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Hazard Characterization Document

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### SCREENING-LEVEL HAZ ARD CHARACTERIZATION

Cashew, Nutshell Liquid (CASRN 8007-24-7)

The High Production Volume (HPV) Challenge Program 1 was conceived as a voluntary initiative aimed at developing and making publ icly available screen ing-level health and

environmental effects information on chemicals manufactured in or imported into the United States in quantities greater than one million pounds per year. In the Challenge Program, producers and importers of HPV chemicals vol untarily sponsored chemicals; sponsorship

entailed the identification and initial assessm ent of the adequacy of existing toxicity data/information, conducting new testing if adequa te data did not exist, and making both new and existing data and information available to the public. Each complete data submission contains data on 18 internationally agreed to “SIDS” (Screening Information Data Set 1

, 2 ) endpoints that are screen ing-level indicators of poten

e

The Environmental Protection Agency’s Office of Pollution Prevention and Toxics (OPPT) is evaluating the data submitted in the HPV Cha llenge Program on approximately 1400 sponsored chemicals by developing hazard characterizations (H Cs). These HCs consist of an evaluation the quality and completeness of the data set pr ovided in the Challenge Program submissions. They are not intended to be definitive

in

The evaluation is performed according to established EPA guidance 2

, 3 and is based primaril hazard data provided by sponsors; however, in preparing the hazard characterization, EPA considered its own comments and public comments on the original submission as well as the sponsor’s responses to comments and revisions made to the subm ission. In order to determine whether any new hazard information was develo ped since the time of the HPV submissi search of the following databases was made fr om one year prior to the date of the HPV Challenge submission to the present: (ChemID to locate available data sources including Medline/PubMed, Toxline, HSDB, IRIS, NTP, ATSDR, IARC, EXTOXNET, EPA SRS, etc.), STN/CAS online databases (Regis try file for locators, ChemAbs for toxicology data, RTECS, Merck, etc.) and Science Direct. OPPT’s focus on these specific sources is based on

o

OPPT does not develop HCs for those HPV ch emicals which have already been assessed internationally through the HPV program of the Organization for Economic Cooperation an Development (OECD) and for which Screening In itial Data Set (SIDS) Initial Assessment Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documen presented in an international forum that i nvolves review and endorsement by governmental

1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm

. 2 U.S. EPA. HPV Challenge Program – Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm

. 3 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm

.

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uthorities around the world. OPPT is an active pa rticipant in these meetings and accepts these

ublic. However, they do provide a vehi cle for public access to a concise assessment of

the raw technical data on HPV chemicals and info rmation previously not readily available to the public. a documents as reliable screening-level hazard assessments.

These hazard characterizations ar e technical documents intended to inform subsequent decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general p

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Hazard Characterization Document

Chemical Abstract Service Registry Number (CASRN) 8007-24-7

Chemical Abstract Service

Name Cashew, nutshell liquid

Structural Formula Mixture of anacardic acid, carda nol, and cardol (see Section 1) Summary This chemical is a liquid with low water solubility and low vapor pressure. It is expected to have low mobility in soil. Volatilization of cashew nutshell liquid is considered low to moderate. The rate of hydrolysis is considered negligible. Th e rate of atmospheric pho tooxidation is considered rapid. It is expected to have low persiste nce (P1) and low bioaccumulation potential (B1).

The acute hazard to fish, aquatic invertebrates, and aquatic plants is based on estimated toxicity values for cardanol of 0.001 mg/L, 0.004 mg/L, and 0.010 mg/L, respectively.

Acute oral toxicity of this chemical in rats is lo w. It is a dermal sensit izer in guinea pigs. An oral combined repeated-dose/reproductive/developmental screening study in rats showed histopathological effects on th e lung and lymph nodes, and he matological effects in adult animals at a dose of 1000 mg/kg-day; the NOAEL fo r systemic toxicity was 150 mg/kg-day. In the same study, there was reproductive toxicity at 1000 mg/kg-day as demonstrated by an increase in dyctocia; the NOAEL for reproductiv e toxicity was 150 mg/kg-day. There was no evidence of developmental toxicity in this study and the NOAEL was 1000 mg/kg-day. This chemical did not induce gene mutations or chromosomal aberrations when tested in vitro

.

