Document ID: EPA-HQ-OPP-2007-0589-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-07-25T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

  AND TOXIC SUBSTANCES

Date: July 12, 2007

MEMORANDUM

SUBJECT:	Naphthenate Salts: Toxicology Chapter in support of the
Reregistration Eligibility Decision (RED) Document.  PC Codes: 023102,
088301, 863508, 900436 and 025101. 

FROM:	Timothy F. McMahon, Ph.D. 

Senior Toxicologist/Risk Assessor

Antimicrobials Division (7510P)

  TO:		Rebecca Cool, Chemical Review Manager

		Diane Isbell, Team Leader 

		Mark Hartman, Branch Chief

		Regulatory Management Branch II

		Antimicrobials Division (7510P)

	Attached is the Naphthenate Salts Toxicology Disciplinary chapter for
the purpose of issuance of the reregistration eligibility decision
(RED).  

1.0  HAZARD
CHARACTERIZATION………………………………………………
………3

2.0 TOXICOLOGY
DATA…………………………………………………………
…..……....6

3.0 DATA
GAPS…………………………………………………………
………………………7

4.0 HAZARD
ASSESSMENT……………………………………………………
……………..7

 	3.1 Acute
toxicity………………………………………………………
………………….7

	3.2 Subchronic
toxicity………………………………………………..……
…………….8

	3.3 Developmental
toxicity………………………………………………………
………10

	3.4 Reproductive
toxicity………………………………………………………
………...11

	3.5 Chronic
toxicity………………………………………………………
…...…………12

	3.6
Carcinogenicity…………………………………………………
……………………12

	3.7
Mutagenicity……………………………………………………
……………………12

	3.8
Neurotoxicity…………………………………………………
……………………...14

	3.9
Metabolism……………………………………………………
…………………….14

5.0 TOXICITY ENDPOINT
SELECTION…………………………………………………..14

	5.1 Summary of Toxicity
Endpoints…………………………………………………….14

	5.2 Dermal
Absorption……………………………………………………
……………..14

	5.3 Classification of Carcinogenic
Potential……………………………………………14

6.0 FQPA
CONSIDERATIONS…………………………………………………
……………15

	

7.0 SUMMARY OF TOXICOLOGICAL
ENDPOINTS……………………………………16

8.0 TOXICITY PROFILE
TABLES…………………………………………………………
.17

9.0
REFERENCES……………………………………………………
……………………….25

1.0	  SEQ CHAPTER \h \r 1 HAZARD CHARACTERIZATION

The naphthenate salts (copper and zinc naphthenate) are both salts of
naphthenic acid, which is essentially a mixture of cyclic carboxylic
acids, predominantly cyclopentane derivatives with an average molecular
weight of 200-300 (BIBRA, 1999).  The mixture may also contain some
cyclic hydrocarbons (BIBRA, 1999).  The naphthenate salts are considered
together for hazard characterization.  The presence of a zinc or copper
ion does not have a significant influence on the mammalian toxicity of
naphthenic acid. 

Both   SEQ CHAPTER \h \r 1 copper and zinc naphthenate are
microbiocide/microbiostat, miticide, fungicide, insecticide, algaecide
and herbicide/terrestrial chemicals. Use sites for copper naphthenate
include pressure treatment and non –pressure treatment of wood for
exterior uses (residential and non-residential), wood used in contact
with fresh or salt water, and exterior wood exposed to moisture or
weather. Copper naphthenate is also used in brush, dip, roller, and low
pressure spray applications for the same uses listed above, and in
addition is used for greenhouse and horticultural uses (non-food
applications including wooden seedling trays, plant and flower boxes for
ornamental plantings, trellises, arbors, greenhouse benches, and nursery
flats).  Application by occupational applicators only includes  brush,
dip, roller, and low pressure spray to beverage cases, baskets, tents,
awnings, tarpaulins, canvas products, nets [except fishnets], ropes,
cordage, lumber for ammunition boxes, other boxes, crates, and
miscellaneous non –food contact containers, truck and boat covers,
non-rubber fabrics, and burlap. Copper naphthenate is also used as a
remedial treatment for standing wood utility poles, mine timbers, bridge
timbers, and cross-ties and stakes.  

Zinc naphthenate use sites are the same as for copper naphthenate but do
not include remedial treatments  or to beverage cases, etc. as listed
for copper naphthenate. 

There is also one tolerance exemption for residues of copper naphthenate
when used in accordance with good agricultural practice as an inert
ingredient in pesticide formulations applied to growing crops only (40
CFR 180.920). No more than 2.5% copper naphthenate can be present, and
products containing copper naphthenate can only be applied before the
edible portions of plants begin to form.

The acute toxicity database for Copper naphthenate is incomplete.  There
are no acceptable acute toxicity studies for the technical grade
(80-89%) active ingredient in the toxicology database. The highest
concentration of active ingredient that was tested in acceptable acute
toxicity studies was 45.4% a.i.  In an acute oral toxicity study with
copper naphthenate (45.4%), a toxicity category III was assigned based
on testing of a single dose of 501 mg/kg (MRID 266172).  A toxicity
category of III was also assigned for acute dermal toxicity testing of
copper naphthenate but the submitted study was not acceptable (HED
document number 008158).  Acute inhalation toxicity testing of 48% and
58% a.i. copper naphthenate (HED document number 008158) indicated a
toxicity category of IV, but the studies were unacceptable.  Skin and
eye irritation testing of copper naphthenate at 45.4% showed the
compound to be a severe irritant in both cases, with a toxicity category
of I assigned for skin and eye irritation effects (MRID 266172).  Dermal
sensitization studies on copper naphthenate from the BIBRA Toxicity
profile (1999) indicate that copper naphthenate is not a dermal
sensitizer; there is no acceptable dermal sensitization data available
to the Agency on the technical grade of the a.i., although the available
data also indicate no sensitization potential  

 In contrast to copper naphthenate, there are acceptable acute toxicity
data available for the technical grade active (60%) of zinc naphthenate.
  A battery of tests (acute oral, dermal, inhalation, primary eye,
primary skin, and dermal sensitization) was conducted using 60% a.i.
zinc naphthenate (MRID 244277).  With the exception of an acute
inhalation study, acute oral, acute dermal, skin irritation, eye
irritation and dermal sensitization studies were considered acceptable.
In an acute oral toxicity study with zinc naphthenate (60%), a toxicity
category IV was assigned based on a LC50 greater than 5000 mg/kg (MRID
244277).  A toxicity category of III was also assigned for acute dermal
toxicity testing of zinc naphthenate with a LD50 for males and females
greater than 2000 mg/kg (MRID 244277).  Acute inhalation toxicity
testing of 60% a.i. zinc naphthenate (MRID 244277) indicated a toxicity
category of IV with a LC50 greater than 11.6 mg/L over a 4 hour exposure
period, but the study was unacceptable.  Skin and eye irritation testing
of zinc naphthenate at 60% showed the compound to be moderate to severe
and slight irritants respectively, with a toxicity category of (II,
skin) and (III, eye)  assigned for skin and eye irritation effects (MRID
244277).   In a dermal sensitization study with zinc naphthenate (60%),
the material appeared to be a primary skin irritant and a possible
sensitizing agent (MRID 244277).

