Acute toxicity: oral

Oral LD₅₀
rat (m/f)

LD₅₀ = 251 mg/kg-bw

(International Research and Development Corporation, 1978a)

[Additional studies: Hazleton Laboratories America, Inc., 1987a; Hazleton Wisconsin, Inc., 1994a; Corning Hazleton, Inc., 1997a]

Oral LD₅₀ rat (m/f)

LD₅₀ = 1467 mg/kg-bw

(International Research and Development Corporation, 1978b)

Oral LD₅₀
rat (m/f)

LD₅₀ = >
500 and <5000 mg/kg-bw

(Riker Laboratories, Inc., 1981b)

[Additional study: Riker Laboratories, Inc., 1987]

Oral LD₅₀ rat (m/f)

LD₅₀ = >1000 and <5000 mg/kg-bw

(Riker Laboratories, Inc., 1979)

Oral LD₅₀ rat (m/f)

LD₅₀ = 350 mg/kg-bw

(Hazleton Laboratories America, Inc., 1985a)

[Additional studies: Riker Laboratories, Inc., 1981c; Hazleton Laboratories America, Inc., 1985b]

Oral LD₅₀ rat (m/f)

LD₅₀ = >0.5 and <5 ml/kg-bw

(Biosearch, Inc., 1978c)

[Additional studies: Biosearch, Inc., 1978a; Hazleton Laboratories America, Inc., 1988a]

Oral LD₅₀ rat (m/f)

LD₅₀ = >5 g/kg-bw

(Hazleton Wisconsin, Inc., 1991a)

Acute toxicity: dermal

Dermal LD₅₀ rabbit (m/f) 24-hour covered

LD₅₀ = >2000 mg/kg-bw

(Hazleton Laboratories America, Inc., 1988b)

Acute toxicity: inhalation

Inhalation LC₅₀ rat (m/f) LC₅₀ = 5200 mg/m³

(Bio/Dynamics, Inc., 1979a)

Inhalation
LC₅₀ rat (m/f) LC₅₀ = >6.5 g/m³

(Hazleton Laboratories America, Inc., 1981)

Inhalation LC₅₀ rat (m/f)

LC₅₀ = >22 g/m³ and <66 g/m³

(Bio/Dynamics, Inc., 1979b)

Irritation: ocular

Severe irritation: rabbit 0.1 ml ocular application, washout after 5 or 30 seconds

(Riker Laboratories, Inc., 1981a)

[Additional studies: mild to moderate irritation: Warf Institute, Inc., 1974, 1975; Hazleton Laboratories America, Inc., 1987b; Hazleton Wisconsin, Inc., 1994b; Corning Hazleton, Inc., 1997b]

Minimal irritation: rabbit (f) 0.1 g ocular application

(Riker Laboratories, Inc., 1984)

No irritation:

rabbit 0.1 g ocular application

(Biosearch, Inc., 1978b)

Minimal irritation: rabbit (f) 0.09 g ocular application

(Hazleton Laboratories America, Inc., 1985c)

[Additional study: Hazleton Laboratories America, Inc., 1985d]

Mild irritation: rabbit 0.1 ml ocular application (unwashed)

(Hazleton Laboratories America, Inc., 1988c)

[Additional study: Biosearch, Inc., 1978d]

Moderate irritation: rabbit 0.1 ml ocular application (unwashed)

(Hazleton Wisconsin, Inc., 1991b)

Short-term repeated-dose toxicity

Oral gavage LOAEL rat (m/f), 28 days

LOAEL = 3 mg/kg-bw per day

hepatocellular hypertrophy (m/f); increased relative liver weight (m/f); increased relative kidney weight (f); reduced body weight (f)

(NOTOX, 1999)

[Additional study: Austin et al., 2003]

Dietary LOEL rat (m/f), at least 4 weeks

LOEL (m/f) = 2.4-4.1 mg/kg-bw per day

increased relative liver weight (f), hepatocellular hypertrophy (m) (investigators give LOAEL of 35-63 mg/kg-bw per day, ignoring liver effects at lower doses)

(Covance Laboratories, Inc., 2000a)

Subchronic toxicity

Oral gavage LOEL rhesus monkey (m/f), 90 days

LOEL = 0.5 mg/kg-bw per day

clinical signs of toxicity and increased leukocytes

(International Research and Development Corporation, 1978e)

