Document ID: EPA-HQ-OPP-2005-0123-0287
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-02T04:00Z

SEQ CHAPTER \h \r 1 	Appendix A: Toxicity Profile

Acute Neurotoxicity Study Executive Summary for Acute Reference Dose in
the General Population

In an acute neurotoxicity study (MRID No. 42793601), CD rats (15
rats/sex/dose) were exposed by whole body inhalation to 0, 30, 100 or
350 ppm MeBr vapor for 6 hours (equivalent to males: 0, 27, 90 or 314
mg/kg/day and females: 0, 30, 101, or 354 mg/kg/day).  Test animals were
observed for 16 days.  Functional observation battery (FOB) was
conducted at pre-test and days 1, 2, 8 and 15 post-treatment.  Motor
activity measurements was conducted at pre-test and days 1, 8 and 15
post-treatment.

Under the conditions of this study, MeBr did not produce any mortality,
body weight loss, gross or microscopic changes at all dose levels. 
However, at 350 ppm, decreased activity, increase in number of animals
with drooping/half-closed eyelids and alertness as measured in a FOB
examination, decreased rears, decreased motor activity, increased
piloerection and decreased body temperature in males and females were
observed.  A slight decrease in hind-limb grip strength in males may
have been treatment-related.  Effects were transient and all animals
were assessed to be normal by 1 week post-exposure.  At 30 or 100 ppm,
no treatment-related effects on FOB or motor activity were observed.

This study is classified as acceptable/guideline and satisfies the
guideline requirement  (§81-81-8) for an acute neurotoxicity study in
rats. 

Developmental Toxicity Study Executive Summaries for Selection of Acute
Reference Dose in Females 13-49 Years of Age

In a developmental toxicity study (MRID No. 41580401), pregnant New
Zealand White rabbits (26 animals/dose) were exposed by whole body
inhalation to 0, 20, 40 or 80 ppm MeBr vapor for 6 hr/day on Days 6-16
of gestation.  Mating was conducted using artificial insemination. 
Based on the insemination record the females were inseminated with sperm
pooled from several bucks.  

Maternal Toxicity

At 80 ppm, clinical signs of maternal toxicity including decreased
appetite, lethargy, right side head tilt, slight ataxia and slight
lateral recumbency were observed.  These signs were mostly observed in
three rabbits: #5427, #5428 and #5431.  One doe (#5428) in this
treatment group delivered on gestation day 27 and it was determined that
this early delivery may have been related to the toxicity that this
animal was experiencing.  In addition, a treatment-related, but not
dose-related, decrease in body weight was observed in the maternal
animals in the high dose group.  Three animals (# 5427, 5428, and 5431)
caused decrease in the mean body weights of the high dose group.  The
body weight loss of these animals prior to delivering their litters were
604, 464, and 136 g, respectively.  No clinical signs of toxicity were
present in the lower treatment groups.

Developmental Toxicity

The fetal data indicate an increase in the incidence of agenesis
(absence) of the gall bladder in the fetuses of the high dose group
(13/159) (8.2%) relative to the control group (2/190) (1.1%).  The
litter incidences of agenesis of the gall bladder were 5/19 (26.3%) in
the high dose group and 1/21 (4.8%) in the control group.  The litter
incidences of agenesis of the gall bladder in the low- and mid-dose
groups were 1/15 (6.7%) and 1/19 (5.3%), respectively.  The individual
animal data indicate 9 fetuses with missing gall bladder were from 4
does with maternal toxicity in the high dose group.  The litter
incidences of agenesis was seen in 6 fetuses from one litter (animal #
5427) and 1 fetus each from 3 litters [animal # 5428, 5431 and 5430]. 
One doe (animal # 5432) with no maternal toxicity had 4 fetuses with
missing gall bladder.  Two does (animal # 5426 and 5433) with maternal
toxicity (lethargy only) had normal fetuses. 

In a repeated study, it was confirmed that the observed finding of
agenesis of the gall bladder was related to treatment and was not
attributed to a particular male used for artificial insemination.  The
incidence of agenesis of the gall bladder found in this repeat study is
similar to the incidence in the main study.  The incidence of agenesis
of the gall bladder in the fetuses were 4/92 (4.3%) in the high dose
group and 1/114 (0.9%) in the control group.  The incidence of agenesis
of the gall bladder in the litters were 4/14 (28.6%) in the high dose
group and 1/16 (6.3%) in the control group.  At 80 ppm, the signs of
severe maternal toxicity (lethargy, right side head tilt, slight ataxia
and slight lateral recumbency) were not observed in this repeat study.

