UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC 20460

OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES

 

MEMORANDUM:								June 28, 2007

Subject:	Toxicology Chapter for Copper 8-Quinolinolate (Oxine-Copper) in
Support of the Reregistration Eligibility Decision (RED) Document for
the Copper Salts (RED Case 4026). 

To:		Kathryn Jakob, Chemical Review Manager

		Regulatory Management Branch II

Antimicrobials Division (7510P)

			 

From: 		Timothy McMahon, PhD., Risk Assessor

		Senior Toxicologist

Antimicrobials Division (7510P)	 

 

DP Barcode: 	D337758

							CAS

Chemical Name:			PC Code:	Registry No.: 	Common Names:

Copper, bis(8-quinolinolato-N1,O8)-,	024002		10380-28-6	Copper
8-Quinolinolate;										Oxine-Copper; Oxine-Cu; 									Copper-8

Attached is the draft Toxicology Chapter for Copper 8-Quinolinolate in
support of the RED assessment for the Copper Salts (RED Case 4026). 

1.0	  SEQ CHAPTER \h \r 1 HAZARD CHARACTERIZATION

Copper 8-quinolinolate is a greenish solid that is practically insoluble
in water and most organic solvents. Currently, there are 27 active
copper 8-quinolinolate labels registered.  

  SEQ CHAPTER \h \r 1 Copper 8-quinolinolate is a fungicide, mildewcide
and wood preservative chemical.  Copper 8-quinolinolate is approved for
use as a wood preservative for control of sapstain, mold and decay in
unfinished wood and wood products such as millwork, siding, decks,
outdoor furniture, shingles, structural lumber, boats, decks and
baseboards.  Treated wood materials may be used in contact with fruit,
vegetables and other foodstuffs in an area such as greenhouses and
greenhouse items, produce picking boxes, mushroom trays and vegetables
stakes.  Copper 8-quinolinolate is also used as a disinfectant to
control potato ring rot in planters, seed handling equipment, seed
cutters, storage areas and transportation equipment.  Copper
8-quinolinolate is used in the manufacturing of kraft paper, paperboard,
adhesives, paints, and textiles as a fungicide and mildewcide.  Copper
8-quinolinolate is additionally used to control mold and mildew on
industrial textiles such as canvas, burlap, rope, leather and nets
(non-aquatic uses only).  Clearances exist in 21 CFR 176.170 and 21 CFR
178.3800 for the use of copper 8-quinolinolate as a component of the
food contact surface of paper and paperboard (as a preservative for
coating formulations) and as a preservative on wooden articles that are
used or intended for use in packaging, transporting, or holding raw
agricultural commodities. 

The acute toxicity database for Copper 8-quinolinolate is complete. 
Copper 8-quinolinolate has a low order of acute toxicity via the oral
route of exposure (Toxicity Category IV).  Copper 8-quinolinolate has a
moderate order of toxicity via the dermal route of exposure (Toxicity
Category III), whereas the inhalation exposure route produced a higher
order of toxicity (Toxicity Category II).  Copper 8-quinolinolate is
classified as corrosive to the eye (Toxicity Category I), But does not
produce dermal irritation,  (Toxicity Category IV).  Copper
8-quinolinolate is not a dermal sensitizer.

For subchronic toxicity, five studies were provided to the Agency; three
of the five studies were considered acceptable (MRIDs 42986801,
42986802, 42957802). The other two studies were supplementary (MRID
42937301) and range-finding (MRID 42957801), respectively.

  SEQ CHAPTER \h \r 1 In a 90-day oral toxicity test (MRID 42986802),
copper 8-quinolinolate (>99.5% purity) was administered in feed via
capsules to 4 dogs/sex/dose at concentrations of 0, 5, 50, or 250
mg/kg/day for males and females, respectively) for 13 weeks.  The NOAEL
was determined to be 5 mg/kg/day (males/females), based on vomiting,
reduced total plasma protein and albumin, reddened mucosa and hyperemia
in the stomach and/or small intestine observed at the LOAEL of 50
mg/kg/day.

  SEQ CHAPTER \h \r 1 In a 28-day dermal toxicity study (MRID 42957802),
Tif: RAIF (SPF) albino rats (5/sex) were administered copper
8-quinolinolate (99.7% a.i.) at doses of 0, 50, 200, or 1000 mg/kg/day
for 6 hours per day, for 4 weeks.  Histopathologic examination revealed
an increased incidence of necrosis of the thymic lymphocytes in male
rats exposed to 1,000 mg/kg/day of test material. The systemic toxicity
NOAEL is 200 mg/kg/day, and the systemic toxicity LOAEL is 1000
mg/kg/day based on necrosis of thymic lymphocytes.  The dermal toxicity
NOAEL is 1000 mg/kg/day; the LOAEL could not be determined for dermal
toxicity.

The database for developmental toxicity is considered complete with
three studies.  (MRID 41063701, 41063702 and 42986803). In one study
(MRID 42986803), copper 8-quinolinolate (98.5% a.i.) in 0.5% aqueous
carboxymethylcellulose was administered via oral gavage to mated female
Fu-Albino rats at dose levels of 0, 50, 200, or 800 mg/kg/day from
gestation day (GD) 6 to 15  inclusive.  Maternal toxicity was noted at
800 mg/kg/day (clinical toxicity, decreased body weight gain).    No
developmental toxicity was noted at any dose level tested in this study.
 The maternal toxicity NOAEL is 200 mg/kg/day and the LOAEL is 800
mg/kg/day. The developmental toxicity NOAEL is 800 mg/kg/day and the
developmental toxicity LOAEL is > 800 mg/kg/day. 

 In a range-finding developmental toxicity study (MRID 41063701),  K37
(copper 8-hydroxyquinolate ) was administered orally to 5 timed-mated
female New Zealand White rabbits per dose at dose levels of 0, 7, 18, or
45 mg/kg bw/day from days 6  through 18 of gestation. In a concurrent
study, K37 was also orally administered to two groups of 5 non-mated
female New Zealand White rabbits using the following dose scheme: dosing
began at 5 mg/kg/day and was increased every 5 days to 10 mg/kg  (days
6-10), 20 mg/kg (days 11-15), and 40 mg/kg (days 16-20).   The maternal
LOAEL in the first study was determined to be 45 mg/kg bw/day, based on
clinical signs of toxicity, reduced body weight and body weight gain,
and reduced food consumption.  The maternal NOAEL was determined to be 7
mg/kg bw/day.  In the non-mated female study, the LOAEL was 40 mg/kg
bw/day, based on clinical signs of toxicity, reduced body weight and
body weight gains, and reduced food consumption.  In non-mated females,
the NOAEL is 20 mg/kg bw/day. There were no treatment-related effects
observed in developmental parameters. 

In a developmental toxicity study (MRID 41063702), K37 (96.5% a.i., lot
382) was administered to 64 New Zealand White rabbits by gavage at dose
levels of 0, 7, 15, or 30 mg/kg/day from days 7 through 19 of gestation
(i.e., gd 7-19).  In this study, a maternal LOAEL was not established. 
The maternal NOAEL was 30 mg/kg/day (highest dose tested). There was no
evidence of developmental toxicity in this study.  

In a 2-generation reproductive toxicity study (MRID 43267202), copper
8-quinolinolate was administered to Cr1:CD rats, 32/sex/dose for the F0
generation and 28/sex/dose for the F1 generation, in the diet at
concentrations of 0, 25, 250, or 2500 ppm.  [In the F0 generation: 0,
1.8, 18.2, and 181 mg/kg/day for males and 0, 2, 20.8, and 203 mg/kg/day
for females; in the F1 generation: 0, 2, 19.8 and 196 mg/kg/day for
males and 0, 2.2, 22.8 and 218 mg/kg/day for females].  

The parental (systemic) toxicity NOAEL was determined to be 250 ppm and
the parental (systemic) toxicity LOAEL was determined to be 2500 ppm
based on increased liver weight in F1 males. Although the liver toxicity
occurred only in F1 males, this effect is expected to be real since the
liver was reported as a target organ in a rat subchronic feeding study
[MRID No. 42986801] and in a mouse carcinogenicity study [MRID No.
43267201]. No significant compound-related effects were noted in the
pregnancy rate, pre-coital time, duration of pregnancy, and implantation
sites/litter for rats fed oxine-copper for two successive generations.
The reproductive toxicity NOAEL was determined to be 250 ppm and the
reproductive toxicity LOAEL was determined to be  2500 ppm based on
decreased mean number of live pups at birth (87% of controls; p<0.05)
and at day 4 pre-cull (85% of controls; p<0.01) and decreased litter
weights observed at day 0 and during lactation in F1 generation.

In a chronic toxicity study in the dog, (MRID 00099606), copper
8-quinolinolate (96%) was administered to 4 Beagle dogs/dose/sex at dose
levels of 0, 10, 40, 200, or 1000 ppm (equivalent to 0, 0.2, 1.30, 6.49,
or 32.98 mg/kg/day for males, and 0, 0.30, 1.12, 7.29, or 30.67
mg/kg/day for females, respectively) for 104 weeks.  A fifth treatment
group initially receiving concentrations of 4000 ppm (3000 ppm from
weeks 10-104) was also used. The LOAEL is 1000 ppm (32.98 and 30.67
mg/kg/day for males and females, respectively) based on changes in liver
enzymes, total blood albumin, body weight, body weight gain, and food
consumption. The NOAEL is 200 ppm (6.49 and 7.29 mg/kg for males and
females, respectively). This study was classified
Unacceptable-Nonguideline. 

The database for carcinogenicity consists of three submitted studies
(MRID 00083777, 42957801 and 43267201) for copper 8-quinolinolate and 2
studies on 8-hydroxyquinolone conducted by the National Toxicology
program (NTP, 1985).  

In a carcinogenicity study (MRID 00083777), copper-8-quinolinolate (96%)
was orally administered to 180 male rats and 180 female rats (30
animals/sex/group) via dietary mixture. The nominal dietary
concentrations received were 0, 5, 20, 100, 500, and 2000 ppm. Estimates
of compound intake were 0, 2, 8, 38, 188, and 761 mg/kg/day for males
and 0, 2, 9, 46, 229, and 922 mg/kg/day for females.  Five
animals/sex/group were sacrificed at 52 weeks and all surviving rats
were sacrificed at 102 weeks via exsanguination under sodium
pentobarbital anesthesia. Interstitial tumors of the testes, 2
unilateral and 1 bilateral, were observed in three 2000 ppm males but
this rate is consistent with historical data for rats of this age in the
laboratory. The incidence of neoplasia was considered comparable between
control and treated animals. The LOAEL was determined to be 2000 ppm
(approximately 761 mg/kg/day for males and 922 mg/kg/day for females)
based on increased incidence of pigment deposition observed in the
spleens and small intestines of males and females at 52 weeks; and
increased incidence of hemosiderin deposition in the spleens, small
intestines, livers, and kidneys of males and females at 102 weeks). The
NOAEL is 500 ppm (188 mg/kg/day for males and 229 mg/kg/day for
females). 

A supplementary study (MRID 42957801) utilized 42 day old male and
female Crl:CD-1 (ICR)BR strain (VAF plus) mice (10/sex/group) and
exposed them orally to concentrations of 0, 300, 1000, 3000, or 6000 ppm
in the diet for 13 weeks. There were no deaths attributable to treatment
with copper 8-quinolinolate. No treatment –related increase in the
incidence of epithelial hyperplasia of the glandular mucosa of the
stomach was seen in either sex compared to controls. Follicular cysts
were seen in 2/10, 1/10, and 3/10 female mice at 300, 3000, and 6000
ppm, respectively. 1000 ppm was considered to be the NOAEL in this
study. A dose below 1000 ppm was recommended for the low dose level for
a long-term study to represent a low multiple of the expected human
exposure level. This study was conducted as a range-finding study and
does not satisfy a guideline requirement. 