[Additional study: International Research and Development Corporation, 1978c]

Oral diet
LOEL rat (m/f), 90 days

LOEL (m) = 2 mg/kg-bw per day

slight hepatocellular vacuolization; decreased hemoglobin
and hematocrit

(International Research and Development Corporation, 1978d)

[Additional study: International Research and Development Corporation, 1979]

Oral diet LOEL rat (m/f), 13 weeks LOEL (m) = 2 mg/kg-bw per day

increased relative brain, kidney, liver and testis weights; histopathological changes in the liver, reductions in serum cholesterol and triglycerides

(Covance Laboratories, Inc., 1999d)

Carcinogenicity/

chronic

Oral diet LOAEL rat (m/f), 104 weeks

LOAEL = 0.06-0.23 mg/kg-bw per day

increased incidence of non-neoplastic changes in the liver (statistically significant increased incidence of hepatocellular adenoma in males and females at intakes of 0.64-2.21 mg/kg-bw per day)

(Covance Laboratories, Inc., 2002a)

Oral LOEL cynomolgus monkey (m/f), 26 weeks

LOEL (m/f) = 0.03 mg/kg-bw per day

m: reduced high-density lipoprotein and triiodothyronine levels, thymic atrophy

f: thymic atrophy

(Covance Laboratories, Inc., 2002b)

Oral diet LOEL rat (m/f) 104-week cancer bioassay with
N-EtFOSE
narrow range (98.1%)

LOEL (m) =
0.86-2.618 mg/kg-bw
per day

LOEL (f) =
4.213-10.166 mg/kg-bw
per day

m/f:
increased incidence of histopatho-
logical effects
in liver

f: significant
(p < 0.05) reduced
serum triglycerides after 104
weeks

(statistically significant increased incidences of thyroid
follicular adenoma in males at intakes of
3.1-8.72 mg/kg-bw
per day and
of hepato-
cellular adenoma in females at intakes of 4.213-10.166 mg/kg-bw per day)

(Covance Laboratories, Inc., 2001)

[Additional study: Riker Laboratories, Inc., 1983]

Genotoxicity and related endpoints: in vivo

Negative: mouse (m/f) bone marrow micronucleus 950 mg/kg-bw; acute oral gavage

(Corning Hazleton, Inc., 1996b)

Negative: mouse (m/f) bone marrow micronucleus 2200 mg/kg-bw; acute oral gavage

(Corning Hazleton, Inc., 1996a)

[Additional studies: Corning Hazleton,
Inc., 1993; Hazleton Washington, Inc., 1993a]

Negative: mouse (m/f) bone marrow micronu-
cleus, 4000 mg/kg-bw, acute oral gavage

(Corning Hazleton, Inc., 1996c)

Negative: rat (m/f) bone marrow micronucleus, 5000 mg/kg-bw, acute oral gavage, and rat hepatic unscheduled DNA synthesis in vivo/in vitro

(Hazleton Washington, Inc., 1993b,c)

Genotoxicity and related endpoints: in vitro

Negative: with/without metabolic activation: Ames Salmonella/E. coli mutagenicity, S. cerevisiae mitotic recombinogenicity, rat hepatocyte unscheduled DNA synthesis and human lymphocyte chromosomal aberration in vitro assays

(Litton Bionetics, Inc., 1978; SRI International, 1978, 1980, 1981; Covance Laboratories, Inc., 1999a,b,c)

Negative
(-S9), questionable (+S9): mouse lymphoma L5178Y;
in vitro
mutation -S9/+S9

(NOTOX,
1998)

[Additional negative
in vitro study: Covance Laboratories, Inc., 2000b]

Negative:

Ames Salmonella mutagenicity and Chinese hamster
ovary sister chromatid exchange in vitro assays

(U.S. EPA, 1989)

Negative: with/without metabolic activation: Ames Salmonella mutagenicity, mouse L5178Y lymphoma mutation and human lymphocyte chromosomal aberration in vitro assays

(NOTOX, 1994a,b,c)

Negative: with/without metabolic activation: Ames Salmonella mutagenicity and yeast recombination in vitro assays