At 80 ppm, the number of fused sternebrae were increased in the high
dose group (12.6%) when compared to the control group (0%).   In
addition, mean fetal body weight was slightly lower (4.4%;
non-statistically significant) compared to the control group.  Although
the nominal fetal weight decrement was not statistically significant,
the decrease is consistent with other effects occurring at the high
dose.  

The data seemed to indicate that the failure of gall bladder development
was due to the direct effects of  MeBr and it might not be caused by the
parental influence.

This study is classified as acceptable/guideline and satisfies the
guideline requirement  (§83-3) for a developmental toxicity study in
rabbits. 

Chronic/Carcinogenicity Study Executive Summaries for Selection of
Chronic Reference Dose in All Populations

In a combined chronic toxicity/carcinogenicity study (MRID 44462501),
micro encapsulated MeBr was administered to 4 groups of male and female
Crl:CD®(SD)BR rats for a period of 12 or 24 months (interim and main
study, respectively) in the diet at concentrations of 0 (diet control),
0 (placebo control), 0.5, 2.5, 50, or 250 ppm.  These concentrations
were equivalent to 0, 0.02, 0.11, 2.20 and 11.10 mg/kg/day in males and
0, 0.03, 0.15, 2.92 and 15.12 mg/kg/day in females.  Groups of 50 males
and 50 females were designated for the main study and were maintained on
the treated food for up to 104 weeks.  Groups of 20 males and 20 females
were sacrificed at 52 weeks in the diet control, placebo control, 50 ppm
group and the 250 ppm group.

Survival was not affected by the test substance in any of the treated
groups compared to either of the control groups.  No treatment-related
clinical signs or effects on hematology, serum chemistry, urinalysis, or
organ weight data were observed.  The test article did not produce
changes in ophthalmoscopic examinations for the treated groups compared
to the controls.  Macroscopic and microscopic evaluations of organs and
tissues at the interim and final sacrifices revealed only normal
age-related changes, changes that were observed with equal frequency in
the controls.  No treatment-related increase in tumor incidence was
found in this carcinogenicity study. 

Statistically significant treatment-related effects were observed on
body weights, body weight gains and food consumption in males and
females treated with 250 ppm of the test substance during the first 12
to 18 months of the study.  Males in the 250 ppm group had decreases of
5.5% in mean body weight compared to the diet control at week 2, by week
14 this decrease was 10% and remained consistently lower through week
70.  During the second year of the study these animals gradually
regained the weight and were comparable to controls at the end of the
study.  Females in the 250 ppm group had a decrease of 3.7% in mean body
weight compared to the diet control at week 2, by week 14 this decrease
was 8.3% and also remained consistently lower through week 57.  After
week 57 females in the 250 ppm group gained weight gradually and the
decreases disappeared by the end of the study (week 104) at which time
this group had mean body weight values that were similar to controls. 
Mean body weight gain was markedly decreased during the first 18-months
of the study for animals treated with 250 ppm MeBr; decreases of 9-18%
and 12-21% were observed for males, and 7-22% and 11-19% were observed
for females when compared to the basal diet and placebo control groups,
respectively.  Males receiving 250 ppm had decreased food consumption
that ranged from 3.7 - 11.5 % for week 71-72, and females at this
concentration had decreases of 4.8 - 10.5% for week 54-55 compared to
their respective control groups.

This chronic toxicity/carcinogenicity study in the rat is
Acceptable/guideline and satisfies the guideline requirements for a
combined chronic toxicity/carcinogenicity oral study (§83-5) in rats. 

Subchronic Inhalation Study Executive Summaries for Short- and
Intermediate Term Inhalation Risk

Executive Summary (5-7 week):  

In a subchronic (5- to 7-week) inhalation toxicity study (MRID
43386802), MeBr (tech., 100% a.i.) was administered 7 hours/day, 5
days/week to 4 beagle dogs/sex/dose by whole body exposure at target
concentrations of 0, 5, 10/150, 25, 50 or 100 ppm (actual mean
concentrations 0, 5.3, 11.0/158.0, 26.0, 53.1 or 102.7 ppm; equivalent
to 0, 0.021, 0.043/0.614, 0.101, 0.206 or 0.399 mg/L), as follows: 



5 Week sacrifice - 2 dogs/sex, 0 ppm group and all dogs, 25, 50 and 100
ppm groups, for 5 weeks (total 24 exposures); 

7 Week sacrifice - 2 dogs/sex, 0 ppm group and all dogs, 5 ppm group for
7 weeks (total 34 exposures); and all dogs, 10/150 ppm group for 5 weeks
at 10 ppm (24 exposures), then at 150 ppm for 6 additional exposures and
terminated.  In addition to standard evaluations performed in a
guideline subchronic study, a neurological examination was performed by
a veterinarian after termination of exposures and serum bromide levels
were measured weekly.