 In a carcinogenicity study (MRID# 43267201), Cr1:CD-1 mice (50/sex/dose
group) received copper 8-quinolinolate (97.2% a.i.; Lot# 777) in the
diet for 80 weeks at dose levels of 0, 100, 400, 1500 and 6000 ppm. (0,
14.49, 57.15, 207.7, and 855.8 mg/kg/day for males; and 0, 16.3, 66.18,
246.2 and 1051.7 mg/kg/day for females). A satellite group of ten
animals/sex/dose group were sacrificed at 12 months. There was no
treatment-related difference in the overall tumor incidence (22 and 23
for control and high dose animals, respectively) seen in male mice. More
variation was seen in the tumor incidence in females with different dose
levels; however, the tumor incidence tended to be higher at 1500 and
6000 ppm (18, 28, 26 for the control, 1500 and 6000 ppm groups,
respectively) although there was no clear dose effect. The incidence of
lymphomas in female mice at 1500 ppm was higher than expected from
historic controls (2/50-11/50) with no dose effect and the high dose
resulting in no increase over the control incidence. Other tumor
occurrences were within the range of spontaneous incidences for the
tumor types and the age and strain of mice. The systemic toxicity LOAEL
was determined to be 1500 ppm (207.7 mg/kg/day males, 246.2 mg/kg/day in
females), based on an increased incidence of stomach ulcers in males;
and mild anemia and adverse lever effects including increased incidence
of abnormal liver coloration and increased alkaline phosphatase activity
in females.  The systemic toxicity NOAEL is 400 ppm (57.1 mg/kg/day in
males, 66.2 mg/kg/day). 

The database for mutagenicty is considered adequate with three studies
(MRID 429623-01, 429623-02, 429623-03). One gene mutation study (MRID
429623-01) concluded that there was a weak positive response for reverse
gene mutation in S9-activated bacterial strains TA97, TA100, TA102 of S.
typhimurium exposed to toxic doses. An in vivo mammalian cytogenetics
study (MRID 429623-02) showed negative results for micronucleus
induction in bone marrow cells of mice treated once at doses up to 7500
mg/kg, (non-toxic but limiting dose). A third study  (MRID 429623-03)
reported negative results for induction of unscheduled DNA synthesis in
primary rat hepatocyte cultures isolated from male rats that were
treated orally up to 3000 mg/kg, as determined by radioactive tracer
procedures [nuclear silver grain counts]. 

The database for neurotoxicity consists of three studies (MRID not
assigned). One study used the accelerating rotarod test to assess the
effects of oral administration of copper 8-quinolinolate at doses of
100, 300 and 1000 mg/kg on motor co-ordination in mice. There was little
or no effect on performance on the accelerating rotarod. A second study
examined for possible neurological effects of oral doses at 100, 300 and
1000 mg/kg using the tilting plate test. This study used 20 male and 20
female Wistar rats. Male animals exhibited small decreases in mean angle
of slip when compared to the vehicle-treated control group. Little or no
such effect was observed in females treated at 1000 mg/kg. The effect on
bodyweight gain observed over days 4-8 was less severe in females
(4.2-6.5% inhibition) than observed in males (9.2-14.8%). 

A third study examined the effects of oral administration at above
mentioned doses on hexobarbital induced sleeping time in mice. No
statistically significant effect on hexobarbital –induced sleeping
time was noted at the doses tested in the study.

The database for metabolism consists of two studies (MRID 42962304,
42962305). These metabolism studies in male and female Wistar rats dosed
the animals with 14C-labeled oxine copper at oral doses of 30 or 1000
mg/kg and at repeated oral doses (14 daily doses) of unlabeled oxine
copper at 30 mg/kg followed by administration of a single oral dose of
14C-labeled oxine copper at 30 mg/kg. Major routes of excretion were
urine (62-86%) and feces (8-26%) over a 4-7 day period. Most (54-59%) of
the compound was excreted in urine and feces within 48 hours of dosing.
Saturation of absorption following high dose was indicated by large
amounts (23%) of radioactivity in the feces. Radioactivity in tissue
residues was very low in all tissues including blood (<0.05%). The
potential for bioaccumulation was considered to be minimal even after
high dose or low dose (single or repeated) exposures. In urine,
radioactivity was associated with the parent (5 to 16% of dose), sulfate
(12 to 18%) and glucuronide conjugates (36 to 66%) of the parent while
in the feces it was associated with the parent (4 to 23% of the dose)
and the glucuronide conjugate of the parent (0.1 to 4%). Expired air as
CO2 accounted for 0.4-2.2% of the administered dose and less than 8% was
excreted via bile, mainly as glucuronide conjugate. 

TOXICOLOGY DATA

The available toxicology data are listed in Table 1. 

Table 1.

Test

	

MRID Number	

Acceptable



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

	

42921501

42921502, 43558501

43611901

41678402

42921503

42921504

	

Y

Y

Y

Y

Y

Y



870.3100    Oral Subchronic (rodent)

870.3150    Oral Subchronic (non-rodent)

870.3200    28-Day Dermal

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (non-rodent)

870.3800    Reproduction

	

42986801, 43572401

42986802

42957802

42986803

41063701, 41063702

43267202	

Y

Y

Y

Y

Y

Y



870.4100a  Chronic Toxicity (rodent)

870.4100b  Chronic Toxicity (non-rodent)

870.4200a  Oncogenicity (Rat)

870.4200b  Oncogenicity (Mouse) 

870.4300    Chronic/Oncogenicity

	

00099606

43267201, 42957801

00083777

	

N

Y

N



870.5100    Mutagenicity–Gene mutation-bacterial

870.5395    Mutagenicity- Gene mutation-mammalian

870.5xxx    Mutagenicity-Other Genotoxic Effects

	

42962301

42962302

42962303	

Y

Y

Y

870.7485    General Metabolism	42962304, 4296305	Y

Y- Yes; N- No

3.0	DATA GAPS

870.3465 90-Day Inhalation-Rat

4.0	HAZARD ASSESSMENT

4.1	Acute Toxicity

Adequacy of database for Acute Toxicity:  The acute toxicity database
for copper 8-quinolinolate and salts is considered complete. Copper
8-quinolinolate has a low order of acute toxicity via the oral route of
exposure (Toxicity Category IV).   Copper 8-quinolinolate has a moderate
order of toxicity via the dermal route of exposure (Toxicity Category
III), whereas the inhalation route of exposure yielded a higher order
(Toxicity Category II).   The primary eye irritant study classified
oxine copper as corrosive (Toxicity Category I).  For dermal irritation,
copper 8-quinolinolate is a non-irritant (Toxicity Category IV).  Copper
8-quinolinolate is not a dermal sensitizer. The acute toxicity data for
copper 8-quinolinolate are summarized below in Table 2.

	

Table 2.  Acute Toxicity Profile for Copper 8-quinolinolate and Salts

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

Citation	Results	Toxicity Category

870.1100

(§81-1)	Acute Oral- Rat

Copper 8-quinolinolate purity 99.5%	42921501	LD50 > 5000 mg/kg M/F	IV

870.1200

(§81-2)	Acute Dermal- Rabbits

Copper 8-quinolinolate, purity 99.5%	42921502, 43558501	LD50 = 2000
mg/kg M/F	III

870.1300

(§81-3)	Acute Inhalation- Rat

Copper 8-quinolinolate, purity 96%	43611901	LC50 = 0.089 ± 0.031 mg/L
M/F	III

870.2400

(§81-4)	Primary Eye Irritation- Rabbit

Copper 8-quinolinolate purity 98%	41678402	Corrosive	I

870.2500

(§81-5)	Primary Dermal Irritation- Rabbit

Copper 8-quinolinolate purity 99.7%	42921503	Non-Irritant	IV

870.2600

(§81-6)	Dermal Sensitization - Guinea pig

Copper 8-quinolinolate purity 99.7%	42921504	Not a sensitizer	No



4.2	Subchronic Toxicity

Adequacy of database for Subchronic Toxicity:  For subchronic toxicity,
several in-house studies were provided.  Two oral studies and one 28 day
dermal study were considered acceptable (MRID 42986801, 42986802 and
42957802, respectively).

870.3100	90-day Oral Toxicity – Rats

  SEQ CHAPTER \h \r 1 In a 90-day oral toxicity test (MRID 42986801)
designed to determine the subchronic toxicity effects of repeated
dietary exposure to copper 8-quinolinolate (>99.5% purity) in Wistar
rats.  Copper 8-quinolinolate was administered in feed to 10
rats/sex/dose or 16 rats/sex/dose (HDT) at concentrations of 0, 30, 100,
300, or 1000/700 mg/kg/day for 13 weeks.  Animals were observed weekly
for changes in body weight and food consumption.  Water consumption was
measured during weeks 2-3 and 9-10.

Mortality occurred in females after (weeks 3-10) the top-dose was
reduced in week 3, while the deaths in males occurred before (weeks 2-7)
the top-dose was reduced in week 6. Anorexia from extreme weight loss
and generally poor condition were considered the main causes of death. 
The top dose was reduced from 1000 to 700 mg/kg/day in week 3 (females)
and week 6 (males) because of reduced food consumption, reduced body
weight gain, poor general condition, and mortality due to anorexia in
both sexes.

in was significantly (p≤0.01) reduced in both top dose (by 80% in
males and 73% in females) and high-dose animals (by 37% in males and 22%
in females).      

There were slightly elevated red blood cell counts, hemoglobin, and
packed cell volume (top-dose males at week 7); slightly elevated mean
corpuscular volume in top-dose males at week 7; slightly reduced mean
corpuscular volume in top-dose females at week 13; slightly reduced
(males) and elevated (females) mean corpuscular hemoglobin concentration
at week 7; and reduced (males, week 7) and elevated (females, week 13)
reticulocytes.  However, all the changes appeared to be within the
normal range for this species (no hematological control data were
available).  In addition, the changes were variable, inconsistent
between males and females, and were probably related to reduced water
consumption and dehydration.

The NOAEL is 30 mg/kg/day (M/F).  The LOAEL is 100 mg/kg/day (M/F),
based on statistically significant increases in ALT, AST and bilirubin
in males, increased spleen weights in females, increased incidence of
diffuse degeneration, focal necrosis, and extramedullary hematopoises in
liver.

This study is classified as Acceptable - Guideline.

90-day Oral Toxicity – Mouse

  SEQ CHAPTER \h \r 1 In a 90-day oral toxicity test (MRID 43572401) 
copper 8-quinolinolate (97.2% a.i.) was administered in feed to 10
Crl:CD-1 mice/sex at dose levels of 0, 300, 1000, 3000, or 6000 ppm (0,
50, 148, 438 or 979 mg/kg/day in males; 0, 67, 200, 578 or 1066
mg/kg/day in females) for 13 weeks.  Animals were observed weekly for
changes in body weight and food consumption.  

No treatment-related clinical signs of toxicity were observed in males
and females in the 0, 300, 1000, and 3000 ppm groups.  At 6000 ppm,
generalized yellow staining of the fur was observed in 10/10 males and
10/10 females (p ≤ 0.01) beginning on day 2 or 3 of treatment.  This
effect was attributed to the color of the test material rather than a
direct compound-related toxicity.  All females survived to terminal
sacrifice.  There were several deaths in the control and treated male
groups during week 13; these were attributed to anesthetic overdose
during blood sampling.

There were no statistically or biologically significant differences
between treated and control groups of either sex for body weights, body
weight gains, hematology and clinical chemistry, urinalyses, absolute
and relative organ weight.  Statistically significant  findings of
urethral plugs were seen in approximately 50% of males [significant at
300 (5/10, p<0.05), 1000 (5/10, p<0.05), 3000 (3/10, p>0.05) and 6000
(6/10, p<0.05) ppm].  Since this finding was examined microscopically
only at 6000 ppm [called eosinophilic plugs], the high incidence of
these findings are assumed to be correct.  Control mice showed no
similar finding.  