(SRI International, 1985)

Negative: with/without metabolic activation: Ames Salmonella mutagenicity and yeast recombination in vitro assays

(SRI International, 1982)

Reproductive/ developmental toxicity, rat

LOEL maternal/LOEL fetal rat (f) oral gavage, days 6-15 of gestation

LOEL maternal = 5 mg/kg-bw per day

LOEL fetal = 1 mg/kg-bw per day

maternal: decreased weight gain; decreased body weight minus gravid uterine weight; clinical effects

fetal: incomplete skull closure twice that of controls

(Hazleton Laboratories America, Inc., 1983b)

[Additional studies: Riker Laboratories, Inc., 1980; Argus Research Laboratories, Inc., 1999e,f]

LOEL
maternal/
LOEL fetal
rat (f) oral gavage, days 6-17 of gestation

LOEL
maternal =
10 mg/kg-bw per day

LOEL fetal =
10 mg/kg-bw per day

maternal: reduced body weight gain

fetal: reduced live fetal body weight and increased skeletal alterations, ossification alterations

(Argus Research Laboratories, Inc., 1998)

[Additional studies: Riker Laboratories, Inc., 1981d; Hazleton Laboratories America, Inc., 1983a, 1984]

Reproductive/ developmental toxicity, rat two-generation

LOEL F₀/LOEL F₁/LOEL F₂: rat (m/f) oral gavage, F₀ males: from 6 weeks before to the end of mating, F₀ females: from 6 weeks before mating through to the 21st day of lactation (DL 21), F₁ males: from 22 days after birth to the end of mating (started 90 days after birth), F₁ females: from 22 days after birth to DL 21 (for F₂)

LOEL F₀ (m) = 0.4 mg/kg-bw per day

LOEL F₀ (f) = 1.6 mg/kg-bw per day

LOEL F₁ (m/f) = 1.6 mg/kg-bw per day

LOEL F₂ (m/f) = >0.4 mg/kg-bw per day

F₀ (m) reduced body weight gains, F₀ (f) reduced body weight gains during precohabitation, F₁ (m/f) significantly reduced litter sizes and both viability and lactation indices; reductions in development, including delayed eye opening, surface righting, pinna unfolding and air righting reflex

(Argus Research Laboratories, Inc., 1999a)

[Additional study: Argus Research Laboratories, Inc., 2000]

LOEL F₀/
LOEL F₁/
LOEL F₂: rat (m/f) oral gavage, F₀ males: from
28 days
before to end of mating, females: from 28 days before through to the 21st day of lactation (DL 21), F₁ males from 22 days after birth to end of mating (started 90 days after birth), F₁ females: from 22 days after birth through
to DL 21
(for F₂)

LOEL F₀ (m/f) = 5 mg/kg-bw per day

LOEL F₁ (m/f) = 1 mg/kg-bw per day

LOEL F₂ (m/f) = 5 mg/kg-bw per day

F₀reduced
body weight gains (m/f); increased relative left testis weight; reduced duration of gestation, F₁ reduced body weight gains (m/f), F₂ reduced
viability and lactation indices; reduced mean litter weight

(Argus Research Laboratories, Inc., 1999b)

Reproductive/ developmental toxicity, rabbit

LOEL maternal/ LOEL fetal rabbit (f) oral gavage, days 7-20 of gestation

LOEL maternal = 1.0 mg/kg-bw per day

LOEL fetal = 2.5 mg/kg-bw per day

maternal: reduced body weight gain over entire exposure period

fetal: decreased ossification of sternal centres per fetus per litter; reduced body weight

(Argus Research Laboratories, Inc., 1999d)

LOEL maternal/
LOEL fetal rabbit (f) oral gavage, days 7-20 of gestation LOEL maternal = 2.5 mg/kg-bw
per day

LOEL fetal = >3.75 mg/kg-bw per day

maternal: reduced body weight gain; increased late resorptions and abortions

(Argus Research Laboratories, Inc., 1999c)

[Additional study: Riker Laboratories, Inc., 1981e]

LOEL offspring rabbit (f)
oral gavage; days 19-28
of gestation

LOEL offspring = 0.3 mg/kg-bw per day

increased neonatal mortality throughout pre-weaning period

(Stump et
al., 1997)