5 Week sacrifice: 

At 5.3, 11, or 26 ppm, there were no treatment-related effects on food
consumption, ophthalmological findings, hematology parameters, organ
weights or gross findings (Table 2).  However,  at  53.1 ppm, 2/8 dogs
showed decreased activity during exposure beginning day 14.  And, at
102.7 ppm, 3/8 dogs showed decreased activity beginning exposure day 9,
and by exposure day 12 and continued until sacrifice all dogs showed
decreased activity.  One male developed tremors on day 10.   In
addition, these dogs at 102.7 ppm lost body weight (9% less than
controls).   Cumulative weight loss of males and females were 0.6 kg and
1.0 kg, respectively.  The systemic toxicity NOAEL for 5 weeks (24
exposures) is 26 ppm.  The LOAEL is 53.1 ppm based on decreased
activity. 

7 Week sacrifice:  

In this study, MeBr at 5 ppm dose demonstrated an unresponsiveness in 1
female dog and unresponsiveness and depressed appearance in another
female at the end of 34 exposures.  However,  these effects are not
considered as treatment-related because these effects did not show clear
dose-response relationship (similar effects of unresponsiveness and
depressed appearance were not observed at higher exposure levels of
shorter duration) and were not corroborated with other findings. 

No clinical signs of toxicity were observed at 26 ppm.  At 53 ppm,
decreased activity (lack of interest when approached) was first observed
in 2 dogs on day 14.  Thereafter, 1 to 4 of the dogs in that group
showed decreased activity on most exposure days.  At 103 ppm, 3 dogs
showed decreased activity on day 9; by day 12, all animals had decreased
activity during most of the remainder of the exposure period.  One
animal (sex not indicated) had tremors on day 10.  When exposure of
Group III animals (11 ppm) was increased to 158 ppm on exposure day 25,
decreased activity was observed in all animals beginning on day 27.  All
dogs were in poor condition by day 30, including one male that was
prostrate and had tremors.

This subchronic toxicity study is classified Acceptable/Non-Guideline
(§82-4) and fulfills the intent of the study.  A subchronic inhalation
study in the dog was not required by the US EPA for reregistration of
MeBr; this study was conducted as a range-finding study for a chronic
inhalation study in dogs to satisfy CDPR’s data requirements. 

Executive Summary (6 week):

In a six-week nonguideline inhalation toxicity study (MRID 45722801),
four groups of beagle dogs consisting of 4 males and 4 females/group
were administered MeBr (Lot No: 1010PK15A; purity: 100% a.i.) by whole
body exposure at concentrations of 0, 5.3, 10, and 20 ppm (equivalent to
0, 1.8, 3.4 and 6.9 mg/kg/day).  The exposures were for seven hours/day,
five days/week for six weeks (total of 30 exposures).  There were no
compound related effects on mortality, clinical signs, body weight, food
consumption, spleen weights, or gross or histological pathology. 
Functional observational battery and locomotor activity tests showed no
abnormalities relative to controls with one exception.  In this study,
one male at 10 ppm dose demonstrated an absence of proprioceptive
placing response, although no evidence of weakness in motor strength or
other signs of neurotoxicity was found.  These effects are considered
treatment-related because, all dogs also had the increased incidence
(not supported by statistics) of feces-findings (soft, mucoid feces,
and/or diarrhea) mostly later in the study.   At the 20 ppm dose, one
male and one female demonstrated an absence of proprioceptive placing
response due to treatment.  In addition, all dogs had the increased
incidence of feces-findings (soft, mucoid feces, and/or diarrhea) and 2
dogs at this dose showed higher incidence of discharge around the eyes
compared to the controls.

The LOAEL for MeBr was 10 ppm for male dogs and 20 ppm for female dogs
based on the absence of proprioceptive placing and the increased
incidence (not supported by statistics) of feces-findings (soft, mucoid
feces, and/or diarrhea).  The NOAELs was 5.3 ppm for male dogs and 10.0
ppm for female dogs.   This six-week inhalation toxicity study in beagle
dogs is Acceptable/Nonguideline and fulfills the intent of the study.