In subchronic (repeat dose) testing, copper naphthenate administered by
the dermal route for 90 days (MRID 41676101) showed no evidence of
systemic toxicity up to  and including a limit dose of 1000 mg/kg, but
showed evidence of dermal irritation at a dose of 300 mg/kg/day  Zinc
naphthenate administered by the dermal route for 90 days (MRID 41615001)
showed systemic toxicity at a dose of 300 mg/kg/day, while dermal
irritation was observed at all dose levels (100 mg/kg/day and above).

 

In developmental toxicity testing of copper naphthenate (MRIDs
41615101), maternal toxicity was shown in rats at doses of 100 and 300
mg/kg by decreases in body weight and food consumption.  There was no
evidence of developmental toxicity in this study at any dose.   In a
second developmental toxicity study conducted with zinc naphthenate in
rats (MRID 41615002),  the only observed clinical sign of maternal
toxicity was a dose-related increase in staining around the mouth and
anogenital area at doses of  250 and 500 mg/kg/day.  There was no
evidence of developmental toxicity at any dose level in this study.  In
another study conducted by the United States Army (Angerhofer, 1991) 
zinc naphthenate was tested up to 938 mg/kg/day  in rats with increased
resorptions and decreased fetal body weight observed at this dose, which
is close to a limit dose (i.e. 1000 mg/kg/day) for such studies and is
not considered toxicologically significant based on the magnitude of the
dose at which these effects were observed. 

There were no reproductive or carcinogenicity submitted for either
copper or zinc naphthenate. Mutagenicity studies were submitted for
copper naphthenate and included a mouse lymphoma assay (MRID 41402502),
chromosome aberration test (MRID 41402503) and an unscheduled DNA
synthesis (UDS) study (MRID 41402504).  In the  L5178Y TK+/- mouse
lymphoma mutagenesis assay, copper naphthenate caused an increase in
mutant frequency in the presence of microsomal S9.  In the chromosomal
aberration test using Chinese hamster ovary cells, copper naphthenate
caused no increase in mitotic index at any of the concentrations tested
and no significant increase in CHO cells with aberrations at any of the
concentrations tested.  In the unscheduled DNA assay, copper naphthenate
did not induce an increase in UDS in primary rat hepatocytes at any
concentration tested.

Mutagenicity studies were submitted for zinc naphthenate and included a
mouse lymphoma assay (MRID 41400701), chromosome aberration test (MRID
41400702) and an unscheduled DNA synthesis (UDS) study (MRID 41400703). 
In the  L5178Y TK+/- mouse lymphoma mutagenesis assay, zinc naphthenate
caused an increase in mutant frequency in the presence of microsomal S9.
 There was also a greater increase in small colonies versus large
colonies with exposure to zinc naphthenate as opposed to copper
naphthenate exposure.  In the chrosomal aberration test using Chinese
hamster ovary cells, zinc naphthenate caused an increase in chromosomal
aberrations with increasing concentrations of zinc naphthenate.  In the
unscheduled DNA assay, zinc naphthenate did not induce an increase in
UDS in primary rat hepatocytes at any concentration tested.

TOXICOLOGY DATA 

The available toxicology data for copper and zinc naphthenate is listed
below. 

 

Table 1. Copper Naphthenate

Test 

	

Technical a.i.

	

MRID	

Satisfied

870.1100	Acute Oral Toxicity	

870.1200	Acute Dermal Toxicity	

870.1300	Acute Inhalation Toxicity	

870.2400	Primary Eye Irritation	

870.2500	Primary Dermal Irritation	

870.2600	Dermal Sensitization		

No study

No study

No study

No study

No study

No study	

no

no

no

no

no

no

870.3250	90-Day Dermal	

	

41676101

	

yes

870.3700	Developmental Toxicity (rodent)	

	

41615101	yes

870.5300	Mutagenicity—Gene Mutation - mammalian	

870.5385	Mutagenicity—chrmomsomal aberration test	

870.5550	Mutagenicity—UDS in mammalian cells in culture		41402502

41402503

41402504

	no

no

no

Table 2. Zinc Naphthenate

Test 

	

Technical a.i.

	

MRID	

Satisfied

870.1100	Acute Oral Toxicity	

870.1200	Acute Dermal Toxicity	

870.1300	Acute Inhalation Toxicity	

870.2400	Primary Eye Irritation	

870.2500	Primary Dermal Irritation	

870.2600	Dermal Sensitization		

00244277

00244277

00244277

00244277

00244277

00244277	

yes

yes

yes

yes

yes

yes

870.3250	90-Day Dermal	

	

41615001

	

yes

870.3700	Developmental Toxicity (rodent)	

	

41615002

	             yes

870.5300	Mutagenicity—Gene Mutation - mammalian	

870.5380	Mutagenicity—chromosomal aberration test	

870.5550	Mutagenicity—UDS in mammalian cells in culture		        
41400701

41400702

41400703

	no

no

no

3.0	DATA GAPS

Acute toxicity studies for technical grade copper naphthenate are
required.  Information on the purity of the test material used in the
mutagenicity studies is also required. 

4.0	HAZARD ASSESSMENT

4.1	Acute Toxicity

Adequacy of database for Acute Toxicity:  The acute toxicity database
for copper naphthenate is incomplete.  There are no studies available on
the technical grade active ingredient for copper naphthenate. In
contrast, the acute toxicity database for zinc naphthenate technical is
complete.  Copper naphthenate tested at 45.4% (or other %) a.i. has a
moderate order of acute toxicity via the oral, dermal and inhalation
routes of exposure (Toxicity Category III).  For dermal irritation,
copper naphthenate  also has a moderate order of acute toxicity
(Toxicity Cateogry III).   Copper naphthenate is neither a significant
eye irritant  or dermal sensitizer. Zinc naphthenate has a low to
moderate order of acute toxicity via the oral, dermal and inhalation
routes of exposure (Toxicity Category IV, III and IV, respectively). 
For dermal irritation, zinc naphthenate has a moderate to severe order
of acute toxicity (Toxicity Cateogry II).   Zinc naphthenate is a
possible dermal sensitizer. 

The acute toxicity data for copper and zinc naphthenate is summarized
below in Table 1.