Because only two cages per treatment group were used (5
animals/sex/cage), statistical analyses were not performed on food
consumption data.  Food consumption and food scattering was similar
between the controls and the 300, 1000, and 3000 ppm male and female
groups throughout the study.  During week 1, high-dose males ate 81% of
the control level (30 vs 37 g/animal/week, respectively), and had
increased food scattering.  However, among all treated male groups, the
overall (weeks 1-12) food consumption was 97-110% of the control group
value.  During weeks 1-6, high-dose value females ate 70-85% of the
control level, however, food consumption was similar to that of the
controls for weeks 7-13.  Food scattering was increased only during week
1 for the 3000 and 6000 ppm groups.  Among treated female groups,
overall (weeks 1-12) food consumption was 113, 100, 95, and 87%,
respectively, of the control group value.  The lack of significant
effects on body weight and the sometimes large variation in food
consumption values between the two cages within a treatment group,
suggest that the effects of food consumption in high-dose males and
females were not a result of compound-related toxicity.

The NOAEL is 6000 ppm (979 mg/kg/day in males, 1066 mg/kg/day in
females). (HDT)  The LOAEL was not achieved.

This study is classified as Acceptable - Guideline.

870.3150	90-day Oral Toxicity – Dogs

  SEQ CHAPTER \h \r 1 In a 90-day oral toxicity test (MRID 42986802),
copper 8-quinolinolate (>99.5% purity) was administered in capsules to 4
dogs/sex/dose at dose levels of 0, 5, 50, or 250 mg/kg/day for 13 weeks.
 Animals were observed weekly for changes in body weight and food
consumption.  No treatment-related body weight changes were observed.

There were no deaths during the study.  The only clinical sign of
toxicity was vomiting, which was observed in all treatment groups. 
Vomiting occurred sporadically from  30 minutes to 4 hours post dosing,
but was more frequent, severe, and affected more animals in the
high-dose groups.  General weakness during vomiting, and transient
episodes of soft stool and/or diarrhea with bloody content were
observed, although the overall the behavior and condition of the dogs
appeared normal.  

The subchronic toxicity NOAEL is (5 mg/kg/day, M/F).  The subchronic
toxicity LOAEL is (50 mg/kg/day, M/F), based on vomiting, reduced total
plasma protein and albumin, and reddened mucosa and hyperemia in the
stomach and/or small intestine.  

This study is classified as Minimum – Guideline.

	

870.3200	28-Day Dermal Toxicity Study – Rat

  SEQ CHAPTER \h \r 1 In a 28-day dermal study (MRID 42957802) male and
female albino rats  (5/sex/dose) were administered copper
8-quinolinolate (99.7% a.i.) over a 20 day study period for a total of
15 doses of 0, 50, 200, or 1000 mg/kg/day for 6 hours per day.

No animals died during the study.  No treatment-related effects on
bodyweight, food consumption, hematology, blood chemistry, organ
weights, or gross pathology were observed.  Histopathologic examination
revealed an increased incidence of necrosis of the thymic lymphocytes in
the male rats exposed to 1000 mg/kg/day of test material (HDT).

The systemic toxicity NOAEL is 200 mg/kg/day, and the systemic toxicity
LOAEL is 1000 mg/kg/day, based on necrosis of thymic lymphocytes.  The
dermal toxicity NOAEL is 1000 mg/kg/day; no LOAEL could be determined.  


This study is classified as Acceptable-Guideline.

4.3	Prenatal Developmental Toxicity

Adequacy of database for Prenatal Developmental Toxicity:  The database
for developmental toxicity is considered complete with three acceptable
guideline studies, one in the rat (MRID 42986803) and two in the rabbit
(MRID 41063701, 41063702).

870.3700	Prenatal Developmental Toxicity– Rat

  SEQ CHAPTER \h \r 1 In a prenatal developmental toxicity study (MRID
42986803), Copper 8-quinolinolate (purity 98.5%) aqueous
carboxymethylcellulose, was administered by oral gavage to groups of 36
Fu-Albino rats/dose by gavage at dose levels of 0, 50, 200, or 800
mg/kg/day, respectively, from gestation days (GD) 6 to 15, inclusive. 
The animals were checked daily from gestation day 6 for indications of
toxicity.  Body weights were recorded daily from gestation days 6
through 16 and on gestation day 20.  Food and water consumption was not
determined.  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 kidney, lung and liver weights.

Compound-related maternal toxicity was observed at 800 mg/kg/day (HDT)
as evidenced by an increased incidence of clinical signs (piloerection,
poor general condition, and encrustation of mouth and nose) and
decreased body weight gain during the dosing period. 

The maternal toxicity NOAEL is 200 mg/kg/day.  The maternal toxicity
LOAEL is 800 mg/kg/day, based on increased clinical signs (piloerection,
poor general condition, encrustation of nose and mouth), and decreased
body weight on GD 16 (93% of control) and weight gain during the dosing
period (48% of control). .

No developmental toxicity was noted at the dose levels tested.  The
developmental toxicity NOAEL was 800 mg/kg/day (highest dose tested);
the developmental toxicity LOAEL was not determined.  

This study is classified as Acceptable - Guideline.

870.3700	Prenatal Developmental Toxicity– Rabbit

In a prenatal development toxicity study (MRID 41063701), copper
8-hydroxyquinolate (96.5%) was administered orally to 5/dose timed-mated
female New Zealand White rabbits at dose levels of 0, 7, 18, or 45 mg/kg
bw/day from days 6 through 18 of gestation. In a concurrent study,
copper 8-quinolinolate was also orally administered to two groups of 5
non-mated female New Zealand White rabbits per dose group. The first
group was dosed at levels of 50 mg/kg bw/day for 5 days and the second
group was dosed once daily for 20 days at 5 mg/kg bw/day for days 1-5,
10 mg/kg bw/day for days 6-10, 20 mg/kg bw/day for days 11-15, or 40
mg/kg bw/day for days 16-20.

Treatment-related effects were observed at 45 mg/kg bw/day in mated
females and included clinical signs of toxicity (reduced amount of
feces, stomach mucosal lesions, blood in cage, lethargy, and emaciation)
and decreased body weight, body weight gains, and food consumption. The
maternal LOAEL is 45 mg/kg bw/day, based on clinical signs of toxicity,
reduced body weight and body weight gains, and reduced food consumption.
The maternal NOAEL is 7 mg/kg bw/day. 

Treatment-related effects were observed at 40 mg/kg bw/day in non-mated
females and included clinical signs of toxicity (green stained feces or
urine and reduced amount of feces) and decreased body weight, body
weight gains, and food consumption. In non-mated females, the LOAEL is
40 mg/kg bw/day, based on clinical signs of toxicity, reduced body
weight and body weight gains, and reduced consumption. In non-mated
females, the NOAEL is 20 mg/kg bw/day.

870.3700	Prenatal Developmental Toxicity– Rabbit

In a developmental toxicity study (MRID 41063702), copper
8-hydroxyquinolate (96.5%) was administered to 64 New Zealand White
rabbits by gavage at dose levels of 0, 7, 15, or 30 mg/kg/day from days
7 through 19 of gestation.

A statistically significant decrease in food consumption was observed
between days 7 to 11 for the 30-mg/kg/day dams; however, this change did
not affect body weight or body weight gain and was not considered an
adverse effect of treatment. The maternal LOAEL could not be determined
based on a lack of adverse treatment related effects. The maternal NOAEL
is 30 mg/kg/day.

4.4	Reproductive Toxicity

Adequacy of database for Reproductive Toxicity:  There was one
2-generation reproductive toxicity study (MRID 43267202).  

870.3800	Reproduction and Fertility Effects – Rat

In a two-generation reproduction study (MRID 43267202), Copper
8-quinolinolate (>99.7% a.i., Lot # 8293/3) was administered to groups
of 32/sex/dose (F0) and 28/sex/dose (F1) Cr1:CD rats in the diet at
concentrations of 0, 25, 250, or 2500 ppm. [F0: 0, 1.8, 18.2, and 181
mg/kg/day for males and 0, 2, 20.8, and 203 mg/kg/day for females; F1:
0, 2, 19.8, and 196 mg/kg/day for males and 0, 2.2, 22.8 and 218
mg/kg/day for females].  Each group was administered the control or test
diets continuously for 10 weeks prior to mating, during mating,
gestation, and lactation through the production of the litter (F1).  
Stability, concentration, and homogeneity of the test material in the
diet were analyzed before the start of the study.  In addition,
concentration analyses were conducted on samples from all dosage levels
for each generation at the start of pre-mating and mating periods and at
the end of pregnancy/start of lactation.

Clinical signs in both sexes of both generations in the 2500 ppm group
included dark feces.  Dark feces were observed from week 2 to
termination for the F0 generation and week 4 to termination for the F1
generation.  No other treatment-related clinical signs were observed at
any dose..

No compound-related mortalities were observed.  One F1 male at 2500 ppm
(196 mg/kg) died during week 14.  Clinical signs on the day before death
included a pallor, cold to touch, loss of body tone and labored
respiration.  Necropsy did not reveal the cause of death.  Post mortem
findings included a thrombus at the base of the pulmonary artery in the
right ventricle of the heart and yellow serous fluid in the thoracic
cavity.  

In both sexes of both generations, the body weight gains at all doses
were essentially similar to those of the controls throughout the
treatment period.  At all doses, mean food consumption during the
pre-mating phase was similar to that of the controls throughout the
treatment period.  At all doses, water consumption during the pre-mating
phase was similar to that of the control in both sexes of the F0
generation and in females of the F1 generation.  In males of the F1
generation, water consumption at the 2500 ppm (196 mg/kg) was
significantly higher than that of the controls during the weeks 5 (109%
of controls, p<0.01), 6 (110%, p<0.05) and 16 (113%, p<0.05) of
treatment.

No significant compound-related effects were noted in the pregnancy
rate, pre-coital time, and duration of pregnancy for rats fed oxine-Cu
for two successive generations. In the F0 generation, the numbers of
implantation sites/litter were 4, 8 (non-significant), and 8% (p<0.05)
lower than the controls for the 25, 250, and 2500 ppm groups,
respectively.  However, the compound-related effects on the number of
implantation site were considered not biologically significant because
the effects do not appear to be dose related.  Overall the litter size
was not affected in the treated groups because implantation losses at
250 (5.5%, p<0.05) and 2500 ppm (2.0%, p<0.01) were significantly lower
than the controls (8.8%).

In the F1 generation the numbers of implantation sites/litter were 6, 3,
and 13% lower than the controls for the 25, 250, and 2500 ppm groups,
respectively, however, the effect was not statistically significant. 
The incidental findings observed in the F1 generation were as follows: 
One female had a single implantation site with no evidence of giving
birth.  Four females lost their entire litter by day 3 post partum (2
controls, 1 - 25 ppm and 1 – 250 ppm groups).  These incidences in the
F1 generation were not observed in the F0 generations.

The Parental/Offspring LOAEL is 2500 ppm based on increased liver weight
in F1 males.  In males of the F1 generation at 2500 ppm (HDT), liver
weight was significantly increased (8.3%, p<0.01) as compared to
controls.  Dark feces wereas also observed in both sexes at 2500 ppm
(HDT) from week 2 to termination for the F0 generation and week 4 to
termination for the F1 generation.  The corresponding Parental/Offspring
NOAEL is 250 ppm.  No significant treatment-related reproductive
toxicity occurred in male and female rats; therefore, the reproductive
toxicity NOAEL is 2500 ppm (highest dose tested) and the LOAEL is 2500
ppm, based on decreased mean number of live pups at birth and  decreased
litter weights observed in the F1 generation.

This study is classified as Acceptable - Guideline.

4.5	Chronic Toxicity

Adequacy of database for Chronic Toxicity: The database for chronic
toxicity is considered incomplete. There is only one study in the dog
and the study is unacceptable.  