Use of the endpoint from the subchronic inhalation studies conducted in
dogs is appropriate for the exposure time period of 1day to 6 months. 

Chronic/Carcinogenicity Inhalation Study Executive Summaries for Long
Term Inhalation Risk

In a chronic toxicity/carcinogenicity study (MRIDs 41213301, 42418301,
44359101), 50 Wistar (Cpb:Wu) rats/sex/dose were exposed to MeBr (>98.8%
a.i.) by whole body exposure at concentrations of 0, 3, 30 or 90 ppm (0,
0.0117, 0.117 or 0.335 mg/L) for 127 weeks (males) or 129 weeks
(females).  Four additional groups of 10 animals/ sex/dose were also
included for sacrifice as follows:  (a) week 13, clinical
chemistry/hematology evaluations; (b) week 53, clinical
chemistry/hematology evaluations and gross/microscopic pathology; (c)
week 105, gross/microscopic pathology and (d) week 41, behavioral
evaluations (males only).  A reexamination of nasal cavity microscopic
lesions was later conducted by an independent reviewing pathologist and
the final diagnosis reached after discussion with the study pathologist
(MRID 44359101).  (The reexamination was not performed according to
recommended protocol for peer review and therefore the conclusions of
this review are based on the results from the original report).



	At 3 ppm, statistically significant increases in incidence (but not
severity) of basal cell hyperplasia of the nasal cavity were observed at
termination (27.0%, males and 31.7%, females, vs. 8.7% and 11.9%,
controls, respectively.  The severity of most lesions was very slight.  

	At 30 ppm, severity as well as incidence of basal cell hyperplasia of
the nasal cavity was increased at termination (46.9%, males and 40.8%,
females).  The severity of lesions was slight or moderate.  

	At 90 ppm, decreased survival (at termination, males 30% vs. 16%,
controls and females 14% vs. 30%, controls; statistically significant
only on a few occasions in each sex), decreased mean body weight (at
termination 5%, males; significant frequently during study and 12%,
females; significant throughout most of study after Week 4).  There were
also increased incidence of grossly visible hemothorax in animals found
dead or sacrificed in extremis, significantly increased incidence of
thrombus (43% vs. 10%, controls, males and 33% vs. 8%, females),
cartilaginous metaplasia (24% vs. 4%, controls, males) and moderate to
severe myocardial degeneration (73% vs. 41%, controls, females; not
significant in males - 84% vs. 65%).  Irritation of the esophagus and
forestomach may have been related to inadvertent ingestion of test
material (e.g., during grooming).  In males, increases in hyperkeratosis
of the esophagus (67% vs. 39%, controls; statistically significant) and
stomach (52% vs. 30%, controls; not significant) were observed. 
However, in these males at 90 ppm, MeBr did not produce
treatment-related effects on clinical signs, hematology, clinical
chemistries, urinalysis parameters or behavioral parameters.  

		There were no increases in the incidence of neoplastic lesions
attributed to exposure to MeBr in males or females.

	This chronic toxicity/carcinogenicity study is classified
Acceptable/Guideline for 83-2(a) carcinogenicity study and satisfies the
guideline requirements for an inhalation carcinogenicity study in the
rodent. 

Acute Toxicity Data on MeBr Technical

Guideline No.	Study Type	MRID # (s)	Results	Toxicity Category

870.1100	Acute oral 

(MeBr in vegetable oil)	43510301

	LD50 = 120-160 mg/kg (males)

LD50 = 86 mg/kg (females)	II

870.1200	Acute dermal 	N/Ad	    N/Ad	N/A

870.1300	Acute inhalation 	Kato et al (1986)a 	LC50 = 3.03 mg/L, 4 hr
exposure	IV 

870.2400	Primary eye irritation	Alexeef, G.; Kilgore, W. (1983)b and
Hezemans-Boer et al (1988)c	Severe irritation following accidental
exposure to humans	  I  

870.2500	Primary skin irritation	Alexeef, G.; Kilgore, W. (1983) and
Hezemans-Boer et al (1988)	Severe irritation following accidental
exposure to humans	I

870.2600	Skin sensitization	N/Ad	     N/Ad	 N/A 

a: Kato, N.; Morinobu, S.; Ishizu, S. (1986) Subacute inhalation
Experiment for MeBr in Rats. Industr. Health. 24: 87-103.

