE following dermal exposure

.

No repeat

- dose dermal toxicity studies have been identified that quantified the dose to whic h humans were exposed. Although no chronic toxicity studies were identified in animals, the potential of dichlorvos to cause systemic toxicity has been evaluated in two repeat

- dose and two subchronic dermal toxicity studies. Dermal application of dichlorvo s over shorter durations, e.g. daily doses of 50 mg/kg, 75 mg/kg, and 100mg/kg resulted in death in monkeys after 8, 10, and 4 doses, respectively, while cholinergic signs (incoordination, muscle fasciculation, excessive salivation, labored breathing, mios is, and eventually inability or indisposition to move), and significant inhibition of cholinesterase activities in the plasma and red blood cells were qualitatively similar at all dosage levels [ Durham et al. 1957]. Luty et al. [1998] also reported dose

- de pendent histopathological changes in multiple organs (lungs, lymphatic glands and thymus, liver, kidneys and heart muscle) and stimulation of the bactericidal and phagocytic activity of neutrophils in rats exposed for 4 hours/day to 7.5 and 37.5 mg/kg

- day dichlorvos
for 4 weeks. In a subchronic study, dermal painting of rats with dichlorvos at a dose of 30 mg/kg per day (mg/kg

- day) for 90 days did not elicit any symptoms of intoxication or mortality [Ali and Abdalla 1992]. However, histopathological examina tion revealed changes in testicular and liver tissues, with the cellular damage being prominent in animals treated for 30 days or more [Ali and Abdalla 1992]. Degenerative seminiferous tubules and fewer Leydig cells were observed in the testis, while conge stion, atrophy, and cells at different stages of necrobiotic changes were observed in the liver [Ali and Abdalla 1992]. In an earlier 90

- day subchronic dermal painting study, rats exposed to 21.4 mg/kg

- day for 5 days/week exhibited few clinical symptoms or histopathology changes in the skin or testes [Dikshith et al. 1976]. Histopathologic changes in the testes occurred in one control animal, however, the power to detect a difference between the cases and controls was low, thus the possibility of an effect of the compound at 21.4 mg/kg

- day cannot be fully ruled out. The dose of 21.4 mg/kg

- day can be regarded as
the Lowest Observed

- Adverse

- Effect Level (LOAEL) for the testicular and hepatic effects. These studies demonstrate that dermal exposure to dichlorvos is systemically toxic, causing histopathological changes in internal organs, ChE inhibition, and central nervous system effects at doses significantly lower than the critical dermal LOAEL value of 1,000 mg/kg for repeat

- dose toxicity that identifies
chemi cal substances with the potential for subchronic dermal toxicity [NIOSH 2009].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. No standard toxicity or specialty studies evaluating biological system/function

- specific effects (including developmental effects ) following dermal exposure to dichlorvos were identified in humans or animals. However, reproductive system effects were identified when histopathology examination following a 90

- day subchronic dermal exposure to 30 mg/kg/day observed testicular effects [Ali and Abdalla 1992]. The study by Luty et al . [1998] also demonstrates the potential of dichlorvos to affect immune system components (including lymphatic glands and thymus) following dermal exposure.

No studies that evaluated the potential of dermally

- applied dichlorvos to cause cancer in humans or animals were identified. Table 2 summarizes carcinogenic designations of multiple governmental and nongovernmental organizations for dichlorvos.

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

Organization Carcinogenic designation NIOSH [2005] No designation NTP [2014] No designation USEPA [2014] B2: probable human carcinogen European Parliament [2008] No GHS designation
IARC [2012] Group 2B: possibly carcinogenic to humans EC [2013] † No designation ACGIH [2014] A4: not classifiable as a human carcinogen 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, the toxicokinetic data in animals [Tos

- Luty et al. 1994] 1 , results from the predictive mathematical algorithm, acute toxici ty studies in animals [Gaines 1969; Durham et al. 1957]

, and subchronic dermal toxicity in animals [Durham et al. 1957; Dikshith et al. 1976; Ali and Abdalla 1992; Luty et al. 1998] are sufficient to demonstrate the potential of dichlorvos to be absorbed t hrough the skin and be systemically toxic, causing histopathological changes in testis, lungs, liver, lymphatic glands, thymus, and heart; neurotoxicity; and inhibition of cholinesterase activity following dermal exposure. Therefore, this assessment assign s a skin notation of SK: SYS for dichlorvos.