The acute toxicity for aquatic organisms is considered a data gap under the HPV Challenge Program.

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The sponsor, Cardolite Corporation, submitted a Test Plan and Robust Summaries to EPA for Cashew Nutshell Liquid (CAS No. 8007-24-7; 9 th CI Name: Cashew Nutshell Liq.) on June 5, 2002. EPA posted the submission on the Chem RTK HPV Challenge website on June 5, 2002 ( http://www.epa.gov/chemrtk/pubs/summaries/casntliq/c13793tc.htm ). EPA comments on the original submission were posted to the website on November 12, 2002. Public comments were also received and posted to the website. Th e sponsor submitted updated/revised documents on December 20, 2002, November 2, 2006 and April 6, 2007, which were posted to the ChemRTK website on January 21, 2003, November 16, 2006 and July 24, 2007, respectively.

1 Chemical Identity

1.1 Identification and Purity

The following description is taken from the final Test Plan (2006):

Cashew nutshell liquid is obtained from the she ll of a cashew nut and is a source of naturally occurring phenols. About 30-35% of this chemical is present in the shell, which amounts to approximately 67% of the nut. Cashew nutshell liquid is tradi tionally obtained as a by-product during the process of removing the cashew kernel from the nut.

Natural (i.e. cold, solvent extracted) cashew nutshell liquid is a liquid that contains approximately 70% anacardic acid, 18% cardol, a nd 5% cardanol (Fig 1), with the remainder being made up of other phenols and less polar su bstances. Anacardic acid, cardanol and cardol consist of mixtures of components having various de grees of unsaturation in the alkyl side-chain.

Figure 1: Structures of Anacardi c acid, Cardanol and Cardol

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In technical (i.e. heat extr acted) cashew nutshell liquid, th e heating process leads to decarboxylation of the anacardic acid to form card anol. Typically, the co mposition of technical cashew nutshell liquid is approxi mately 52% cardanol, 10% car dol, 30% polymeric material, with the remainder being made up of other subs tances. The technical cashew nutshell liquid is often further processed by distilla tion at reduced pressure to rem ove the polymeric material. The composition of distilled technical cashew nutshe ll liquid (Cardolite NC 511) is approximately 78% cardanol, 8% cardol, 2% polymeric materi al, < 1% 2-methyl cardanol, 2.3% heptadecyl homologue triene, 3.8% heptad ecyl homologue diene and the remainder other homologous phenols.

1.2 Physical-Chemical Properties

The physical-chemical properties of cashew nutshell liquid are summarized in Table 1. Cashew nutshell liquid is a liquid with low wa ter solubility and low vapor pressure.

Table 1. Physical-Chemical Prop erties of Cashew Nutshell Liquid 1
Property Value

CASRN 8007-24-7 Molecular Weight 298-320 Physical State Liquid Melting Point Liquid at room temperature Boiling Point Polymerizes and decomposes prior to boiling 3
Vapor Pressure 3.8×10 -7 mm Hg at 25°C (measured) Water Solubility 0.305 mg/L at 20°C (measured) Dissociation Constant (pK
a ) ~10.06 (estimated) 2
Henry’s Law Constant 2.6×10 -10 –9.7×10 -5 atm-m 3 /mole (estimated) Log K
ow >6.2 (measured)

1 Cardolite Corporation, Inc. November 2, 2006. Revi sed Robust Summary and Test Plan for Cashew Nutshell Liquid. http://www.epa.gov/chemrtk/pubs/summaries/casntliq/c13793tc.htm

. 2 SPARC. 2008. Online pK

a and Property Calculator v. 4.2.1405-s4.2.1408. Accessed September 7, 2008. http://ibmlc2.chem.uga.edu/sparc/index.cfm?CFID=32727&CFTOKEN=65477992

. 3 BP 225 °C @ 10 mm Hg US Patent 2,098,824

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2 General Information on Exposure

2.1 Production Volume and Use Pattern

Cashew, nutshell liquid had an aggregated produc tion and/or import volume in the United States of 50 to 100 million pounds during calendar year 2005.