870.4100b	Chronic Toxicity – Dog

In a chronic toxicity study in the dog (MRID 00099606) copper
8-quinolinate (96%) was administered to 4 Beagle dogs/sex/dose at
concentration levels of 0, 10, 40, 200, or 1000 ppm (equivalent to 0,
0.2, 1.30, 6.49, or 32.98 mg/kg/day for males, and 0, 0.30, 1.12, 7.29,
or 30.67 mg/kg/day for females, respectively) for 104 weeks.  There was
a fifth treatment group, which initially received concentrations of 4000
ppm; however, this was reduced to 1000 pm after the first week of
treatment because it was not tolerated well by the animals. The dose was
gradually increased to acclimate the animals, however, 4000 ppm in the
diet was no better tolerated the second time around; the tolerated
concentration of 3000 ppm was employed from Weeks 10 to 104 and is
hereafter referred to as the 3000 ppm dose group. The mean test article
intake in this group was equivalent to 77.90 and 92.51 mg/kg/day in
males and females, respectively. One animal per treatment group was
sacrificed at 52 weeks as an interim group. 

Toxicity was notable at the highest dose levels. Four 3000 ppm group
animals (2 males and 2 females) died or were sacrificed in a moribund
condition during the course of the study. Treatment-related effects in
the 3000 ppm group included clinical signs of toxicity (anorexia,
thinness, pale gums, and lethargy), decreased body weight, decreased
body weight gain, decreased food consumption, decreased hematocrit and
hemoglobin, increased serum alanine aminotransaminase (SGPT), aspartate
aminotransferase (SGOT), alkaline phosphatase (AP), decreased serum
proteins and albumin, and increased incidence of liver, kidney, and
stomach injury. Macroscopic findings in animals that died prior to
scheduled sacrifice included numerous hemorrhages in several organs,
small or flaccid organs, rough and discolored livers, thickened stomachs
and bladder necks, and clear fluid in several body cavities, while two
surviviors had light colored livers, enlarged and greenish-brown
mesenteric lymph nodes near the pancreas and duodenum, and distended
gall bladders. Microscopic findings were pigment in Kupffer cells and
hepatocyte cytoplasm, bile duct proliferation, periportal fibrosis,
edema of the submucosa of the stomach, edema of the mesenteric lymph
nodes with distension of sinusoid, nephrosis, interstitial fibrosis
atrophy of the convoluted tubules in the kidney, pancreatic edema and
loose areolar connective tissue, and distension of the medullary sinus
also occurring in the dead animals. Treatment-related effects at 1000
ppm included slightly decreased body weight and body weight gain,
slightly decreased food consumption, increased SGPT in males at Weeks 52
and 78, increased SGOT and BSP (not at Week 78 in females), and
decreased serum albumin (males and females at Week 52 and males only at
Week 78). Green feces and increased organ copper content were also noted
in both the 1000- and 3000-ppm-dose groups. Consequently, the LOAEL is
1000 ppm (32.98 and 30.67 mg/kg/day for males and females, respectively)
based on changes in liver enzymes, total blood albumin, body weight,
body weight gain, and food consumption. The NOAEL is 200 ppm (6.49 and
7.29 mg/kg for males and females, respectively). However, there was high
variability in the end points measured, likely due to the large
difference in initial body weights (possibly an indication of different
ages), that may mask any effects in the lower-dose groups. Body weight
gain and food efficiency were lower than those of controls in all the
treatment groups (except an increase in body weight gain for 200-ppm
males), but there was no relation to dose. 

This chronic toxicity study in the dog is classified Unacceptable-not
upgradable. 

4.6	Carcinogenicity

Adequacy of database for Carcinogenicity:The database for
carcinogenicity consists of  three studies on copper 8-quinolinolate
(MRIDs 42957801, 43267201, 00083777) and two studies on
8-hydroxyquinoline conducted by the National Toxicology Program.   

870.4200b	Carcinogenicity (feeding) – Mouse

  SEQ CHAPTER \h \r 1 In a carcinogenicity study (MRID# 43267201)
Cr1:CD-1 mice (50/sex/dose group) from Charles River Laboratory (UK)
Limited, Margate, England received copper 8-quinolinolate (97.2% a.i.;
Lot# 777) in the diet for 80 weeks at dose levels of 0, 100, 400, 1500
and 6000 ppm. (0, 14.49, 57.15, 207.7, and 855.8 mg/kg/day for males;
and 0, 16.3, 66.18, 246.2 and 1051.7 mg/kg/day for females). A satellite
group of ten animals/sex/dose group was sacrificed at 12 months.

No significant changes in body weights were observed with oxine copper
treatment.  Male and female mice in the 6000 ppm groups (HDT) consumed
slightly less food than the control groups  during the first week of
treatment (males: 34 g, 6000 ppm, 36 g, control; females: 31g, 6000 ppm,
32 g, control).  By the third week, however, both sexes had adjusted to
the oxine copper in the diet, and the amount of food consumed by males
was similar to that of the control group.  The total food consumption
for the first 3 weeks was significantly (p<0.05) increased in treated
females (99 g, control; 103, 103, 108, and 102 g, at 100, 400, 1500 and
6000 ppm respectively).  Gross pathology findings included increased
incidence of abnormal liver color that was significant in females at
1500 and 6000 ppm.  There was also an increased incidence of chronic
liver inflammation at the HDT and a significant increase in enlarged
hepatic lymph nodes at 1500 and 6000 ppm in females.  Increased
incidences of enlarged spleen and abnormal spleen color were seen in
both sexes at 6000 ppm, but the increases were significant only in
males.  Splenic extramedullary hematopoieses was significantly increased
at 1500 ppm in males and at 600 ppm in females.   The LOAEL is 1500 ppm
(207.7 mg/kg/day males, 246.2 mg/kg/day in females), based on an
increased incidence of stomach ulcers in males; and mild anemia and
adverse liver effects including increased incidence of abnormal liver
coloration and increased alkaline phosphatase activity in females.  The
NOAEL is 400 ppm (57.1 mg/kg/day in males, 66.2 mg/kg/day). 

There were no treatment-related increase in incidence of neoplastic
lesions in this study.  This study is classified acceptable and
satisfies the guideline for a carcinogenicity study in mice. 

A supplementary  range-finding study (MRID 42957801, companion to the
study above) utilized 42 day old male and female Crl-CD-1 (ICR)BR strain
(VAF plus) mice, 10/sex/group, and exposed them orally to concentrations
of 0, 300, 1000, 3000, or 6000 ppm in the diet for 13 weeks. Mice at
6000 ppm dose were observed to have yellow-stained fur, but this was
later attributed to external contamination with the colored test
substance in the food. A total of 12 male mice from all groups died as a
result of blood sampling during week 13. There were no deaths
attributable to treatment with copper 8-quinolinolate. The mean body
weight of male mice decreased the first week on the 6000 ppm diet, and
the males at 3000 ppm failed to gain weight during the first week of the
study. Female mice were affected less, but did not gain weight during
the first week at 6000 ppm .The mean body weights of the female mice
were equivalent to those of the controls by the 4th week of the study.
The male mice at 6000 ppm gained weight at about the same rate as the
control group, but remained consistently below the control group. The
body weight differences, however, were small and did not reach
statistical significance. Significant increases in erythrocyte count,
hemoglobin, and hematocrit were seen at all dose levels in females; a
dose-related increase in platelet counts was seen in both sexes, but the
increase was significant only at 3000 and 6000 ppm in females. Leukocyte
counts were significantly decreased at 300, 1000, and 6000 ppm in males,
but did not show dose-dependency. The examination of the control and
high dose group animals revealed apparent treatment–related thickening
and pallor of the glandular mucosa of the stomach in 4/10 females.
Abnormal coloration (pallor) of the glandular stomach mucosa was seen in
2/10 males at 3000 ppm and 6000 ppm, 1/10 was also thickened at the 6000
ppm dose. An increased incidence of raised, cystic areas in the ovaries
of the female mice at 6000 ppm also occurred. The absolute and relative
spleen weights were significantly decreased (p<0.05) at 6000 ppm in
females compared to controls. The absolute and relative kidney weights
were significantly increased in males, but not in females at 6000 ppm.
The study authors maintained that these changes in the males reflected
the slightly lower terminal body weight of the high dose males. Since
the spleen weight changes did not show a clear dose dependency, the
authors did not believe the changes were a direct effect of treatment.
No treatment –related increase in the incidence of epithelial
hyperplasia of the glandular mucosa of the stomach was seen in either
sex compared to controls. Follicular cysts were seen in 2/10, 1/10, and
3/10 female mice at 300, 3000, and 6000 ppm, respectively. Although no
follicular cysts were seen in the control mice, the incidence was low
and did not show dose dependency. The authors considered the follicular
cysts to not be of toxicological significance.  The 6000 ppm dose was
recommended as the high level for the subsequent carcinogenicity study.
The authors considered 1000 ppm to be a NOAEL in this study. A dose
below 1000 ppm was recommended for the low dose level to represent a low
multiple of the expected human exposure level. 

870.4200a	Carcinogenicity Study - Rat

In a carcinogenicity study conducted by the National Toxicology Program
(MRID not assigned), 8-hydroxyquinoline (~99%) was administered to 50
F344/N/rats/sex/dose in the diet at concentrations of 0, 1500, or 3000
ppm (equivalent to 0, 73, or 143 mg/kg/day for male rats and 0, 89, 0r
166 mg/kg/day for female rats, respectively) for 103 weeks. In a
carcinogenicity study by the National Toxicology Program (MRID not
assigned), 8-hydroxyquinoline (~99% pure, Lot no. 7223-J) was
administered to 50 F344/N/rats/sex/dose in the diet at levels of 0,
1500, or 3000 ppm (equivalent to 0, 73, or 143 mg/kg/day for male rats
and 0, 89, 0r 166 mg/kg/day for female rats, respectively) for 103
weeks. Mean body weights of high-dose rats of each sex at the end of the
study were about 10% lower than those of the controls. Final mean body
weight gain in high-dose male and female rats were reduced 15% and 13%,
respectively, compared to controls. Mean body weight and body weight
gain were relatively unaffected in the low-dose animals. With the
exception of the low-dose females, the changes in body weight and body
weight gain can be explained by a decrease in the food consumption. Mean
food consumption/animal/day revealed a dose-response reduction in the
consumption for both male and female treatment groups compared to
controls. There were no treatment-related effects on food efficiency.
Differences in the incidences of neoplastic lesions between treated and
control rats were generally small and/or occurred only in males. In male
rats, alveolar/bronchiolar adenomas or carcinomas (combined) occurred
with a positive trend in the dosed groups, and the incidence in the
high-dose group was significantly greater than that in the concurrent
controls. However, these findings are not considered to be related to
treatment as they are not supported by an increase in the incidence of
epithelial hyperplasia in the lungs. The incidence of thyroid gland
C-cell adenomas in female rats and combined C-cell adenomas or
carcinomas in male rats also occurred with positive trends, but the
incidences in the high-dose groups were not significant compared with
controls and C-cell hyperplasia was decreased in the high-dose groups as
well. Therefore, the marginally increased incidences of these neoplastic
lesions were not considered to be compound-related. However, decreases
in hyperplasia, both in the thyroid and in the testis, accompanied by
increases in adenomas in these organs, could indicate a progression in
male rats. Because the total number of lesions in these organs are
similar, it is more a matter of degree and not an indication that
8-hydroxyquinoline causes an increase in tumors. This is supported by
the fact that there was no increase in the total number of animals
bearing tumors or in the number of primary tumors in males. In addition,
although non-neoplastic lesions of the pituitary with angiectasis (gross
dilation) were increased in high-dose males and females, when combined
with dilatation of the pituitary there was no difference in incidence of
lesions. There was no evidence of compound-related neoplastic lesions
found in female rats. There is no indication in the study report that
changes in the incidence of any non-neoplastic lesions among dose groups
of either sex were significant. However, several lesions are worth
noting. Changes that occurred in both sexes included the following:
increase in the inflammation of the lungs (possibly dose-related);
decrease in fatty metamorphosis in the liver; atrophy of the pancreatic
acinus (decrease in high-dose males and increase in high-dose females);
and decrease in C-cell hyperplasia (possibly dose-related).
Non-neoplastic changes that occurred only in males included the
following: increase in the incidence of hyperkeratosis of skin (not
related to dose); increase in lymphoid hyperplasia of the lymph node
(possibly dose-related) and Peyer’s patch (not dose-related);
increased incidence of hyperplasia (NOS) of the pancreatic acinus
(possibly dose-related); increased incidence of perivasculitis of the
pancreas (high-dose only); increased incidence of inflammation (NOS) of
the kidney (possibly dose-related); decrease in hyperplasia (NOS) of the
bile duct (possibly dose-related); and decreased interstitial cell
hyperplasia (possibly dose-related). Non-neoplastic changes occurring
only in females included the following: increased incidence of
epithelial hyperplasia of the lungs (high-dose only); increased
incidence of atrophy (NOS) of splenic follicles (possibly dose-related);
increased incidence in epithelial hyperplasia of the stomach (similar
increase with both doses); decreased nephropathy (possibly
dose-related); increased incidence of mineralization of the renal
papilla (similar increase with both doses); and increased incidence of
fat necrosis in the omentum. The LOAEL is 143 and 166 mg/kg/day in males
and females, respectively, based on reduced body weight. The NOAEL is 73
and 89 mg/kg/day in males and females, respectively.  At the doses
tested, there was not a treatment-related increase in tumor incidence
when compared to controls. Dosing was considered adequate based on
reduced body weight and reduced food consumption; however, the addition
of a third treatment group would have been useful.