## 3.0 Direct Effects on Skin (SK: DIR)

No human or animal in vivo studies on corrosivity of dichlorvos 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, cases of irritant contact dermatitis have been reported in humans who came into direct contact

1 References in bold text indicate studies that serve as the basis of the SK assignments.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. with 1% to 10% solutions of, or mixtures containing, dichlorvos [Bisby and Simpson 1975; Cr once and Alden 1968; Mathias 1983] . Flea collar dermatitis

– a primary irritant contact dermatitis

– has been described in cats and dogs wearing dichlorvos

- impregnated PVC flea collars [Breen and Conroy 1971; Fox et al. 1969a, 1969b]. In guinea pigs, Ueda et al. [1994] reported a threshold irritation concentration of 1% dichlorvos, while 0.5% was reported to produce discrete erythema [Fujita 1985]. The structure

activity relationship model, Deductive Estimation of Risk from Existing Knowledge ( DEREK ), predi cted dichlorvos to be negative for skin irritation.

Case reports of irritant contact dermatitis in humans [Bisby and Simpson 1975; Cronce and Alden 1968; Mathias 1983] and animals [Breen and Conroy 1971; Fox et al. 1969a, 1969b] provide
sufficient evidenc e that dilute solutions are irritating to the skin. Therefore, on the basis of the data for this assessment, dichlorvos is assigned the SK: DIR (IRR) notation.



## 4.0 Immune

- mediated Responses (SK: SEN)

There is evidence from occupational exposures that dichlorvos has the potential to cause skin sensitization. For example, human diagnostic patch tests of occupational flower growers or tea growers with a history of pesticide dermatitis have shown allergic contact dermatitis response to dichlorvos [ Fujita 1 985; Ueda et al. 1994 ]. Horiuchi and Ando [1978] reported light

- induced hypersensitization to dichlorvos in photosensitizing patch tests of workers presenting with dermatitis caused by agricultural pesticides. Dichlorvos has been implicated as a causative agent in contact dermatitis in a case

- control study conducted by Matsushita et al. [1985], and may also cause skin sensitization in animals. A positive response was reported in a guinea pig maximization test (GPMT) [Ueda et al. 1994]. Fujita [1985] rated

t he allergenicity of dichlorvos as moderate using the guinea pig maximization test. DEREK also predicted dichlorvos to be a plausible skin sensitizer.

Human diagnostic patch tests conducted on agricultural workers presenting with contact dermatitis show

t hat dichlorvos has the potential to be a skin sensitizer [ Fujita 1985; Matsushita et al. 1985; Ueda et al. 1994] and a photosensitizer [Horiuchi and Ando 1978] . Predictive tests in animals (for example, guinea pig maximization tests) [ Fujita 1985; Ueda et al. 1994] demonstrate that dichlorvos causes skin sensitization. Therefore, on the basis of the data for this assessment, dichlorvos is assigned the SK: SEN
notation.


## 5.0 Summary

No quantitative estimates of dermal absorption in humans were identified. However, toxicokinetic data [Tos

- Luty et al. 1994] , acute toxicity studies [Gaines 1969; Durham et al. 1957] , and repeat

- dose and subchronic dermal toxicity in animals [Durham et al. 1957; Dikshith et al. 1976; Ali and Abdalla 1992; Luty et al. 1998], and results from the predictive mathematical algorithm sufficiently demonstrate the potential of dichlorvos to be absorbed through the skin and be systemically toxic, causing diverse
eff ects including histopathological changes in testis, lungs, liver, lymphatic glands, thymus, and heart; neurotoxicity; and inhibition of cholinesterase activity following dermal exposure. Although cases of skin corrosivity were not identified, case reports of irritant contact dermatitis in humans [Bisby and6

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. Simpson 1975; Cronce and Alden 1968; Mathias 1983] and animals [ Breen and Conroy 1971; Fox et al. 1969a, 1969b] provide sufficient evidence that dilute solutions of dichlorvos are irritating to the
skin. Human diagnostic patch tests conducted on agricultural workers presenting with contact dermatitis show that dichlorvos has the potential to be a skin sensitizer [ Fujita 1985; Matsushita et al. 1985; Ueda et al. 1994] and a photosensitizer [Horiuchi and And o 1978] . Predictive tests in animals (for example, guinea pig maximization tests) [ Fujita 1985; Ueda et al. 1994] demonstrate that dichlorvos causes skin sensitization. Therefore, on the basis of these assessments, dichlorvos is assigned a composite skin n otation of SK: SYS

- DIR (IRR)

- SEN

.

Table 3 summarizes the skin hazard designations for dichlorvos previously issued by NIOSH and other organizations. The equivalent dermal designations for dichlorvos, according to the Global Harmonization System (GHS) of Classification and Labelling of Chemicals, are Acute Toxicity Category 3 (Hazard statement: Toxic in contact with the skin) and Skin Sensitization Category 1 (Hazard statement: May cause an allergic skin reaction) [European Parliament 2008].