b: Alexeef, G.; Kilgore, W. (1983) MeBr.  In:  Gunther, F.; Gunther, J.,
ed.  Residue Reviews.  Residues of Pesticides and Other Contaminants in
the Total Environment, Vol. 88, p. 102-153.  New York, Springer Verlag. 

c: Hezemans-Boer, M; Toonstra, J.; Meulenbelt, J.; et al. (1988)  Skin
Lesions Due to Exposure to MeBr.  Arch. Derm. 124:917-921.

d:  N/A (Not Available): Acute dermal toxicity and dermal sensitization
potential studies were not required because there is already a clear
evidence that severe irritation to skin occurs after acute dermal
exposure to MeBr.



Subchronic, Chronic and Other Toxicity Table

Guideline No./ Study Type	MRID No. (year)/ Classification /Doses	Results

870.3100

90-Day oral toxicity  in rats (peanut oil)	00154564 (1984)

classification: no DER available.	NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day based on slight hyperplasia of the stratified
squamous epithelium of the forestomach.  HDT was 50 mg/kg/day.

870.3150

4-week oral toxicity in rats (capsule)	43776401 (1995) 

acceptable/non-guideline 	NOAEL = 0.835 mg/kg/day. 

LOAEL = 7.99 mg/kg/day (HDT), based on slightly decreased body weight
gain and food consumption. 

870.4300

Chronic toxicity and carcinogenicity  in rats (micro capsulated)
44462501 (1997)

acceptable/guideline

0,  0.5, 2.5, 50, or 250 ppm (M: 0, 0.02, 0.11, 2.2, or 11.1; F: 0,
0.03, 0.15, 2.92, and 15.12 mg/kg/day for 24 months.	NOAEL =  50 ppm
(2.2 mg/kg/day for males and 2.92 mg/kg/day for females).  LOAEL = 250
ppm (11.1 mg/kg/day for males and 15.12mg/kg/day for females), based on
decreased body weight, body weight gain, and food consumption in males
and females during the first 18 months of the study. 

No evidence of carcinogenicity

870.4100b

Chronic toxicity dogs

 (fumigated feed)	 43885201 (1996)

acceptable/guideline

 0, 0.5, 1.5 or 5 ppm (M: 0, 0.06, 0.13 or 0.27; F: 0, 0.07, 0.12 or
0.27 mg/kg/day for 12 months.	NOAEL/LOAEL > 5 ppm (HDT) (equivalent to
0.27 mg/kg/day)

It is noted that this study was conducted to establish a margin of
safety for human dietary exposure rather than to determine a LOAEL. 

870.6200a

Acute neurotoxicity screening battery in CD rats 

(Via inhalation) 	42793601 (1993)

acceptable/guideline

0, 30, 100 or 350 ppm, for 6 hrs

(M: 27, 90 or 314; F: 30, 101, or 354 mg/kg/day).  	NOAEL = 100 ppm 

LOAEL = 350 ppm based on decreased activity and alertness as measured in
a functional observation battery examination, decreased motor activity
and decreased body temperature in males and females were observed.  A
slight decrease in hind-limb grip strength in males may have been
treatment-related.  Effects were transient and all animals were assessed
to be normal by 1 week post-exposure.

870.3700a

Prenatal developmental in Wistar rats 

(via inhalation)	00102990 (1981)

acceptable/guideline

0, 20 or 70 ppm   (equivalent to 0, 20, or 71 mg/kg/day)–7 hrs/day; 5
days/wk	Maternal NOAEL/ LOAEL > 70 ppm (HDT).  Slightly increased
incidence/severity of interstitial nephritis at 70 ppm may represent
threshold effect.

Developmental NOAEL /LOAEL > 70 ppm (HDT)

870.3700b

Prenatal developmental in rabbits  (via inhalation)

	41580401 (1990)

acceptable/guideline

0, 20, 40, or 80 ppm  (equivalent to 0, 7.1, 14 or 28 mg/kg/day) - 6
hrs/day for 17 days	Maternal NOAEL = 40 ppm; LOAEL = 80 ppm based on
decreased appetite, lethargy, right side head tilt, ataxia and lateral
recumbency.