This carcinogenicity study in rats is Acceptable-Non-Guideline and does
not satisfy guideline requirement for a carcinogenicity study [OPPTS
870.4200; OECD 451] in rats. This study was well conducted and provides
useful data on the carcinogenicity of 8-hydroxyquinoline, however, the
study only used two dose levels, did not perform a differential blood
count, did not weigh any of the organs, and did not examine several
tissues (i.e., cecum, rectum, pharynx, aorta, and epididymides) as
recommended by the study guidelines.

870.4200b	Carcinogenicity (feeding) – Mouse

In a carcinogenicity study  conducted by the National Toxicology Program
8-hydroxyquinoline was administered to 50 B6C3F1 mice/sex/dose in the
diet at concentrations of 0, 1500, or 3000 ppm (equivalent to 0, 217, or
396 mg/kg bw/day in males and 0, 349, or 619 mg/kg bw/day in females)
for 24 months. Body weight was affected in high-dose females only, with
an 11% overall reduction in body weight and 19% in body weight gain.
Mean food consumption was reduced in a dose-dependent manner with
reductions ≥ 14% when compared to the controls. Food consumption in
3000-ppm males and females was affected in the first few weeks, while
1500-ppm males and females had a more gradual reduction in food
consumption. Due to the slight changes in body weight with the large
reduction in food consumption, food efficiency was increased in treated
mice compared to the controls in a possible dose-response manner.
Females generally ate more than the males, causing them to have a
greater intake of the compound. Differences in the incidences of
non-neoplastic lesions between treated and control mice were generally
small, not dose-dependent, and/or only occurred in one sex. The only
significant change was a decrease in hemangioma and hemangioma or
hemangiosarcoma (combined) in low- and high-dose males. There was a
significant negative trend for malignant lymphomas (all types) in males.
In females, there was a significant positive trend for malignant
lymphoma of the lymphocytic type, but no change was noted in the overall
incidence of malignant lymphomas. Both males and females exhibited a
slight increase in alveolar/bronchiolar adenomas that was not
dose-dependent. Male rats (also described in this study report) also had
a slight, not significant, increase (i.e., 0%, 4%, and 6% in 0, 1500
ppm, and 3000 ppm groups, respectively) in alveolar/bronchiolar
adenomas.

 

Notable non-neoplastic changes occurring in the males included the
following: increase in the incidence of inflammation of the subcutaneous
tissue (possibly dose-related); increase in hematopoiesis in multiple
organs (possibly dose-related); increase in focal necrosis of the liver
with a possible decrease in ischemic necrosis; increase in inflammation
(acute/chronic) and abscess in the kidney in high-dose males; and
mineralization of the preputial gland (possibly dose-related).
Non-neoplastic changes in females included the following: increase in
hematopoiesis of the spleen; increase in liver necrosis (focal and
ischemic); increase in the incidence of dilatation of the pituitary;
increase in the incidence of follicular-cell hyperplasia in the thyroid;
and increase in inflammation of the uterus.  Necrotizing inflammation
occurring in the ovaries, uterus, and thoracic or abdominal cavities of
females, including the controls, was related to Klebsiella infection in
22, 13, and 12 of the control, low-, and high-dose females,
respectively. The LOAEL is 396 and 619 mg/kg/day in males and females,
respectively, based on reduced body weights. The NOAEL is 217 and 396
mg/kg/day in males and females, respectively. 

At the doses tested, there was not a treatment-related increase in tumor
incidence when compared to controls. Dosing was considered adequate
based on reduced body weight and reduced food consumption; however, the
addition of a third treatment group would have been useful.

This carcinogenicity study in mice is Acceptable-Non-Guideline and does
not satisfy guideline requirement for a carcinogenicity study [OPPTS
870.4200; OECD 451] in mice. This study was well conducted and provides
useful data on the carcinogenicity of 8-hydroxyquinoline; however, the
study only used two dose levels, did not perform a differential blood
count, did not weigh any of the organs, and did not examine several
tissues (i.e., cecum, rectum, pharynx, aorta, and epididymides) as
recommended by the study guidelines.

870.4300	Chronic/Carcinogenicity Study – Rat

In a chronic toxicity/carcinogenicity study (MRID 00083777),
copper-8-quinolinolate (96%) was orally administered to 180 male rats
and 180 female rats (30 animals/sex/group) via dietary mixture. The
nominal doses received were 0, 5, 20, 100, 500, and 2000 ppm. Estimates
of compound intake were 0, 2, 8, 38, 188, and 761 mg/kg/day for males
and 0, 2, 9, 46, 229, and 922 mg/kg/day for females. Five
animals/sex/group were sacrificed at 52 weeks and all surviving rats
were sacrificed at 102 weeks via exsanguination under sodium
pentobarbital anesthesia. Signs of toxicity were observed at 2000 ppm
and included: increased incidence of pigment deposition observed in the
spleens and small intestines of males and females at 52 weeks; and
increased incidence of hemosiderin deposition in the spleens, small
intestines, livers, and kidneys of males and females. Increased copper
content in the livers and kidneys of males and females at 52 and 102
weeks was observed, as well as slightly increased copper content in the
brain in males at 102 weeks. With regard to the tissue copper analysis,
increased copper concentrations were noted in animals treated with 5,
100, and 500 ppm; however, the increases were not considered to be
toxicologically significant. No other treatment-related gross pathology
findings were noted. Consequently the LOAEL is 2000 ppm (approximately
761 mg/kg/day for males and 922 mg/kg/day for females based on increased
incidence of pigment deposition observed in the spleens and small
intestines of males and females at 52 weeks; and increased incidence of
hemosiderin deposition in the spleens, small intestines, livers, and
kidneys of males and females at 102 weeks). The NOAEL is 500 ppm (188
mg/kg/day for males and 229 mg/kg/day for females). 

This study is unacceptable/not upgradable.  There were several major
deficiencies in this study, including an inadequate historical control
database, and examination of too few animals histologically, especially
in light of the testicular tumors that were observed in this study. 

Mutagenicity

Adequacy of database for Mutagenicity: The database for Mutagenicity is
considered complete.  Three studies (MRID 42963201, 42963202 and
42963203) were considered acceptable for this purpose.

870.5100	Bacterial Reverse Mutation Test - Ames

 In   SEQ CHAPTER \h \r 1 a gene mutation assay genetic toxicology study
(MRID 42963201) it was determined that there was a dose-related weakly
positive response for reverse gene mutation in S9-activated bacterial
strains TA97, TA100, TA102 of S. typhimurium exposed up to toxic doses
of copper 8-quinolinolate (99.7%).  In standard plate assays, no
increase in revertents in TA 1538 (±S9), TA98 (±S9), TA100 (-S9),
TA1535 (±S9), TA1537 (±S9) up to cytotoxicity doses (33, 100
ug/plate), but slight increases (1.2 x background) in S9-activated TA97,
TA100 and TA102.  In pre-incubation series, no increase up to
cytotoxicity in any non-activated cultures, but dose-dependent increased
reversions were noted for activated TA97, TA100 and TA102 (all less than
2X background).  Hence the investigator concluded that the test article
was weakly mutagenic in some activated Salmonella strains at mild to
moderate toxic concentrations

This study is classified as Acceptable-Guideline.

Micronucleus Test in the Mouse Bone Marrow

In a micronucleus test mutagenicity study (MRID 42962302), mice
(5/sex/dose group) from Biological Research Laboratories, Fullindorf,
Switzerland received copper 8-quinolinolate (98.5% a.i.; Lot# 8293/3) in
the diet for sampling times of 24, 48 and 72 hours at dose levels of 0,
3750 and 7500 mg/kg.  It was determined that the test material was
negative for micronucleus induction in bone marrow cells of mice treated
once at doses up to 7500 mg//kg, a non-toxic (but limiting) dose.

This study is classified as Acceptable-Guideline.

870.5550	Mutagenicity - Other Genotoxic effects

In a mutagenicity study (MRID 42962303), unscheduled DNA synthesis (UDS)
in hepatocytes (HPC) was tested for in male rats. The animals (1-3 per
dose group) were gavaged once at six dose levels (100-3000 mg/kg) and
sacrificed 4 to 16 hours later. The study reported copper
8-quinolinolate negative in inducing unscheduled DNA synthesis in
primary rat hepatocyte cultures for rats treated orally up to 3000 mg/kg
as determined by radioactive tracer procedures [nuclear silver grain
counts].  

This study is classified Acceptable-Guideline.

4.8	Neurotoxicity

Adequacy of database for Neurotoxicity: The database for neurotoxicity
consists of three studies (MRID not assigned). These studies do not
fulfill a specific guideline but were submitted to the Agency. 

870.6XXX	Neurotoxicity Study

The effect of oral administration of copper 8-quinolinoate at doses of
100, 300 and 1000 mg/kg on motor co-ordination was assessed in mice
using the accelerating rotarod test. 50 male CD-1 mice (Swiss
originated, caesarian derived), approximately 5 weeks in age were
acclimatized in polypropylene cages for five days employing a 12 hour
light/dark cycle. Environmental conditions were monitored continuously
with temperature and humidity set at 21°C and 50% respectively.
Pre-dose ‘performance time’ was measured on the morning of the test
day based on which mice were randomly assigned to five groups: Vehicle, 
100, 300, 1000 mg/kg and Mephenesin (400mg/kg). The test compound and
Mephenesin prepared by suspension in 0.5% w/v carboxymethylcellulose
(CMC) were orally administered at a constant dose volume of 10 ml/kg. 
Forty-five minutes after oral administration each mouse was given three
successive trials on a rotarod accelerating uniformly from 4
revolutions/minute to 40 revolutions/minute in a period of five minutes.
Maximum performance time was used to calculate the mean results and for
each treatment group this value was compared with pre-dose performance
times using analysis of variance.  Copper 8-quinolinolate administered
at doses of 100, 300 and 1000 mg/kg by the oral route had little or no
effect on the rotarod performance of mice. Slight and statistically not
significant increases in performance were noted in each of the tested
doses. Mephenesin at an oral dose of 400 mg/kg produced a marked and
statistically highly significant decrease in the performance of trained
mice on the accelerating rotarod. 