Table 3. Summary of previous skin hazard designations for dichlorvos

Organization Skin hazard designation NIOSH [2005] [skin]: Potential for dermal absorption; prevent skin contact OSHA [2015] * [skin]: Potential for dermal absorption ACGIH [2014] [skin]: symptoms of organophosphate poisoning have been seen in

humans and animals following dermal contact. DSEN: based upon positive patch

- test responses in humans and positive responses in the guinea pig maximization test. EC [2013] * R24: Toxic in contact with skin

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

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- 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.

*Ali FA, Abdalla MH [1992]. Pathological changes in testes and liver of male albino rats after dermal exposure to DDVP insecticide. J Egypt Public Health Assoc 67 (5

- 6):565

- 78.

*ACGIH (American Conference of Governmental Industrial Hygienists) [2002]. Dichlorvos. In: TLVs and BEIs: Based on the documentation of threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH: Amer ican Conference of Governmental Industrial Hygienists.

*ATSDR [1997]. Toxicological profile for dichlorvos. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substance and Disease Registry (ATSDR), http://w ww.atsdr.cdc.gov/toxprofiles/tp88.pdf. Accessed: 01

- 27

- 15

.

*Bisby JA, Simpson GR [1975]. An unusual presentation of systemic organophosphate poisoning. Med
J Aust 2 :394

- 395.

*Breen PT, Conroy JD [1971]. Flea

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*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 pac kaging 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

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*Fox I, Bayona IG, Armstrong JL [1969a]. Cat flea control through use of dichlorvos

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*Fujita Y [1985]. Studies on contact dermatitis from pesticides in tea growers. Acta Med Univ Kagoshima 27 (1):17

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*Gajewsk i D, Katkiewicz M [1981]. Activity of certain enzymes and histomorphological changes in subacute intoxication of rats with selected organophosphates. Acta Physiol Pol 32 (5):507

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*Horiuchi N, Ando Y [1978]. Photosensitivity Caused by Pesticides. Proce edings of the VII International Congress of Rural Medicine, September 17

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† HSDB (Hazardous Substances Data Bank) [2009]. Dichlorvos. In: HSDB (Hazardous Substances Data Bank), http://toxnet.nlm.nih.gov/cgi

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*NIOSH [2005]. NIOSH pocket guide to chemical hazards. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Con trol and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2005

- 149, http://www.cdc.gov/niosh/npg/.
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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. *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

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for small animals and man.] Igaku Seibutsugaku (Med. Biol.) 57 (3):98

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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: Calculati on of the SI Ratio for Dichlorvos

This appendix presents an overview of the SI ratio and a summary of the calculation of the SI ratio for dichlorvos. 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 fo r 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 not ation.

The algorithm evaluation includes three steps: (1) determining a skin permeation coefficient ( 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 sk in 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 su bstance to describe the transdermal penetration rate of the substance [NIOSH 2009]. The 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 m olecular 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 outlined in Table A1. Other mode l

- 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 solubility ( 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 o f 360 squared centimeters [cm 2 ]).

Equation 2: Determination of Skin Dose

Skin dose = k

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

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

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 (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 ) th e 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 dichlorvos. The calculated SI ratio was 2.55. On the basis of these results, dichlorvos is predicted to represent a skin absorption hazard.

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

Variables Used in Calculation Units Value Skin permeation coefficient
Permeation coefficient of stratum corneum lipid path( k psc ) cm/hour 8.2281 × 10 - 4 Permeation coefficient of the protein fraction of the stratum corneum ( k

pol ) cm/hour 1.0218 × 10 - 5 Permeation coefficient of the watery epidermal layer ( k aq ) cm/hour 0.1682 Molecular weight ( MW

) * amu 220.98 Base

- 10 logarithm of its octanol

– water partition coefficient (Log K

ow ) * None 1.47 Calculated skin permeation coefficient ( k p ) cm/hour 8.2892 × 10 - 4

Skin dose
Water solubility ( S w ) * mg/cm 3 8 Calculated skin permeation coefficient ( k p ) cm/hour 8.2892 × 10 - 4
Estimated skin surface area (palms of hand) cm 2 360 Exposure time hour 8
Calculated skin dose mg 19.1
Inhalation Dose Occupational exposure limit (OEL) † mg/m 3 1

Inhalation volume m 3 10 Retention factor (RF) None 0.75
Inhalation dose mg 7.5
Skin dose

– to

– inhalation dose (SI) ratio None 2.55

* Variables identified from SRC [ND].
† The OEL used in calculation of the SI ratio for dichlorvos 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

- 27

- 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 Insti tute 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

- 27

- 15

.

SRC [2009]. Interactive PhysProp database demo, http://esc.syrres.com/fatepointer/webprop.asp?CA S=62737 . Accessed: 01

- 27

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.