	

Table 3.  Acute Toxicity Profile for Copper/Zinc Naphthenate

Guideline Number	Study Type/Test substance (% a.i.)	MRID Number/

Citation	Results	Toxicity Category

870.1100

(§81-1)	Acute Oral- Rat

purity 45.4% -copper naphthenate	00266172	LD50 > 501 mg/kg	III

870.1100

(§81-1)	Acute Oral- Rat

purity 58% -copper naphthenate	433342402	Not determined	N/A

870.1100

(§81-1)	Acute Oral- Rat

purity 60%- zinc naphthenate	00244277	LD50 > 2000 mg/kg	IV

870.1200

(§81-2)	Acute Dermal- Rabbit

purity not determined – copper naphthenate	41140710	LD50 > 2000 mg/kg
III

870.1200

(§81-2)	Acute Dermal- Rabbit

Purity 60%-zinc naphthenate	00244277	LD50 > 2000 mg/kg	III

870.1300

(§81-3)	Acute Inhalation- Rabbit

- copper naphthenate	41486301	LC50 > 2.966 mg/L	III

870.1300

(§81-3)	Acute Inhalation- Rabbit

Purity 60%- zinc naphthenate	00244277	LC50 > 11.6 mg/L	IV

870.2400

(§81-4)	Primary Eye Irritation- Rabbit purity 80% -copper naphthenate
00260891	Redness cleared on day 4	III

870.2400

(§81-4)	Primary Eye Irritation- Guinea pig purity 60% -zinc naphthenate
00244277	Redness cleared on day 2	III

870.2500

(§81-5)	Primary Dermal Irritation- Rabbit

–copper naphthenate	41140710	Moderate Irritant	III

870.2500

(§81-5)	Primary Dermal Irritation- Rabbit

60% -zinc naphthenate	00244277	Moderate to severe Irritant	II

870.2600

(§81-6)	Dermal Sensitization - Guinea pig

purity 58 % - copper naphthenate	41140710	Not a sensitizer.	No

870.2600

(§81-6)	Dermal Sensitization - Guinea pig

purity 60 % - zinc naphthenate	00244277	Primary skin irritant/possible
sensitizing agent	No

4.2	Subchronic Toxicity

Adequacy of database for Subchronic Toxicity:  For subchronic toxicity,
two in-house studies were available.  The copper naphthenate study is
considered acceptable (MRID 41676101) and the zinc naphthenate study
(MRID 41615001) is considered acceptable.

\

870.3250	90-day Dermal Toxicity – Rats

  SEQ CHAPTER \h \r 1 In a 90-day dermal toxicity test (MRID 41676101)
designed to determine the subchronic toxicity effects of repeated dermal
exposure to copper naphthenate (>9.5% purity) in Crl:CD®BR albino rats.
 The rats were dermally exposed to 0, 100, 300, or 1000 mg/kg/day of
copper naphthenate 6 hours a day, 5 days a week for 13 weeks.  Animals
were observed twice daily for signs of mortality and moribundity and
daily for signs of toxicity.    SEQ CHAPTER \h \r 1  

No mortalities were reported to have occurred in the study.  There was
only one animal, a low dose female was sacrificed due to adverse
clinical signs not seen in any other animal.  This occurred in the
copper naphthenate study.

≥1000 mg/kg/day, M/F).  The systemic toxicity LOAEL is (›1000
mg/kg/day, M/F, based on reductions in body weight gain and food
efficiency in the high dose males.  The dermal toxicity NOAEL is (100
mg/kg/day).  The dermal toxicity LOAEL is (300 mg/kg/day).

This study is classified as Core-Minimum - Guideline.

In another 90-day dermal toxicity test (MRID 41615001) designed to
determine the subchronic toxicity effects of repeated dermal exposure to
zinc naphthenate (14.5% purity) in New Zealand white rabbits,  rabbits
were dermally exposed to 0, 100, 300, or 1000 mg/kg/day of zinc
naphthenate 6 hours a day, 5 days a week for 13 weeks.  Animals were
observed twice daily for signs of mortality and moribundity and daily
for signs of toxicity.  

Systemic toxicity was observed in the form of significantly  reduced
body weight gain in the high dose group throughout the study.  In male
rabbits, body weight gain decrement was also seen in the mid dose group
throughout the study.  No treatment related clinical signs of systemic
toxicity were noted (hematology, clinical chemistry or histopathology). 
In terms of dermal effects there were apparent dose related increases in
macroscopic and microscopic lesions related to dermal irritation.

The systemic  toxicity NOAEL is (100 mg/kg/day, M/F).  The systemic
toxicity LOAEL is (300 mg/kg/day, M/F), based on reductions in body
weight gain.  The dermal toxicity NOAEL is less than (100 mg/kg/day). 
The dermal toxicity LOAEL is less than or equal to (100 mg/kg/day).

This study is classified as Core-Minimum - Guideline.

4.3	Prenatal Developmental Toxicity

Adequacy of database for Prenatal Developmental Toxicity:  The database
for developmental toxicity is considered complete with two acceptable
guideline studies and one upgradeable study, all in the rat (MRIDs
41615101 and 41615002).

870.3700	Prenatal Developmental Toxicity– Rat

  SEQ CHAPTER \h \r 1 In a prenatal developmental toxicity study (MRID
41615101), Copper naphthenate (purity assumed to be 100%) in corn oil,
was administered by gastric intubation to 4 groups of 25 rats/dose by
gastric intubation at dose levels of 0, 30, 100, or 300 mg/kg/day,
respectively, from gestation days (GD) 6 to 15.  The animals were
checked daily from gestation day 6 for indications of toxicity.  Body
weights were recorded daily from gestation days 6 through 15 and on
gestation days 16 and 21.  Food and water consumption were measured at 3
day intervals beginning on gestation day 6.  Examinations at sacrifice
consisted of a determination of the number and position of live, dead,
and resorbed fetuses and staining of apparent nonpregnant uteri along
with liver weights.

Maternal toxicity was noted in the 100 and 300 mg/kg/day groups in the
form of decreases in body weight and food consumption.  Evaluation of
developmental toxicity revealed an increase in the mean number of early
resorptions only, however the mean litter size of the treated and
control groups was comparable.  Therefore, these increases were
considered to be of no biological significance.  The maternal NOAEL is
30 mg/kg/day and the maternal LOAEL is 100 mg/kg/day.  The
developmental; toxicity NOAEL was determined to be greater than or equal
to 300 mg/kg/day and the developmental toxicity LOAEL was greater than
300 mg/kg/day. 

This study is classified as Acceptable - Guideline.

In another developmental toxicity study (MRID 41615002), Zinc
naphthenate (purity assumed to be 100%) in corn oil, was administered
via oral gavage to 4 groups of 25 female rats/dose by oral gavage at
dose levels of 0, 50, 250, or 500 mg/kg/day, respectively, from
gestation days (GD) 6 to 15.  The animals were checked daily from
gestation day 6 for indications of toxicity.  Body weights were recorded
daily from gestation days 6 through 15 and on gestation days 16 and 21. 
Food and water consumption were measured at 3 day intervals beginning on
gestation day 6.  Examinations at sacrifice consisted of a determination
of the number and position of live, dead, and resorbed fetuses and
staining of apparent nonpregnant uteri along with liver weights.