870.6XXX	Neurotoxicity Study

Copper 8-quinolinolate was examined at oral doses of 100, 300 and 1000
mg/kg for possible neurological effects in rats using the tilting plate
test. 20 male (187-205g) and 20 female (170-187g) Wistar rats, caged
according to sex in suspended polypropylene cages were allowed to
acclimatize for two days. A 12 hour light/dark cycle was maintained with
the temperature and humidity kept at 21°C and 50% respectively. Using
random number tables, the rats were randomized according to their
bodyweight into treatment groups: Vehicle (0.5% CMC), 100, 300 and 1000
mg/kg test compound. The test compound or vehicle was administered
orally on two consecutive days (Days 1 and 2 of the study) at a constant
dose volume of 10 ml/kg. A tilting plane test: placing animals on a
platform tilted at a constant rate of 7.5 degrees and then measuring the
angle of inclination at which the animals begin to slide down the slope,
was performed on the animals every second from Day 4 to Day 16 of the
study. Bodyweights were recorded on the days of dosing and every second
day from Day 4 to Day 16 of the study. The mean angle of slip and
bodyweights in the treatment groups were compared with the vehicle group
using analysis of variance and ‘t’ distribution. Male animals
exhibited small decreases in mean angle of slip when compared to the
vehicle-treated control group. These differences were statistically
significant on day 4 for animals in the 100 mg/kg group, day 14 for the
300 mg/kg group and Days 10, 12 and 14 for the 1000 mg/kg treatment
group. No effect was seen in female animals alone.  Significant
inhibition in bodyweight gain was seen in animals treated with the
highest dose of 1000 mg/kg on Days 2, 4 and 6 for males and Days 2, 3
and 10 for females. Female animals treated with an intermediate dose of
300 mg/kg also showed a significant inhibition in weight gain. Animals
treated with the high dose exhibited mild to moderate diarrhea
especially on Days 2, 3 and 4 in the study. The small decrease in mean
angle of slip observed in the male animals at 1000 mg/kg may be a
function of the diarrhea and decrease in bodyweight gain that was
observed in that group rather than being a direct effect of the
compound. Little or no effect on mean angle of slip was observed in
female animals treated at 1000 mg/kg, but the effect on bodyweight gain
observed over Days 4-8 was less severe in these females (4.2-6.5%
inhibition) than observed in the males (9.2-14.8%). 

870.6XXX	Neurotoxicity Study

The effect of oral administration of copper 8-quinolinolate at doses of
100, 300 and 1000 mg/kg on hexobarbital induced sleeping time was
assessed in mice. 20 male and 20 female mice of the CD-1 strain (Swiss
originated, caesarian derived), approximately 4-6 weeks in age were
acclimatized in polypropylene cases for three days employing a 12 hour
light/dark cycle. Environmental conditions were monitored continuously
with temperature and humidity set at 21°C and 50% respectively.
Following acclimatization, the mice were randomized into groups: Vehicle
(0.5% CMC), 100, 300 and 1000 mg/kg test compound according to
bodyweight and deprived of food for approximately 18 hours prior to the
test. Thirty minutes after the test compound or vehicle was administered
orally using a constant dose volume of 10 ml/kg, each mouse was
administered an intraperitoneal injection of 100 mg/kg hexobarbital
sodium using a constant dose volume of 10 ml/kg.  The animals were then
placed on a plate kept at 32°C and the time of onset of sleep and
duration of sleep time (as indicated by loss and the re-appearance of
righting reflex) was recorded The sleeping time for males, females and
combined sexes for each group were compared using analysis of variance.
Slight decreases in sleeping time, which were not statistically
significant, were recorded in male and female mice from the group
receiving the lowest tested dose level of 100 mg/kg.  Female mice from
the groups receiving intermediate and higher dose levels also exhibited
decreases in sleeping time that were not statistically significant. 

4.9	Metabolism and Pharmacokinetics

Adequacy of database for Metabolism and Pharmacokinetics:  The database
for metabolism is considered complete with two studies (MRID 42962304,
42962305).

870.7485       Metabolism and Pharmacokinetics

  SEQ CHAPTER \h \r 1 In a metabolism study (MRID# 42962304; 42962305),
Wistar rats (5/sex/dose group) from Biological Research Laboratories,
Fullindorf, Switzerland received copper 8-quinolinolate (>98.5% a.i.,
unlabeled; >98% a.i. radio labeled) at oral doses of  30 or 1000
mg/kg/day, and at repeated oral doses (14 daily doses) of unlabeled
oxine copper at 30 mg/kg followed by administration of a single oral
dose of 14C-labeled oxine copper at 30 mg/kg.  The major routes of
excretion of radioactivity were via the urine and feces.  The excretion
of radioactivity into urine and feces was rapid and over a 4- to 7-day
period, most (89-97%) of the test compound administered was excreted in
the urine (62-86%) and feces (8-26%) from the animals.  Most (54-59%) of
the dose was eliminated in the urine and feces within 48 hours of
dosing.  Rapid absorption may be inferred by the rapid excretion of
metabolites in the urine.  Saturation of absorption following high dose
administration was indicated by a large amount (23%) of radioactivity in
the feces being associated with parent compound.  Radioactivity in
tissue residues was very low in all tissues including blood (<0.05%). 
Recoveries of the administered doses in the tissues including carcass
were not more than 0.4% indicating that the potential for
bioaccumulation of oxine copper is minimal even after high dose or low
dose (single or repeated) exposures.  In the urine, the radioactivity
was associated with the parent (5 to 16% of the dose) and the sulfate
(12 to 18%) and glucuronide conjugates (36 to 66%) of the parent.  In
the feces, the radioactivity was associated with the parent (4 to 23% of
the dose) and the glucuronide conjugate of the parent (0.1 to 4%).  The
expired air as CO2 accounted for 0.4-2.2% of the administered dose. 
Less than 8% of the dose was excreted via bile mainly as glucuronide
conjugate.  Since the total radioactivity in the organs and tissues from
all groups were below 0.05% of the administered dose, no further
analysis of these samples was carried out.

This study is classified as Minimum-Guideline.

TOXICITY ENDPOINT SELECTION

See Section 7.1 Summary of toxicology endpoint selection for oxine
copper. Table3. 

5.2	Dermal Absorption

Dermal Absorption Factor: A route-specific study is available for dermal
risk assessments.  Therefore, a dermal absorption factor is not
required. 

5.3	Classification of Carcinogenic Potential

Oxine copper has not been formally classified for carcinogenicity by the
Office of Pesticide Programs.  Oxine copper has been examined for
carcinogenicity in the rat (MRID 00083777) and in the mouse (MRID
43267201) in studies reviewed by the Office of Pesticide Programs.   The
National Toxicology Program has examined the 8-hydroxyquinoline moiety
for carcinogenicity (NTP Technical Report no. 301).  Additional studies
not reviewed by the EPA but reviewed by Health Canada, Pest Management
Regulatory Agency include a 3 week gavage plus 50 week dietary
carcinogenicity study in mice, a 2 year carcinogenicity study in B6C3F1
mice, and a 2 year carcinogenicity study in Fischer 344 rats.   

In the mouse carcinogenicity study with oxine copper, Health Canada
noted in their review that the lymphomas noted in the mouse study were
discounted based on the observations that (a) the tumors were not
dose-related (also noted in the EPA’s own review, HED document number
011915), (b) the tumors occurred in only one sex, and (c) the tumors
were not increased further at the next highest dose.  With regard to the
uterine tumors, although Health Canada noted that these tumors were
outside historical control at the high dose, the EPA notes that the
incidence of the tumors that were outside historical control occurred at
a dose above the limit dose (1000 mg/kg/day) for carcinogenicity
studies. Therefore, the biological significance of the tumors is
questionable. 

In the rat carcinogenicity study with oxine copper, interstitial cell
tumors of the testes, 2 unilateral and 1 bilateral, were observed in
three males at the 761 mg/kg/day dose level. The study report indicated
that this incidence was within historical control range for ‘rats of
this age in this laboratory.’ However, only one set of historical
control data were submitted that indicated benign interstitial cell
tumor incidence of 10% (from examination of 70 male rats). In addition,
only 10 rats at the high dose in the present study were examined
histologically. 

As noted by both the EPA and by Health Canada, this rat study had
several significant deficiencies, including high mortality rates in all
treatment groups, assessment of too few rats for carcinogenicity (only
30 animals/sex/dose), and inadequate historical control data. 
Therefore, the significance of the interstitial cell tumors are not
known and cannot be determined from these data. 

	

6.0	FQPA CONSIDERATIONS

6.1	Developmental Toxicity Study Conclusions

There are two acceptable developmental toxicity studies available for
oxine copper. There was no evidence for a primary developmental effect
of oxine copper in either the rat or rabbit developmental toxicity
study. 

6.2	Reproductive Toxicity Study Conclusions

There is one acceptable reproductive toxicity study available for oxine
copper. There was no evidence of a primary reproductive effect of oxine
copper in this study.

	

The ADTC concluded that the special hazard-based FQPA factor can be
reduced to 1x. The available developmental and reproductive toxicity
data for oxine copper show no evidence of teratogenicity or reproductive
toxicity. The studies are conducted according to guidelines and show no
evidence of increased susceptibility of offspring. There is no evidence
for neurotoxicity of oxine copper.  

6.3	Recommendation for a Developmental Neurotoxicity Study

A developmental neurotoxicity study for oxine copper is not needed at
this time. 

7.0	SUMMARY OF TOXICOLOGICAL DOSES AND ENDPOINTS FOR Oxine Copper FOR
USE IN HUMAN RISK ASSESSMENT

7.1	Summary Table of Toxicological Dose and Endpoint Selection for Oxine
Copper (Table 2)

  SEQ CHAPTER \h \r 1 Exposure

Scenario	Dose Used in Risk Assessment

(mg/kg/day) 	Target MOE, UF, 

Special FQPA SF* 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

(all populations)	NOAEL = 

5 mg/kg/day

	FQPA SF = 1

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

Chronic RfD (cPAD) = 0.05 mg/kg/day	Subchronic Toxicity in the Dog

MRID 42986802

LOAEL = 50mg/kg/day, based on vomiting, decreased plasma protein and
albumin, and reddened mucosa and hyperemia in the stomach and small
intestine.



Non-Dietary Risk Assessments

Incidental Oral Short-Term 

(1-30 days)

Intermediate-term

(30-days – 6months) 

	NOAEL (maternal)  =  200 mg/kg/day	Target MOE = 100

(10x inter-species extrapolation, 10x intra-species variation) 

FQPA SF = 1

	Prenatal Developmental Toxicity Study in the Rat  MRID 42986803

LOAEL = 800 mg/kg/day, based on clinical signs of toxicity and decreased
body weight gain in maternal rats.   

Dermal

Short-Term (1 to 30 days) and Intermediate-term (30 days- 6 months)
NOAEL = 

200 mg/kg/day  

	Target MOE = 100 

(10x inter-species extrapolation, 10x intra-species variation)

	28-day dermal toxicity study in the rat  

MRID 42957802

LOAEL(systemic)  = 1000 mg/kg/day, based on  necrosis of thymic
lymphocytes

No evidence of dermal irritation from either this study or the acute
dermal study

Dermal

Long-Term (>6 months)	A long-term dermal endpoint is not required for
oxine copper. 

Inhalation

(all durations)	NOAEL = 5 mg/kg/day  

	UF = 1000

(10x inter-species extrapolation, 10x intra-species variation, 10x route
extrapolation)	Subchronic Toxicity in the Dog

MRID 42986802

LOAEL = 50mg/kg/day, based on vomiting, decreased plasma protein and
albumin, and reddened mucosa and hyperemia in the stomach and small
intestine.