Non-confidential information in the IUR indicated that the industrial processing and uses of the

chemical include intermediates in the manufact ure of other basic organic chemicals. Nonconfidential information in th e IUR indicated that the comm ercial and consumer products containing the chemical include automotive care products. The HPV submission states that the chemical is primarily used in antioxidants, pl asticizers and processing aids for rubber compounds and modifiers for plastic materials. Cashew nutsh ell liquid resins have be en used extensively in

the manufacture of friction-resistan t components in applications such as brake and clutch linings.

2.2 Environmental Exposure and Fate

No quantitative information is available on releases of this chemical to the environment.

The environmental fate properties are provided in Table 2. Cashew nutshell liquid is expected to have low mobility in soil. Cashew nutshell liquid was shown to be readily biodegradable using a modified Sturm test (OECD 302D). The rate of volatilization of cashew nutshell liquid from

water and moist soil is consider ed low to moderate. The rate of hydrolysis is considered negligible under environmental conditions. Cash ew nutshell liquid is e xpected to have low persistence (P1) and low bioaccumulation potential (B1).

Table 2. Environmental Fate Charac teristics of Cashew Nutshell Liquid 1
Property Value Photodegradation Half-l ife 0.351–1.254 hours (estimated) Hydrolysis Half-life Stable Biodegradation 96% after 28 da ys (readily biodegradable)

Bioconcentration BCF = 4.5 (estimated) Log K
oc 7.5–8.6 (estimated) Fugacity (Level III Model; simultaneous 1,000 kg/hour emission to air, water, and soil compartments) Air = 0%
Water = 1.86%
Soil = 30.9 %
Sediment = 67.2%

Persistence 2 P1 (low)

Bioaccumulation 2 B1 (low)

1 Cardolite Corporation, Inc. November 2, 2006. Revi sed Robust Summary and Test Plan for Cashew Nutshell Liquid. http://www.epa.gov/chemrtk/pubs/summaries/casntliq/c13793tc.htm

. 2 Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal Register 64, Number 213 (November 4, 1999) pp. 60194–60204.

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3 Human Health Hazard

Acute Oral Toxicity

Acute toxicity data conducted according to esta blished guidelines were not submitted. However, during a range-finding study for the combined to xicity study (see below), Sprague-Dawley rats (3/sex/dose) were orally dosed with 0 or 1,000 mg/kg-bw/day for 14 days. No mortality occurred during the 14 day observation period. No clinically observable signs of toxicity were observed. No macroscopic abnormalitie s were observed at necropsy.

LD 50 > 1000 mg/kg-bw (14 daily exposures-only one dose tested) Repeated-Dose Toxicity

In a combined repeated-dose/reproductive/develo pmental toxicity screen ing test, groups of Sprague-Dawley rats (10 sex/dose) were dosed via gavage daily at 0, 15, 150, or 1000 mg/kgbw/day for up to 49 days. Increased salivation was noted in animals ofboth sexes at the highdose level after day 9. Two high-dose females had d eaths attributed to dyst ocia, slow or difficult labor; one was euthanized on day 21 and anothe r found dead on day 22. High-dose females had statistically significant increased relative liver weights. High-dose males had statistically significant decrease in absolute brain weights. Hematological changes (elevated platelet, hemoglobin, erythrocyte, and hema tocrit counts, elevated mean cell volume, and decreased mean cell hemoglobin concentration) were noted in high- dose males. An increase in mean cell volume was also noted in high-dose females. Clinical biochemistry changes (elevated aspartate and alanine aminotransferases, alkaline phosphata se, and inorganic phos phorus, reduction in

cholesterol and elevated bilirubi n) were noted in males and fema les at the high dose. High-dose males also had increased plasma urea, reduced glucose levels, and elevated albumin/globulin ratios. The significance and magnitude of change s are not noted. Histopa thological changes at the high dose included higher in cidence of alveolar macrophages in the lungs in females, abnormal multiplication of macrophages and/or foamy macrophages in the lymph nodes and overgrowth of the lining of the forestomach in bot h sexes, and thickening of the lining of the

small intestine in males. LOAEL = 1000 mg/kg-bw/day (based on effects to the lungs , lymph nodes, and hematology) NOAEL = 150 mg/kg-bw/day