The only observed clinical sign of maternal toxicity was a dose-related
increase in staining around the mouth and anogenital area in the 250 and
500 ,mg/kg/day groups.  This staining may be due to the increased intake
of the pigmented chemical.  The maternal NOAEL was greater than or equal
to 500 mg/kg/day (HDT), and the maternal LOAEL was greater than 500
mg/kg/day.  The developmental toxicity NOAEL is greater than or equal to
500 mg/kg/day (HDT) with a developmental; toxicity LOAEL greater than
500 mg/kg/day.

This study is classified as  acceptable– Upgradeable.  The study can
be possibly be upgraded if justification for the dose selection, such as
data from a range-finding study, is provided and is acceptable to the
Agency. 

In a study conducted by the U.S. Army (Angerhofer et al. , 1991), zinc
naphthenate was administered by gavage to groups  (33/dose) of pregnant
Sprague-Dawley rats at doses of 0, 94, 188, and 938 mg/kg/day from days
6 through 15 of gestation.  Clinical signs and body weight
determinations were made for maternal rats. Females were sacrificed on
day 20 of gestation and examination was made of corpora lutea,
implantation sites, resorptions, and fetuses.  Fetal variations were
also investigated. Clinical signs of toxicity were observed in maternal
rats at the 938 mg/kg/day dose and included brown staining in the
urogenital area, red nasal and oral exudate, generalized alopecia, and
lethargy. Body weight was significantly decreased on day 10 of dosing
but was not otherwise affected in treated female rats compared to
vehicle control. Total resorptions were increased at the 938 mg/kg/day
dose as well as resorptions/dam.  Average fetal body weight was
decreased at 938 mg/kg/day. There was no clear dose relationship
observedfor fetal variations.  Consequently, the developmental LOAEL is
938 mg/kg/day based on reduced mean fetal body weight. The developmental
NOAEL is 118 mg/kg/day. This study is classified as acceptable and
satisfies the OPPTS guideline for a developmental toxicity study in the
rat. 

870.3700	Prenatal Developmental Toxicity – Rabbit

There were no submitted studies for developmental toxicity in the
rabbit. 

4.4	Reproductive Toxicity

 There were no submitted data on reproductive toxicity of copper or zinc
naphthenate.  Data were located on a 2-generation reproductive toxicity
test performed by the U.S. Army (Michie, M.W. et al., 1988) in which
zinc naphthenate (97 % a.i.) at dietary concentrations of 0, 500, 1000,
and 5000 ppm was fed to groups of parental Sprague-Dawley rats (30
rats/sex/dose).  Doses in mg/kg/day for the 10 week pre-mating period
were reported  for males as 24-48 mg/kg/day, 48-98 mg/kg/day, and
237-487 mg/kg/day respectively.  For females, doses in mg/kg/day for the
10-week pre-mating period were stated as 29-50 mg/kg/day, 61-98
mg/kg/day, and 305-497 mg/kg/day respectively. Parental rats received
test diets 10 weeks prior to mating and females were continued on test
diets through mating, gestation, and lactation.  P1 and F1 parental
animals at the 5000 ppm dose level showed reduced body weight in both
sexes.  Body weight was not reduced at lower dietary levels.  Food
consumption was not significantly affected in P1 rats, indicating an
effect on food efficiency at the 5000 ppm dietary concentration. ). 
Litter size and pup body weight were reduced in first generation
offspring at the 5000 ppm dose level but not at lower dietary
concentrations.  Histopathologic examination of P1 rats showed effects
in the kidney at the 5000 ppm dose level, which consisted of nephrosis
as well as epithelial regeneration of  renal tubules.  A
compound-related effect was suggested at the 5000 ppm dose level based
on the incidence observed vs. control.  This study suggested no adverse
effects of zinc naphthenate in rats at dietary concentrations up to 5000
ppm, a dose of approximately 500 mg/kg/day.  

4.5	Chronic Toxicity

There were no submitted data on chronic toxicity of either copper or
zinc naphthenate. 

4.6	Carcinogenicity

There were no submitted data on carcinogenicity of either copper or zinc
naphthenate. 

4.7	Mutagenicity

Adequacy of database for Mutagenicity Toxicity:   The Agency considers
all of the submitted mutagenicity studies to be unacceptable, but
upgradable, if the test material purity is provided for these studies. 

870.5300	In vitro mammalian cell gene mutation test

There were two gene mutation assays.  In the first study , MRID
41402502, copper naphthenate, at concentrations of 0, 4.2, 5.6, 7.5, 10,
13, 24, 32, 42 and 56 ug/ml without metabolic activation and at 0, 3.2,
4.2, 5.6, 7.5, 10, 13, 18, 24, 32 and 42 ug/ml with metabolic activation
(S-9 Mix) was evaluated for mutagenic potential using the L5178Y TK+/-
mouse lymphoma mutagenesis assay.  A repeat test confirmed the increase
of mutant frequencies with copper naphthenate in the presence of
metabolic activation (S-9).  In another mouse lymphoma assay (MRID
41400701), zinc naphthenate was tested with mouse lymphoma L5178Y TK +/-
cells without and with rat liver activation (male Sprague-Dawley,
Aroclor 1254 induced) in two trials with duplicate cultures per
concentration for 4 hours of exposure. The concentrations used were,
without activation: Trial 1:  (ethanol), 3.2, 4.2, 5.6, 7.5, 10, 13, 18,
24, 32, 42, 56 and 75 ug/ml; trial 2 ) (ethanol), 7.5, 11, 15, 19, 23,
27, 30, 33, 36, 40, 44 and 48 ug/ml.  With activation, the
concentrations were: Trial 1: (ethanol), 4.2, 5.6, 7.5, 10, 13, 18, 24,
32, 42, 56, 75 and 100 ug/ml; trial 2: 0 (ethanol), 23, 27, 30, 33, 36,
40, 44, 48, 52, 56, 65 and 75 ug/ml. Several of the higher
concentrations per trial were too toxic to process.  There was a
possible adverse effect due to the mutation frequency was increased in a
concentration-dependent response both without and with activation. 
There was also a greater increase in small colonies versus large
colonies with exposure to zinc naphthenate as opposed to copper
naphthenate exposure.  Although the Office of Pesticide Programs 
reported these two studies to be unacceptable, California Department of
Pesticide Regulation (CAL EPA) found the studies to be Acceptable.