Cancer	Oxine Copper has not been formally classified as to
carcinogenicity.  



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 (Table 3)



Table 3. Subchronic, Chronic, and other Toxicity Profile for Copper
8-quinolinolate



Guideline number/Study Type/Test Substance

 (% a.i.)

	

MRID number (Year)/Citation/Classification/Doses

	

Results

Copper 8- quinolinolate (case #4026)

Copper 8- quinolinolate (PC code 024002)

870.3100 (§82-1a)

Subchronic oral - rat

99.5% a.i.

	MRID 42986801

Acceptable – Guideline

16/sex/dose at (0, 600 or 1000 mg/kg/day)

10/sex/dose at (30, 100 or 300 mg/kg/day)

for 13 weeks	NOAEL = 30 mg/kg/day

LOAEL = 100 mg/kg/day, based on statistically significant ALT, AST and
bilirubin in males, increased spleen weights in females, increased
incidence of diffuse degeneration, focal necrosis, extramedullary
hematopoises in liver.

870.3100 (§82-1a)

Subchronic oral - mouse

Oxine Cu purity 99.9%

	MRID 42937301

Supplementary

6/sex/dose

0, 30, 600, or 1000 mg/kg/day

(100 and 300 mg/kg/day for 13 weeks) 	No signs of toxicity were observed
at the highest dose tested. (1000 mg/kg/day) The high dose, which is a
mean of three different doses (30, 600 and 1000 mg/kg/day) of only 473
mg/kg/day, was not a limit dose, and therefore, it appeared that the
compound was not tested at a high enough dose.

In the absence of other signs of toxicity, a change in one enzyme level
cannot be used to determine the NOEL and LOEL of this chemical.

870.3100 (§82-1a)

Subchronic oral - mouse

Oxine Cu purity – not given

	MRID 42957801

Range-finding

10 mice/sex/dose

0, 300, 1000, 3000 or 6000 ppm for 13 weeks

	Tentative NOAEL: 1000 ppm

Tentative LOAEL :  

Apparent treatment-related thickening and pallor of the glandular mucosa
of the stomach in 4/10 females.  Abnormal coloration (pallor) of the
glandular stomach mucosa was seen in 2/10 males at 3000 ppm and 6000,
1/10 was also thickened at the 6000 ppm dose. An increased incidence of
raised, cystic areas in the ovaries at 6000 ppm. 



Guideline number/Study Type/Test Substance

 (% a.i.)

	

MRID number (Year)/Citation/Classification/Doses

	

Results



The 6000 ppm dose was recommended as the high level for the subsequent
carcinogenicity study.



870.3150 (§82-1a)

Subchronic - dog

99.5% a.i.

	MRID 42986802

Acceptable

4/sex/dose

0, 5, 50, or 250 mg/kg/day

for 13 weeks	NOAEL = 5 mg/kg/day

LOAEL = 50 mg/kg/day, based on vomiting, reduced total plasma protein
and albumin, reddened mucosa and hyperemia in stomach or small
intestine.

870.3200 (§82-2)

28 day dermal - rat

99.7% a.i.

	MRID 42957802

Acceptable - Guideline

5/sex/dose

0, 50, 200, or 1000 mg/kg/day, 6 hours/day for 4 weeks	Dermal irritation

Tentative NOAEL = 1000 mg/kg/day

Tentative LOAEL > 1000 mg/kg/day, not established

Systemic toxicity

NOAEL = 200 mg/kg/day

LOAEL = 1000 mg/kg/day, based on necrosis of the thymic lymphocytes.

870.4300 (§83-1)

Chronic - rat

96%

	MRID 00083777

Core-Minimum

30/sex/dose

M/F: 0, 5, 20, 100, 500 or 2000 ppm for 102 weeks

            	Tentative NOAEL: 500 ppm

Tentative LOAEL: 2000 ppm, based on increased concentration of copper in
tissues accompanied by histomorphologic effects.  The incidence of
neoplasia was comparable between the control and treated animals.

When compared to the concentration of copper in the tissues of the
control rats, moderate to marked increases in copper content were noted
in the livers of group 6 

(2000 ppm) rats of both sexes sacrificed at 52 and 102 weeks.  Slight to
moderate increases in copper content were also noted in the kidneys of
group 5 (500 ppm) and group 6 (2000 ppm) males and the group 4 (100 ppm)
group 5 (500 ppm) and group 6 (2000 



Guideline number/Study Type/Test Substance

 (% a.i.)

	

MRID number (Year)/Citation/Classification/Doses

	

Results



ppm) females sacrificed at 52 weeks and in the group 6 males and the
group 2, 4, 5 and 6 females sacrificed at 102 weeks.

The copper concentration in the brains of group 5 and group 6 males
sacrificed at 102 weeks were very slightly increased.  The tissue copper
contents in the rats of the other treated groups were generally
comparable to those of the control rats.

There was no evidence of a compound-related effect with regard to
physical appearance and behavior.



870.4100 (§83-1)

Chronic - dog

96%

	MRID 00099606

Core-Minimum

4/sex/dose for 6 groups

M/F: 0, 10, 40, 200, 1000 or 3000 ppm  for 102 weeks

           	Tentative NOAEL: 200 ppm

Tentative LOAEL: 1000 ppm, based on histological alteration in the liver
and lung correlated with an increase in copper content.

In dogs treated at levels up to 1000 ppm, no effects attributable to
compound administration were noted in evaluations of mortality data,
general appearance and behavior, body weight and food consumption
values, clinical lab values or organ weights and organ/body weight
ratios.

In addition, evaluations of tissue copper analyses values and gross and
histologic pathology data revealed no findings indicative of an effect
from compound in animals treated at levels up to and including 200 ppm. 
At the 1000 ppm level, no compound related findings were observed in the
one male and one female sacrificed at 52 weeks.  In those dogs
sacrificed at 104 weeks, moderate 



Guideline number/Study Type/Test Substance

 (% a.i.)

	

MRID number (Year)/Citation/Classification/Doses

	

Results



increase in copper content was noted in the livers of all the dogs and
compound-related histomorphologic alterations of the lung (subpleural
inflammation) and liver (focal accumulations of pigment-laden kupffer
cells) were noted in one female dog.

In the dogs treated with compound at a level of 3000 ppm,
compound-related findings were noted in the majority of the parameters
evaluated.  These findings included the following: inappetence resulting
from the impalatibility of the test diet (primarily noted when being
treated at a level of 4000 ppm), mortality in the second year in 4 of
the 6 animals remaining on study after the 52 week interval sacrifice;
general unhealthy appearance in all dogs during the second year; body
weight losses, suppressions in food consumption, hematology findings
indicative of anemia, and blood chemistry findings indicative of
hepatotoxicity during both years of the study; marked increase in copper
contents of brain, spleen, livers and kidneys of  the males and females
and histomorphologic alterations involving a variety of tissues
examined.  Principal tissue alterations were liver, kidney, lung, spleen
and anterior mesenteric lymph nodes.





Guideline number/Study Type/Test Substance

 (% a.i.)

	

MRID number (Year)/Citation/Classification/Doses

	

Results



870.4200 (§83-2)

Carcinogenicity-Mouse

97.2%

DER #8	

MRID 43267201

Acceptable – Guideline

50/sex/dose

0,100,400, 1500, or 6000 ppm (M: 0, 14.5, 57,1, 207.7, or 855.8
mg/kg/day, F: 0, 16.1, 66.2, 246.2, or 1051.7 mg/kg/day)

	

NOAEL = 57.1 mg/kg/day (M)

        = 66.2 mg/kg/day (F)

LOAEL  = 207.7 mg/kg/day (M)

                = 246.2 mg/kg/day (F), based on increased incidence of
stomach ulcers in males and mild anemia and adverse liver effects in
females.

No dose-related increases in individual neoplastic lesions were
observed. 



870.3700 (§83-3)

Carcinogenicity-Mouse

98.5%

DER #9	

MRID  4298603

Acceptable –Guideline

36/dose

0, 50, 200, or 800 mg/kg/day, 

GD 6-15

	Maternal Toxicity 

NOAEL = 200 mg/kg/day

LOAEL = 800 mg/kg/day, based on increased clinical signs (piloerection,
poor general condition, encrustation of nose and mouth), and decreased
body weight and gain.

Developmental toxicity

No dev. tox observed, Tentative NOAEL = 800 mg/kg/day

Tentative LOAEL > 800 mg/kg/day, not established





870.3700 (§83-3)

Carcinogenicity-Mouse

96.5%

DER # Not Reviewed

	

MRID 41063702

Not Reviewed

4 groups @ 16/dose

0, 7, 15, or 30 mg/kg/day, GD 7-19	Maternal Toxicity

Tentative NOAEL= 30 mg/kg/day (HDT) maternal body weight was not
affected as well as the body weight gain for the treated groups was
similar to the control group.

There was no adverse effect on food consumption at the HDT (30
mg/kg/day).

Developmental toxicity

Tentative NOAEL = 30 mg/kg/day (HDT)





Guideline number/Study Type/Test Substance

 (% a.i.)

	

MRID number (Year)/Citation/Classification/Doses

	

Results



870.3800 (§83-4)

Reproduction - Rat

> 99.7%

DER # 10

	

MRID 43267202

Acceptable – Guideline

F0: 32/sex/dose

F1: 28/sex/dose

0, 25, 250, or 2500 ppm

(F0: 0, 1.8/2, 18.2/20.8, 181/203 mg/kg/day M/F, F1: 0, 2/2.2,
19.8/22.8, 96/218 mg/kg/day M/F)

	Parental / Systemic

NOAEL = 250 ppm

LOAEL = 2500 ppm, based on increased liver weight in F1 males.

Reproduction

NOAEL = 250 ppm

LOAEL = 2500 ppm, based on decreased mean number of live pups at birth
(85% of controls) and decreased litter weights at day 0 and during
lactation in F1 generation.



870.3800 (§83-4)

Reproduction - Rat

> 96%

DER # 11

	

MRID 0079233

Core minimum

P1: 25/sex/dose

P2: 25/sex/dose

P1 & P2: 0, 20, 100 and 500 ppm

	Tentative NOAEL: >500 ppm (HDT) 

Parental:

Food and water consumption showed no treatment-related effects. No
deaths occurred nor were any signs of compound-induced toxicity
observed, during the growth, gestation, or lactation periods of either
parental generation. The pregnancy rates and parturition indices (number
of females delivering viable offspring/total number of females) of all
the groups were considered comparable at both matings of both parental
generations. Evaluations of the live birth 

indices (number of live births/total apparent births) revealed no
significant difference in viability between the treated and control
group offspring obtained from either mating trial of the P1 and P2
generations.

No treatment-related findings were observed in gross pathology in the
selected offspring in the F1b generation sacrificed at 

weaning.



Guideline number/Study Type/Test Substance

 (% a.i.)

	

MRID number (Year)/Citation/Classification/Doses

	

Results





No deaths or signs of compound induced toxicity were observed in the F1b
or F2b generation offspring maintained for 5 weeks and 3 months
postweaning.





870.5100 (§84-2)

Mutagenicity - Ames

Purity not reported 

	

MRID 00248746

Acceptable – Guideline

Strain: TA1535, TA1537, TA1538, TA98 and TA 100

– 0.3 µL/plate (0.2 and 0.3 µL/plate were toxic)	Positive

Induced increase in histidine reverants in one strain TA 100, possibly
also TA 1538 and TA 98 with metabolic activation (weak mutagen).



870.5100 (§84-2)

Mutagenicity - Ames

Purity99.7%

	

MRID 42962301

Acceptable – Guideline

TA97, TA98, TA100, TA102,

TA1535, TA1537, TA1538; S. Typhimurium; concentrations: 0.33 – 100
µL/plate (standard assay), 0.51 – 50 µL/plate (pre-incubation)

	

Positive

Dose-related weakly positive reverse gene mutation in S9-activated
bacterial strains TA97, TA100, TA102 of S. typhimurium exposed up to
toxic doses.