Reproductive/Developmental Toxicity

In the combined repeated-dose/reproductive/deve lopmental toxicity scr eening test described previously, no adverse effects we re reported on mating performance, fertility, precoital interval, duration of gestation, gestation i ndex, number of implantations, or number of corpora lutea. In the high-dose dams, 2/10 had deaths attributed to dystocia, slow or difficult labor, on day 21 and 22. An additional dam in this group died for unexplained reasons (assume gavage error) at a time not specified. No treatment related change s were noted in litter size, weight, sex ratio, viability index, post-nata l growth rate or toxicologically significant effects on offspring. LOAEL (reproductive toxi city) = 1000 mg/kg-bw/day (based on deaths due to slow/difficult labor) NOAEL (reproductive toxi city) = 150 mg/kg-bw/day

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NOAEL (developmental t oxicity) = 1000 mg/kg-bw/day (based on no effects at the highest dose tested)

Genetic Toxicity – Gene Mutation

In vitro (1) In bacterial reversion assays, Salmonella typhimurium strains (TA98, TA100, TA1535, TA1537 and TA1538) were exposed to cashew nuts hell liquid at concentrations of 50, 150, 500, 1500 or 5000 μg/plate in the presence and absence of metabolic activation. Three replicates were conducted per experiment. No cytotoxicity was noted at the maximum concentration of 5000 μg/plate. A precipitate was observed at 150 0 and 5000 μg/plate but it did not impact the scoring of colonies. No signifi cant increase in the frequency of revertant colonies was recorded for any of the bacterial strains at any concentrat ion, either with or wit hout metabolic activation.

Positive and solvent controls were te sted and responded appropriately. Cashew nutshell liquid was no t mutagenic in this assay

.

(2) In forward mutation assays, Chinese hamste r ovary (CHO-KI BH4) cells were exposed to cashew nutshell liquid, in two experiments, in th e presence and absence of metabolic activation. In experiment 1 the concentrations ranged fr om 0.75 – 18 μg/mL and in the second experiment, the concentration range was and 0.75 – 24 μg/m L. Two replicates were conducted per experiment. Positive and solvent controls we re tested and responde d appropriately. The cytotoxic concentration with and without me tabolic activation was 47.19 μg/mL (in the text, though the tables stated 24 μg/mL was toxic with activation). Th e test substance did not induce significant or dose-related mutant frequency in the presence or abse nce of metabolic activation in either of the two experiments. Cashew nutshell liquid was no t mutagenic in this assay.

Genetic Toxicity – Chromosomal Aberrations

In vitro In a chromosomal aberration test, human lymphocy tes were exposed to cashew nutshell liquid in the presence and absence of meta bolic activation in three experime nts. The concentration ranges were 3 – 25 μg/mL, 0.78 – 37.5 μg/mL and 3.125 or 25 μg/mL in the first, second and third experiments, respectively. Harvest time for th e cells was 20 hours for experiments 1 and 2, and 44 hours for experiment 3. Two replicates were conducted for each experiment. Positive and solvent controls were tested which responded appr opriately. The cytotoxic concentrations were 12.5 μg/mL with metabolic activation and > 25 μg /mL without metabolic activation. The test substance did not induce a significant increase in the frequency of cells with chromosome aberrations or polyploid cells in either the presence or absenc e of metabolic activation. Cashew nutshell liquid did not induce ch romosomal aberrations in this assay

.