870.5385	Mammalian bone marrow chromosomal aberration test

There were two chromosome aberration tests submitted to the Agency.  In
the first study (MRID 41402503), copper naphthenate , at concentrations
of 4, 8, 15, 30 and 60 ug/ml without metabolic activation at 2, 4, 8, 15
and 30 ug/ml with Aroclor-induced rat liver S-9 mix was tested in the
first trial in a chromosome aberration assay using Chinese hamster ovary
cells.  Concentrations in the repeat trial –S9 were 40, 80, 120 and
160 ug/ml and +S9 were 20, 30, 40, 50 or 60 ug/ml.  Total incubation was
16 hours –S9 and 12 hours (with a 2 hour exposure to treatment) +S9. 
The mitotic index decreased at 120 ug/ml with no mitotic cells and at
160 ug/ml without activation.  No effect on the mitotic index was seen
at any concentration with activation.  There were  no significant
reproducible increases in CHO cells with aberrations for any of the
copper naphthenate doses.  In the other study (MRID 41400702),zinc
naphthenate was tested in two trials without metabolic activation at
concentrations   0, 5, 10, 20, 40 and 80 ug/ml (first trial) and  0, 80,
110, 140, 170 and 200 ug/ml (second trial). In the presence of metabolic
activation, two trials were also conducted, the first at   0, 10, 20,
40, 80 and 160 ug/ml and the second at 0, 60, 80, 100, 120 and 140
ug/ml.  Exposure without activation was 18 hours followed by an
additional 2 hours with colcemid.  With activation, exposure was 2 hours
followed by 18 hours, both for a total of 20 hours.  In the repeat trial
with results reported at 80, 110 and 140 ug/ml, positive results were
found at all three concentrations.  With activation, in the first trial,
positive results were found at 80 ug/ml  in the repeat +S9 trial,
positive results were reported at 60, 80 and 100 ug/ml..  In both repeat
trials, there was a concentration dependent increase.  There was a 
possible adverse effect of an  increase in chromosomal aberrations with
increasing concentrations of zinc naphthenate. Although the Agency
reported these two studies to be Unacceptable, the California Department
of Pesticide Regulation (CAL  EPA) found the studies to be Acceptable.

Unscheduled DNA synthesis in mammalian cells in culture

 Two Unscheduled DNA Synthesis  (UDS) studies were also reviewed by OPP.
 In the first study (MRID 41402504), copper naphthenate at
concentrations of 0, .15, 0.5, 1.5, 5.0 and 15 ug/ml was evaluated in
the unscheduled DNA synthesis test using rat primary hepatocytes and
autoradiography.  The mean number of net nuclear grains did not increase
significantly at any dose level over the solvent control.  It was
concluded, therefore, that copper napthenate was tested over an
appropriate range of concentrations and failed to induce a genotoxic
response.  In the other UDS study (MRID 41400703), primary rat
hepatocytes, isolated from male livers, were treated with zinc
naphthenate at concentrations of  0, .15, 0.5, 1.5, 5.0 , 15 or 35 ug/ml
for 18-20 hours in the presence of  10 uCi/ml 3H-thymidine.   At
concentrations of 35 ug/ml and higher, the zinc naphthenate apparently
interfered with the LDH assay as the release of LDH with 1% Triton was
less when zinc naphthenate was present.   There was no evidence for the
induction of UDS by zinc naphthenate to toxic doses.  Toxicity was also
evaluated microscopically by cellular morphology.  There was no adverse
effect under the conditions of the assay.  It was concluded, therefore,
that zinc naphthenate was tested over an appropriate range of
concentrations and failed to induce a genotoxic response.               
                                                 

4.8	Neurotoxicity

There were no data submitted on neurotoxicity of either copper or zinc
naphthenate. 

4.9	Metabolism and Pharmacokinetics

No data were submitted on metabolism and pharmacokinetics of naphthenate
salts. 

5.0	TOXICITY ENDPOINT SELECTION

5.1	See Section 7.1, Summary of Toxicological Doses and Endpoint
Selection, Table 2.

5.2	Dermal Absorption

Dermal Absorption Factor:

A dermal absorption factor is not necessary as there are route-specific
studies from which to assess dermal toxicity. 

5.3	Classification of Carcinogenic Potential

There are no data from which to derive a carcinogenicity classification
of copper or zinc naphthenate.  

In Pesticide and Toxic Chemical News dated June 3, 1987, a  dermal
carcinogenicity study by the Chemical Manufacturers Association (CMA) is
summarized in which groups of 50 female STCF mice were treated twice
weekly for up to two years with dermal applications of 0.05 ml of a
mixture of mineral oil and calcium naphthenate (actual dose not stated
in the summary).   According to the summary, Sixteen percent (16%) of
mice developed tumors at the treatment site. Thirteen tumors were
observed in total (2 squamous cell carcinomas, one basal cell carcinoma,
one dermal fibrosarcoma, seven squamous cell papilloma, and two
papilloma which had regressed /sloughed.  Application of carrier oil
alone did not result in any cutaneous tumors.  The testing laboratory,
on the basis of historical control data, determined that the mixture of
calcium naphthenate and mineral oil is a cutaneous carcinogen in mice. 

6.0	FQPA CONSIDERATIONS

FQPA considerations are not applicable to copper and zinc naphthente. 
There are no food use tolerances for these chemicals, and indirect food
contact is not expected from the current uses of these chemicals. 

7.0	SUMMARY OF TOXICOLOGICAL DOSES AND ENDPOINTS FOR COPPER NAPHTHENATE
FOR USE IN HUMAN RISK ASSESSMENT

7.1	Summary Table of Toxicological Dose and Endpoint Selection (Table 4)

Table 4.  Naphthenate Salts (Copper, Zinc) for Use in Human Risk
Assessment

Exposure

Scenario	Dose (mg/kg/day) used in risk assessment

UF	Special FQPA SF and Level of Concern for Risk Assessment	Study and
Toxicological Effects

Dietary Risk Assessments

Acute Dietary

(general population and females 13-49)		No appropriate endpoints were
identified that represent a single dose effect.  Therefore, this risk
assessment is not required.

Chronic Dietary

	No appropriate endpoints were identified that represent a single dose
effect.  Therefore, this risk assessment is not required.