870.5395 (§84-2)

Mutagenicity –Micronucleus test in the Mouse Bone Marrow

Purity 98.5%

	

MRID 42962302

Acceptable – Guideline

Mouse – 5 mice/sex/dose Administered orally at 0, 3750, 7500 mg/kg	

Negative

For induction in bone marrow cells of mice treated once at doses up to
7500 mg/kg, a non-toxic (but limiting) dose. 



870.5550 (§84-2)

Mutagenicity –Unscheduled DNA synthesis 

Purity 99.7%	

MRID 42962303

Unacceptable

Rat – Male 1-3/dose group gavaged once at 100, 500, 1000, 1500,a 2500
and 3000 mg/kg	Negative

For induction of unscheduled DNA synthesis in primary rat hepatocyte
cultures isolated from male rats treated orally up to 3000 mg/kg, as
determined by radioactive tracer procedures [nuclear silver grain
counts].





Guideline number/Study Type/Test Substance

 (% a.i.)

	

MRID number (Year)/Citation/Classification/Doses

	

Results



870. 7485 (§85-1)

Metabolism – rat

Purity >98.5% (unlabeled); >98% radiolabeled material

	

MRIDs 42962304, 42962305

Acceptable – Guideline

30 or 1000 mg/kg (unlabeled, daily for 14 days) single labeled 30 mg/kg
Major route of excretion via urine (62-68%) and feces (8-26%) within 45
hours. Rapid absorption inferred by rapid excretion of metabolites in
urine. Radioactivity in tissue residues very low in all tissues
including blood (<0.05%). Bioaccumulation is minimal. Radioactivity in
urine associated with parent (5-16%) and sulfate (12-18%) of the parent.
In feces, radioactivity associated with parent (4-23%) and glucuronide
conjugate of the parent (0.1-4%).



00083777 (MRID):  Mulligan, T.; Banas, D.A. (1976) Final Report:
Two-year Dietary Administration in the Rat: Project No. 854-104.
(Unpublished study received May 20, 1981 under 42567-1; prepared by
Hazleton Laboratories America, Inc., submitted by La Quinoleine S.A.,
c/o Regst. Consulting, Pacifica, Calif.; CDL:245397-G)

00099606 (MRID):  Mulligan, T.; Voelker, R. (1976) Final Report:
Two-year Dietary Toxicity Study in Dogs: Project No. 854-103.
(Unpublished study received Dec 8, 1978 under 42567-1; prepared by
Hazleton Labo- ratories America, Inc., submitted by La Quinoleine S.A.,
c/o Registration Consulting Associates, Pacifica, CA; CDL:237444-A)

0079233 (MRID):  Mulligan, T.; Durloo, R. (1975) Final Report: A Two
Generation Reproduction Study in Rats: Project No. 854-105. (Unpublished
study received May 20, 1981 under 42567-1; prepared by Hazleton
Laboratories America, Inc., submitted by La Quinoleine S.A., c/o Regst.
Consulting, Pacifica, Calif.; CDL:245397-F)

41063701 (MRID):  Ridgway, P. (1987) K37 (Copper 8-Hydroxyquinolate):
rabbit teratology dose ranging study: Project ID: AKJ/5/87. Unpublished
study prepared by Toxicol Laboratories Ltd.

41063702 (MRID):  Ridgway, P. (1987) K37 (Copper 8-Hydroxyquinolate):
Rabbit Teratology Study: Project ID: AKJ/6/87. Unpublished study
prepared by Toxicol Laboratories Ltd. 106 p.

42921501 (MRID):  Buser, S. (1990) Determination of the Acute Oral
Toxicity of Ro 17-0099/000 (Copper 8-Quinolinolate TGAI) in the Rat: Lab
Project Number: B-157'235: 032A90Z. Unpublished study prepared by F.
Hoffmann-La Roche Ltd. 37 p

42921502 (MRID):  Buser, S. (1990) Determination of the Acute Dermal
Toxicity of Ro 17-0099/000 (Copper 8-Quinolinolate TGAI) in the Rat: Lab
Project Number: B-157'234. Unpublished study prepared by F. Hoffmann-La
Roche Ltd. 21 p.

42921503 (MRID):  Ullmann, L.; Porricello, T. (1993) Primary Skin
Irritation Study with Ro 17-0099/000 (Copper 8-Quinolinolate) in Rabbits
(4-Hour Semi-Occlusive Application on Intact and Abraided Skin): Lab
Project Number: 213344. Unpublished study prepared by Research &
Consulting Co., AG. 29 p.

42921504 (MRID): Ullmann, L.; Kups, A. (1988) Contact Hypersensitivity
to Ro 17-0099/000 (Copper 8-Quinolinolate) in Albino Guinea Pigs
(Maximization Test): Lab Project Number: 213333. Unpublished study
prepared by Research & Consulting Co., AG. 46 p.

42937301 (MRID):  Buser, S. (1983) A 13-Week Toxicity Study with
Ro-17-0099/000 (Copper 8-Quinolinolate) in Mice p.o. (Feed Admix): Lab
Project Number: RRB 104 777: 62 A 81: 104 777. Unpublished study
prepared by F. Hoffmann-La Roche & Co. Ltd. 135 p.

42957801 (MRID):  Coleman, M.; Taupin, P. (1990) K-37 (Copper
8-Quinolinolate): 13-Week Oral (Dietary) Rangefinding Study in the
Mouse: Lab Project Number: TOM/1/90. Unpublished study prepared by
Toxicol Labs, Ltd. 211 p.

42957802 (MRID):  Hagemann, (?) (1990) 28 Day Repeated Dose Dermal
Toxicity Study in the Rat: Lab Project Number: 911205: CGA 281881: Final
Report: Lab No. 911205. Unpublished study prepared by Ciba-Geigy
Limited. 178 p.

42962301 (MRID): Chetelat, A. (1989) Mutagenicity Evaluation of the
Fungicide Ro 17-0099/000 (Copper 8-Quinolinolate) with Salmonella
typhimurium (Ames test): Lab Project Number: B-116'875. Unpublished
study prepared by F. Hoffmann-La Roche Ltd. 38 p.

42962302 (MRID):  Chetelat, A.; Dresp, J. (1990) Micronucleus Test in
the Mouse Bone Marrow In Vivo After Oral Administration of the Fungicide
Ro 17-0099/000 (Copper 8-Quinolinolate): Lab Project Number: B-116'890.
Unpublished study prepared by F. Hoffman-La Roche Ltd. 20 p.

42962303 (MRID):  Strobel, R. (1990) In vivo/in vitro Rat Hepatocyte DNA
Repair Test with the Fungicide Ro 17-0099/000 (Oxine Copper-Copper
8-Quinolinolate) (Unscheduled DNA Synthesis Test: Lab Project Number:
B-154'904. Unpublished study prepared by F. Hoffmann-La Roche Ltd. 158
p.

42962304 (MRID):  Dennis, S. (1991) Ro 17-0099/022 (Carbon 14)-Copper
8-Quinolinolate): Metabolism of Ro 17-0099/022 in the Rat Tissues and
Excreta After Single Oral, Repeated Oral Administrations and After a
Single Oral Administration to Bile Duct Cannulated Rats: Lab Project
Number: RES-MET Q14. Unpublished study prepared by Dr. R. MAAG AG. 48 p.

42962305 (MRID):  Van Dijk, A.; Baranowski, D. (1991) Ro 17-0099/022
(Carbon 14)-Copper 8-Quinolinolate): Absorption, Distribution and
Excretion After Single Oral, Repeated Oral Administration to the Rat and
After Single Oral Administration to Bile Cannulated Rats: Lab Project
Number: 276118. Unpublished study prepared by RCC UMWELTCHEMIE AG. 95 p

42986801 (MRID):  Buser, S.; Mettler, F. (1990) 13-Week Oral (Dietary)
Toxicity in the Rat with the Fungicide Ro 17-0099/000 (Oxine Copper):
Lab Project Number: B-157'249: 269302: 026A90. Unpublished study
prepared by F. Hoffmann-La Roche & Co. Ltd. 465 p.

42986802 (MRID):  Schlappi, B.; Jovanovic, B. (1990) Ro 17-0099/000:
13-Week Oral Toxicity Study (by Capsules) on Dogs with the Fungicide Ro
17-0099/000 (Copper 8-Quinolinolate): Lab Project Number: B-154'807:
024A90: RRB 154'807. Unpublished study prepared by F. Hoffmann-La Roche
& Co. Ltd. 306 p.

42986803 (MRID):  Bacchus, C. (1992) Ro 17-0099/000 (Copper
8-Quinolinolate): Oral (Gavage) Embryo Toxicity Study in the Rat with
the Fungicide Ro 17-0099/000: Segment II Study with Post Natal
Evaluation: Lab Project Number: B-154'980: 284027: 273677. Unpublished
study prepared by F. Hoffmann-La Roche Ltd. 155 p.

43267201 (MRID):  Husband, R. (1994) K-37 (Copper 8-Quinolinolate):
80-Week Oral (Dietary) Carcinogenicity Study in the Mouse: Lab Project
Number: TOM/2B/93. Unpublished study prepared by Toxicol Laboratories
Ltd. 2279 p.

43267202 (MRID):  Bryson, A. (1994) Technical CGA 281881 (Copper
8-Quinolinolate): A Study of the Effect on Reproductive Function of Two
Generations in the Rat: Lab Project Number: 911382: CBG/576/931390:
567/931390. Unpublished study prepared by Huntingdon Research Centre
Ltd. 323 p.

43558501 (MRID): Driscoll, R. (1993). Oxine Copper Technical (K-37):
acute dermal toxicity (limit test) in the rat. Safefarm Laboratories
Limited, Derby, UK. Laboratory Prokject Identification 386/39. October
8, 1993. Unpublished.

43572401 (MRID): Coleman, M. and P. Taupin (1990). K-37 133 week oral
(dietary) rangefinding study in the mouse. Toxico Laboratories Limited,
Bromyard Road, Ledbury, Herefordshire, HR8 1LH, England. Toxicol Report
Reference No. TOM/1/90. November 1990. Unpublished.

43611901 (MRID):  Jackson, G. (1987) K-37 (Copper 8-Quinolinolate):
Acute Inhalation Toxicity in the Rat: Lab Project Number: AGK 1/87926.
Unpublished study prepared by Huntingdon Research Centre Ltd. 54 p.

Algate, D.R., P.L. Munt. and C.Mejer-Aspell. (1990). Copper
8-Quinolinolate Technical Assessment of Effects On Hexobarbital Induced
Sleeping Time in the Mouse. Unpublished report prepared by Huntington
Research Centre, Ltd. Huntington, Cambridgeshire, England. 

Algate, D.R., P.L. Munt. and C.Mejer-Aspell. (1990). Copper
8-Quinolinolate Technical Assessment of Effects On Motor Coordination in
the Mouse. Unpublished report prepared by Huntington Research Centre,
Ltd. Huntington, Cambridgeshire, England.

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D.R., P.L. Munt. and C.Mejer-Aspell. (1990). Copper 8-Quinolinolate
Technical Investigation of Possible Neurological Effects on the Rat
Using The Tilting Plane Test. Unpublished report prepared by Huntington
Research Centre, Ltd. Huntington, Cambridgeshire, England.

National Toxicology program (NTP) (1985). NTP Technical report on the
Toxicology and Carcinogenesis of 8-Hydroxyquinoline (CAS No. 148-24-3)
in F344/N Rats and B6C3F1 Mice (feed Studies). EG&G Mason Research
Institute, Rockville, MD. NTP TR 276 (NIH Publication No. 85-2532;
NTP-83-029), April, 1985. Published by the U.S. Department of Health and
Human Services. 

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