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Additional Information

Skin Sensitization

In an assay using albino Dunkin Hartley guinea pigs (20 females/dose), intra-dermal induction was conducted using 1% (w/v) in liquid paraffin a nd 1% (w/v) in a mixture of Freund’s complete adjuvant plus distilled water. Topical i nduction was conducted usi ng 25% (v/v) in liquid paraffin. Topical challenge was conducted with 5% or 2% (v/v) in li quid paraffin. Following intra-dermal induction, well defined, moderate to severe erythema was seen at 24- and 48-hour observations periods. Skin reac tions observed at 24 and 48 hours af ter 5% topical challenge dose included very slight to well-defined erythema and very slight edema and desquamation. Very slight erythema in one animal and desquamation in three animals was present at 72 hours at the 2% challenge dose. All animals showed an expected gain in body weight over the study period. The test substance produced a 70% (14/20) sensitization rate in th e study and was classified as a “strong” sensitizer. Cashew nutshell liquid was sensitizing in this assay

Conclusion: Acute oral toxicity of this chemical in ra ts is low. It is a dermal sensitizer in guinea pigs. An oral combined repeated-dos e/reproductive/developmental screening study in rats showed histopathological e ffects on the lung and lymph nodes, and hematological effects in adult animals at a dose of 1000 mg/kg-day; th e NOAEL for systemic toxicity was 150 mg/kgday. In the same study, there was reproductive t oxicity at 1000 mg/kg-day as demonstrated by an increase in dyctocia; the NOAEL for reproduc tive toxicity was 150 mg /kg-day. There was no evidence of developmental toxicity in this study and the NOAEL was 1000 mg/kg-day. This chemical did not induce gene mutations or chromosomal aberrations when tested in vitro

.

4 Hazards to the Environment

The sponsor did not submit measured aquatic to xicity data for cashew nutshell liquid, but provided data for log K
ow and water solubility. ECOSAR (v. 1.00a) was used to assess acute aquatic toxicity of cardanol (CASRN 37330-39-5) , the primary component of the sponsored distilled technical grade cashew nutshell liquid, which is a mixtur e of primarily cardanol (78%) and cardol (8%; CASRN 57486-25-6).

Acute Toxicity to Fish

A 96-hour LC 50 value for fish exposed to cashew nutsh ell liquid was estimated by ECOSAR v.

1.00a.
96-h LC 50 = 0.001 mg/L (estimated)

Acute Toxicity to Aquatic Invertebrates

A 48-hour EC 50 value for Daphnia exposed to cashew nutshell liquid was estimated by ECOSAR

v. 1.00a.
48-h EC 50 = 0.004 mg/L (estimated)

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Toxicity to Aquatic Plants

A 96-hour LC 50 value for algae exposed to cashew nut shell liquid was estimated by ECOSAR v.

1.00a.
96-h LC 50 = 0.010 mg/L (estimated)

Conclusion: The acute hazard to fish, aquatic invert ebrates, and aquatic plants is based on estimated toxicity values for cardanol of 0.001 mg/L, 0.004 mg/L, and 0.010 mg/L, respectively..

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Table 3. Summary Table of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program
Endpoints SPONSORED CHEMICAL Cashew Nutshell Liquid (CASRN 8007-24-7)
Summary of Environmental Effe cts – Aquatic Toxicity Data

Fish
96-h LC 50 (mg/L) 0.001 (estimated)
Aquatic Invertebrates
48-h EC 50 (mg/L) 0.004 (estimated)
Aquatic Plants
72-h EC 50 (mg/L) 0.010 (estimated)
Summary of Human Health Data
Acute Oral Toxicity

LD 50 (mg/kg-bw) >1000
Repeated-Dose Toxicity NOAEL/LOAEL (mg/kg-bw/day) NOAEL = 150
LOAEL = 1000
Reproductive/Developmental Toxicity NOAEL/LOAEL (mg/kg-bw/day) Reproductive Toxicity

Developmental Toxicity NOAEL = 150
LOAEL = 1000

NOAEL = 1000
Genetic Toxicity – Gene Mutation

In vitro Negative
Genetic Toxicity – Chromosomal
Aberrations

In vitro Negative

Additional Information –
Skin Sensitization Positive

11