Non-Dietary Risk Assessments

Incidental Oral

Short–Term 

(1 - 30 Days)

 	NOAEL = 30 mg/kg/day

 

 	Target MOE= 100 (10x inter-species extrapolation, 10x intra-species
variation) 

	Developmental Toxicity – Rat (Copper Naphthenate) 

 MRID 41615101

Maternal NOAEL = 30 mg/kg/day, based on decreased body weight and food
consumption at 100 mg/kg/day

Incidental Oral

Intermediate-Term 

(1-6 months)

 	NOAEL = 30 mg/kg/day

 

 	Target MOE= 100 (10x inter-species extrapolation, 10x intra-species
variation) 

	Developmental Toxicity – Rat (Copper Naphthenate) 

 MRID 41615101

Maternal NOAEL = 30 mg/kg/day, based on decreased body weight and food
consumption at 100 mg/kg/day

Short -Term Dermal 

(1 - 30 Days)	LOAEL=100 mg/kg/day

(22,222 µg/cm2)a	Target MOE=300 (10x inter-species extrapolation, 10x
intra-species variation, 3x for use of LOAEL)

	90-day dermal toxicity-rabbit MRID 41515001 (Zinc naphthenate)

LOAEL(dermal) = 100 mg/kg/day, based on erythema, edema, and
desquamation at 100 mg/kg/day

Intermediate -Term Dermal 

(30 Days- 6 months)	NOAEL = 100 mg/kg/day	Target MOE=100 (10x
inter-species extrapolation, 10x intra-species variation)

	90-day dermal toxicity-rabbit MRID 41515001 (Zinc naphthenate)

NOAEL = 100 mg/kg/day, based on reductions in body weight gain observed
at 300 mg/kg/day. 

Inhalationa

( all exposure durations)

	NOAEL= 30 mg/kg/day

MOE = 1000c	Target MOE = 1000 (10x inter-species extrapolation, 10x
intra-species variation, 10x route-extrapolation)	Developmental Toxicity
– Rat (Copper Naphthenate) MRID 41615101 

Maternal NOAEL = 30 mg/kg/day, based decreased body weight and food
consumption at 100 mg/kg/day.

Cancer	Not classified;  no cancer data available. 

a an additional uncertainty factor of 10x is used for route
extrapolation from an oral endpoint.  

The inhalation absorption factor of 100%  should be used since an oral
endpoint was selected for the inhalation exposure scenarios and there
are no inhalation toxicity data available for copper or zinc
naphthenate.

7.2	Rationale for Toxicological Dose and Endpoint Selection

8.0	TOXICITY PROFILE TABLES 

8.1	Acute Toxicity Profile Table - (See Section 4.1, Acute Toxicity,
Table 1).

8.2	Subchronic, Chronic and Other Toxicity Profiles Table (Tables 5a and
5b)

Table 5a:  Subchronic, Chronic, and other Toxicity Profiles for Copper
Naphthenate.

Guideline Number/

Study Type/

Test Substance (% a.i.)	MRID Number (Year)/

Citation/

Classification/ Doses	Results

870.3250

90-day dermal (rat)

Purity: 9.5% Copper	MRID 41676101

Tompkins, E.  (1990) 

Acceptable – Core-Minimum

Copper naphthenate administered dermally at 0, 100, 300, or 1000
mg/kg/day for 13 weeks

10 G. Pigs/sex/dose, 6 hrs/day, 5 days/week for 13 weeks

	Dermal Toxicity:

NOAEL:  = 100 mg/kg/day

LOAEL:  = 300 mg/kg/day, no apparent dose related increases in
macroscopic and microscopic lesions related to dermal irritation.

Systemic Toxicity:

NOAEL: >= 1000 mg/kg/day

LOAEL:  > 1000 mg/kg/day, based on a decrease in body weight gain and
food efficiency in the high dose males along with an increase in kidney
weight and a decrease in testes weight.

870.3700a

Developmental Toxicity – (rat)

Purity: 9.5% Copper	MRID 41615101

Nemec, Mark D. (1990) 

Acceptable – Guideline

Copper naphthenate administered orally at 0, 30, 100, or 300 mg/kg/day
from days 6-15 of gestation.

25 female rats/dose

	Maternal Toxicity:

NOAEL:  > 30 mg/kg/day

LOAEL:  >=  300 mg/kg/day, based on a decrease in body weight gain and
food consumption.

Developmental Toxicity:

NOAEL: >= 300 mg/kg/day

LOAEL: >    300 mg/kg/day. There were no treatment-related effects on
fetal endpoints.

870.5140

Gene mutation test in mouse lymphoma cells

Purity: Not reported	MRID 41402502

Harbell, J.  (1990) L5178Y  TK+/- Mouse Lymphoma Mutagenesis Assay with
Confirmation. Microbiological Associates, Inc. Rockville, MD. Study #:
T9037.701

Copper naphthenate administered at:

Nonactivated  

1. Confirmatory test: 7.5, 11, 15, 19, 23, 27, 30, 33, 36, 40, 44, and
75 ug/ml

S9Activated

2. Confirmatory test: 7.5, 11, 15, 19, 23, 27, 30, 33, 36, 40, 44, and
75 ug/ml

Strain: mouse lymphoma L5178Y cells

Unacceptable – upgradable

	Negative

Copper naphthenate in the absence of S9 activation was cyrotoxic at
doses approximately ≥36 ug/ml but was not mutagenic over a
concentration range of ~4.2-36 ug/ml in two independently performed
forward gene mutation mouse lymphoma assays. In the presence of S9
activation at concentrations of  18, 24, 32, and 42 ug/ml (initial
assay) and 23,27, 30, 33, and 36 ug/ml +S9 (confirmatory assay ), 
dose-related increases in the number of mutant colonies and the mutation
frequency (MF) at the thymidine kinase locus was observed . The increase
in mutation over background ranged from a 1.4-fold at 18 ug/ml to a
3.4-fold at 42 ug/mL.  Copper naphthenate also produced large- and
small-colony trifluro-thymidine (TFT)—resistant mutants at the dose
levels selected to evaluate colony-size distribution (24, 32, and 42
ug/ml - - initial trial and 30, 33, and 36 ug/ml - - confirmatory
trial).  However, the evidence suggesting that copper naphthenate may
also be clastogenic was neither confirmed nor refuted in the CHO cell
clastogenic study conducted with the same batch number of the test
material.   Copper naphthenate is positive for mutagenicity in this test
system. 

870.5385

Cytogenetics assay in CHO cells

Purity: Not reported	MRID 41402503

Putnam, DL and Morris, MJ  (1990) Chromosome Aberrations in CHO Cells
Test Article Copper Naphthenate. Microbiological Associates, Inc.
Rockville, MD, Lab Project #: T9037.337.  

 Nonactivated  concentrations:

Trial 1: 4, 8, 15, 30, and 60 ug/ml (16-hr cell harvest)

Trial 2: 40, 80, 120, and 160 ug/ml (16-hour cell harvest)

Activated concentrations: 

Trial 1: 2, 4, 8, 15, and 30 ug/ml (12-hour cell harvest)

Trial 2: 20, 30, 40, 50, and 60 ug/ml (12-hour cell harvest)

Trial 3: 40, 60, 80, 120, 160, and 200 ug/ml (12-hour cell harvest)

Strain: CHO-K1 cells

Unacceptable – not upgradable

	

Although the test material did not induce reproducible significant
increases in the frequency of structural chromosome aberrations, there
was a consistent trend of increased abnormal chromosome morphology,
particularly at the high dose scored in each S9-activated trial (30
ug/mL - -Trial 1; 60 ug/mL - - Trial 2; and 80 ug/mL- - Trial 3).

No definitive conclusions can be reached regarding mutagenicity of
copper naphthenate in this test system. 

870.5550

UDS in mammalian cells in culture

Purity: Not reported	MRID 41402504

Curren, RD (1989) Unscheduled DNA Synthesis in Rat Hepatocytes. Test
Article Copper Naphthenate. Microbiological Associates, Inc. Rockville,
MD, Lab Project #: T9036.380. 

Concentrations tested:

Preliminary cytotoxicity assay: 0.135, 0.45, 1.35, 4.5, 13.5, 45, 135,
450, 1350, and 4500 ug/ml.

UDS assay: 

0.05, 0.15, 0.5, 1.5, 5.0, 15, 35, and 50 ug/ml.

Unacceptable –  upgradable	Copper naphthenate at five concentrations
ranging from 0.15 to 15 ug/ml did not induce unscheduled DNA synthesis
(UDS) in primary rat hepatocytes.   Information on the purity of the
test material  must be  provided to upgrade the study.  Copper
naphthenate is negative in this test system. 

Table 5b:  Subchronic, Chronic, and other Toxicity Profiles for Zinc
Naphthenate.

Guideline Number/

Study Type/

Test Substance (% a.i.)	MRID Number (Year)/

Citation/

Classification/ Doses	Results

870.3200

dermal (rat)

14-day dermal (rabbit)

Purity: not given	Open-literature (BIBRA)

Muni, IA et al. (1983). US Army Medical Research and Development
Command, Fort Detrick, Frederick, MD 21701. Contract #:
DAMD17-82-C-2301.

Zinc naphthenate administered dermally at 0, 9, 30, 100, 500, 2000
mg/kg/day   for 6 hr/day, 5 days/wk for 2 wks. 

 

BIBRA Toxicity profile

unacceptable

	Occluded application of  zinc naphthenate for 6 hours/day, five
days/week for 2 weeks to groups of ten rabbits (strain not specified) at
doses of 9, 30, 100, 500, and 2000 mg/kg resulted in  lethargy,
diarrhea, reduced food intake and reduced body weight, distended
intestines and fatty changes in the liver at 9 mg/kg/day and above.
Deaths were reported at 9-100 mg/kg/day but not at 500-2000 mg/kg/day. 

870.3250

90-day dermal (rat)

Purity: 14.5% Zinc	MRID 41615001

Tompkins, E.  (1990) 90-Dermal Study in Rabbits with Zinc Naphthenate.
WIL Research Labs. WIL/153006. 442 p.

Zinc naphthenate administered dermally at 0, 100, 300, or 1000 mg/kg/day
for 13 weeks

10 Rabbits/sex/dose, 6 hrs/day, 5 days/week for 13 weeks

Purity: 14.5% Zinc

Acceptable – Core-Minimum	Dermal Toxicity:

NOAEL:  < 100 mg/kg/day

LOAEL:  <=100 mg/kg/day, no apparent dose related increases in
macroscopic and microscopic lesions related to dermal irritation.

Systemic Toxicity:

NOAEL: 100 mg/kg/day

LOAEL:  300 mg/kg/day, based on a decrease in body weight gain in males
and females.

No treatment related clinical signs of systemic toxicity were noted
(hematology, clinical chemistry or histopathology).  In terms of dermal
effects there were apparent dose related increases in macroscopic and
microscopic lesions related to dermal irritation.

870.3700

Developmental Toxicity – oral gavage (rat)

Purity: 100% assumed

	MRID 41615002

Nemec, Mark D. (1990) A Developmental Toxicity Study of Zinc Naphthenate
in Rats.  Study No. WIL-153004. (Unpublished study WIL Research Labs,
Ashland, Ohio)

Zinc naphthenate administered orally at 0, 50, 250, or 500 mg/kg/day
from days 6-15 of gestation.

25 female rats/dose

 	Maternal Toxicity:

NOAEL:  >= 500 mg/kg/day

LOAEL:  >   500 mg/kg/day, there were no treatment-related effects on
maternal endpoints.

Developmental Toxicity:

NOAEL: >= 500 mg/kg/day

LOAEL: >   500 mg/kg/day. There were no treatment-related effects on
fetal endpoints.

870.3700

Developmental Toxicity- rat

Purity: unknown

	Angerhofer, RA (1991): Assessment of  the developmental toxicity of
zinc naphthenate in rats. Phase 4 report No. USAEHA-75-51-0487-91. 
AD-A235 308. US Army Environmental Hygiene Agency. 

Open literature- BIBRA	Oral administration of zinc naphthenate at doses
of  94, 188, and 938 mg/kg/day to rats during the major period of fetal
organogenesis did not produce any teratogenic effects. Maternal toxicity
in the form of lethargy and lower body weight gain was observed at 938
mg/kg/day. No other information was available on this study. 

870.3800

2-generation reproductive toxicity in diet (rat)

Purity: not given	Michie, MW et al. (1983). Effects of ingestion of zinc
naphthenate on the reproductive function of rats.  Phase 5. Rpt #:
USAEHA-75-51-0487-91.  AD-A235 224.  US Army Env Hygiene Agency. APG, MD

Zinc naphthenate administered orally over 2 generations at 250 mg/kg/day
for an undisclosed time

Rats

Purity: not given

Open-literature (BIBRA)

	Mating performance and offspring viability were apparently unaffected
over two generations when rats were fed about 250 mg/kg for an
undisclosed time.

870.5300

In Vitro mammalian cell gene mutation test

Purity: Not reported	MRID 41400701

Harbell, J.W.  (1990) L5178Y TK Mouse Lymphoma Mutagenesis Assay with
Confirmation. Test Article Zinc Naphthenate Microbiological Associates,
Inc. Rockville, MD, Lab Project #: T9036.701. 

 

Nonactivated concentrations: 

1. Confirmatory test: 7.5, 11, 15, 19, 23, 27, 30, 33, 36, 40, 44, and
48 ug/ml

S9Activated

2. Confirmatory test: 23, 27, 30, 33, 36, 40, 44, 48, 52, 56, 65 and 75
ug/ml

Strain: mouse lymphoma L5178Y cells

Unacceptable -upgradable	Mutagenicity observed in two independently
performed forward gene mutation assays. Increases in mutant colonies
were concentration-related. Under non-activated conditions, increases in
mutant colonies ranged from 2.0 fold at 23 µg/ml to 7.2 fold at 42
µg/ml. Under S9 activated conditions, increases in mutant colonies
ranged from 1.7 fold at 32 µg/ml to 4.8 fold at 56 µg/ml.  Zinc
naphthenate also induced formation of small-colony TFT-resistant mutants
in both the absence and presence of metabolic activation. Zinc
naphthenate is classified as a positive mutagen in this test system. 

Information on test material purity must be provided to upgrade the
study. 

870.5380

Cytogenetics assay using CHO cells

Purity: Not reported	MRID 41400702

Putnam, DL and Morris, MJ  (1990) Chromosome Aberrations in CHO Cells
Test Article Zinc Naphthenate. Microbiological Associates, Inc.
Rockville, MD, Lab Project #: T9036.337.  30 p.

Zinc naphthenate administered at:

Nonactivated  

Trial 1: 5, 10, 20, 40, and 80  ug/ml (20-hr cell harvest)

Trial  2: 80, 110, 140, 170, and 200 ug/ml (20-hour cell harvest)

Activated

Trial 1: 10, 20, 40, 80, and 160 ug/ml (20-hour cell harvest)

Trial 2: 60, 80, 100, 120, and 140 ug/ml (20-hour cell harvest)

Strain: CHO-K1 cells

Unacceptable – upgradable	In two independently performed assays, zinc
naphthenate  induced a clastogenic response in CHO cells. Chromatid-type
aberrations were the most frequently scored abnormal figures. Zinc
naphthenate is positive for clastogenicity in this test system. 
Information on test article purity must be provided to upgrade this
study. 

870.5550

UDS in primary rat hepatocytes

Purity: Not reported	MRID 41400703

Curren, RD (1989) Unscheduled DNA Synthesis in Rat Hepatocytes.
Microbiological Associates, Inc. Rockville, MD, Lab Project #:
T9036.380.  28 p.

Concentrations:

Preliminary cytotoxicity assay: 0.05, 0.15, 0.5, 1.5, 5.0, 15, 50, 150,
500, and 1500 ug/ml

UDS assay: 

0.15, 0.5, 1.5, 5.0, 15, and 35 ug/ml

Unacceptable – upgradable	 

Zinc naphthenate at concentrations ranging from 0.15 µg/ml to 15 µg/ml
failed to induce unscheduled DNA synthesis in primary rat hepatocytes. 
Zinc naphthenate is negative in this test system.  Information on test
article purity must be provided to upgrade the study. 



9.0	REFERENCES

00244277 (MRID):  Bioresearch, Inc. (1980): Acute Oral Toxicity Study.
Project #:80-2171A. 

00244277 (MRID):  Bioresearch, Inc. (1980): Acute Dermal Toxicity Study.
Project #:80-2171A. 

00244277 (MRID):  Bioresearch, Inc. (1980): Acute Inhalation Toxicity
Study. Project #:80-2171A. 

00244277 (MRID):  Bioresearch, Inc. (1980): Eye Irritation Study.
Project #:80-2171A. 

00244277 (MRID):  Bioresearch, Inc. (1980): Dermal Irritation Study.
Project #:80-2171A. 

00244277 (MRID):  Bioresearch, Inc. (1980): Dermal Sensitization Study.
Project #:80-2171A. 

00260891 MRID):  Applied Biological Sciences Laboratory, (1975): Study #
2778.

00266172 (MRID): Cannon Laboratories, Inc. (1980): Acute Oral Toxicity.
Project #: OF-7374.

41140710 (MRID): Angerhofer, R.A. and L.W. Metger:  Phase 3 Preliminary
Assessment of the Relative Toxicity of Copper Naphthenate. Acute
Studies: Acute Oral and Dermal Toxicity Studies.

41140710 (MRID): Angerhofer, R.A. and L.W. Metger:  Phase 3 Preliminary
Assessment of the Relative Toxicity of Copper Naphthenate. Acute
Studies: Primary Skin Irritation and Dermal Sensitization Studies.

41400701 (MRID): Harbell, J.W. (1990): L5178Y TK Mouse Lymphoma
Mutagenesis Assay with Confirmation.  Test Article Zinc Naphthenate. 
Microbiological Associates, Inc, Rockville, MD. Study No. T9036.701.

41400702 (MRID): Putnam, D.L. and Morris. M.J. (1990): Chromosome
Aberrations in Chinese Hamster Ovary (CHO) Cells.  Test Article Zinc
Naphthenate.  Microbiological Associates, Inc, Rockville, MD. Study No.
T9036.337.

41400703 (MRID): Curren, R.D. (1989): Unscheduled DNA Synthesis in Rat
Primary Hepatocyte.  Test Article Zinc Naphthenate.  Microbiological
Associates, Inc, Rockville, MD. Study No. T9036.380.

41402502 (MRID): Harbell, J.W. (1990): L5178Y TK Mouse Lymphoma
Mutagenesis Assay with Confirmation.  Test Article Copper Naphthenate. 
Microbiological Associates, Inc, Rockville, MD. Study No. T9037.701.

41402503 (MRID): Putnam, D.L. and Morris. M.J. (1990): Chromosome
Aberrations in Chinese Hamster Ovary (CHO) Cells.  Test Article Copper
Naphthenate.  Microbiological Associates, Inc, Rockville, MD. Study No.
T9037.337.

41402504 (MRID): Curren, R.D. (1989): Unscheduled DNA Synthesis in Rat
Primary Hepatocyte.  Test Article Copper Naphthenate.  Microbiological
Associates, Inc, Rockville, MD. Study No. T9037.380.

41486301 (MRID): Collins, C.J. (1990): Acute Inhalation Toxicity Study
– LC50 Rats (4 hour exposure).Hazleton UK. Study Number  HUK 769/1.

41615001 (MRID): Tompkins, E.C. (1990): 90-Day Dermal Study in Rabbits
with Zinc Naphthenate.  WIL Research Laboratories, Ashland Ohio, Study
No. WIL-153006.

41615002 (MRID): Nemec, Marc D. (1990): A Developmental Toxicity Study
of Zinc Naphthenate in Rats.  WIL Research Laboratories, Ashland Ohio,
Study No. WIL-153004.

41615101 (MRID): Nemec, Marc D. (1990): A Developmental Toxicity Study
of Copper Naphthenate in Rats.  WIL Research Laboratories, Ashland Ohio,
Study No. WIL-153002.

41676101 (MRID): Tompkins, E.C. (1990): 90-Day Dermal Study in Rats with
Copper Naphthenate.  WIL Research Laboratories, Ashland Ohio, Study No.
WIL-153012.

	

	

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Michie, M., Angerhofer, M., Barlow, M. (1988): Phase 5 Effects of
ingestion of zinc naphthenate on the reproductive function of rats.
Toxicological study no. 75-51-0497-91. U.S. Army Environmental Hygiene
Agency. Laboratory report 75-51-0497-91. 

Angerhofer, R., M. Michie, M. Barlow, et al. (1991) Phase 4,
toxicological study no. 75-51

0497-91, assessment of the developmental toxicity of zinc naphthenate in
rats, June 1985 – July

1988. U.S. Army Environmental Hygiene Agency. Laboratory report number
75-51-0497-91,

March 28, 1991. 

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