Developmental NOAEL = 40 ppm; LOAEL = 80 ppm based on agenesis of the
gall bladder, increased incidence of fused sternebrae and decreased
fetal body weight

870.6200b

Subchronic neurotoxicity screening battery

(via inhalation) in rats	42964301; 43077401

(1993)

acceptable/guideline

0, 30, 70 or 140 ppm 6 hr/day, 5 days/week –13 weeks (equivalent to
males:  0, 19, 45, or 90 mg/kg/day; females: 0, 22, 51, 101 mg/kg/day) 
NOAEL = 30 ppm (F) 

LOAEL = 70 ppm (F) based on decreased body weight and motor activity.  

NOAEL = 70 ppm (M)

LOAEL = 140 ppm (M) based on decreased body weight, increased mortality
(2 animals), convulsions (2 animals affected), effects on several FOB
parameters and brain histopathology in males. 

870.3465

Subchronic  Inhalation Toxicity in dogs	43386802 (1994)

acceptable/guideline

0, 5, 10/150, 25, 50 or 100 ppm (actual mean concentrations 0, 5.3,
11.0/158.0, 26.0, 53.1 or 102.7 ppm; equivalent to 1.43, 2.97/42.7,
7.02, 14.3, 27.7 mg/kg/day). 7 hours/day	

Systemic toxicity for a 7 weeks (34 exposures) 

 NOAEL (threshold) = <5 ppm.

 LOAEL (threshold)= 5 ppm (0.021 mg/L), based on decreased
responsiveness in females. 

870.3800

Reproduction and fertility effects in CD rats

(via inhalation)	00160477 (1986)

acceptable/guideline

0, 3, 30, or 90 ppm for 6 hours/day

(equivalent to males: 0, 2.4, 24 or 73 mg/kg/day; females:  0, 2.8, 28
or 85 mg/kg/day)	Parental/Systemic NOAEL = 30 ppm

Parental/Systemic LOAEL = 90 ppm based on reduced body weight

Reproductive NOAEL = 3 ppm 

Reproductive LOAEL = 30 ppm based on reduced pregnancy rates (23%, F2b)

Offspring NOAEL = 3 ppm

Offspring LOAEL = 30 ppm based on reduced pup weight on post-natal day
21 (F1a, F2a, F2b generations) ranging from 10-20%.

870.4300

Chronic toxicity and carcinogenicity  (29-month) in rats (via
inhalation)–Wistar rats	41213301 (1987); 42418301; 44359101

acceptable/guideline

0, 3, 30 or 90 ppm (0, 0.0117, 0.117 or 0.335 mg/L)

(equivalent to males: 0, 1.9, 19 or 58 mg/kg/day; females:  0, 2.2, 22
or 65 mg/kg/day)	Local irritation NOAEL < 3 ppm (0.0117 mg/L); LOAEL = 3
ppm (0.0117 mg/L), based on increased incidence of basal cell
hyperplasia of the nasal cavity in both sexes.

Systemic toxicity NOAEL = 30 ppm (0.117 mg/L); LOAEL  = 90 ppm (0.335
mg/L), based on increased mortality, decreased body weight and relative
brain weight, hemothorax, increased incidence of thrombus, cartilaginous
metaplasia, myocardial degeneration and irritation of the esophagus and
forestomach. 

No evidence of carcinogenicity

870.4300

Chronic toxicity and carcinogenicity  in mice –B6C3F1

(via inhalation)–2 years

National Toxicology Program Study TR 385	42504101 (1992)

acceptable/guideline for carcinogenicity study.

0, 10, 33 or 100 ppm–6 hrs/day; 5 days/week (0, 11.8, 38.9 or 118
mg/kg/day) 	Local irritation NOAEL/LOAEL = not reported

Systemic toxicity NOAEL = 33 ppm (0.1279 mg/l); LOAEL = 100 ppm (0.3876
mg/l), based on mortality (males), neurological signs (abnormal posture,
tremors, ataxia, limb paralysis and emaciation) decreased body
weight/weight gain and microscopic lesions in the brain, heart, sternum
and olfactory epithelium.

No evidence of carcinogenicity

[No data on clinical chemistry, urinalysis, and gross findings] 

Cytogenetic 

 870.5395

Study type: Micro nucleus assay in mice and rats 	43786501 (1986?)

Acceptable/guideline

Dose range: 0, 154, 200, 260, 338 or 440 ppm (equivalent to 0, 0.597,
0.776, 1.008, 1.311 or 1.706 mg/L) for 6 hrs/day, 5 days/week for 14
days, or 10 exposures. 	The test was positive.

 Micro nucleus (MN) induction was evaluated in bone marrow of rats and
mice and in peripheral blood of mice.

Other Genotoxicity study

870.

Study Type: Rat testicular DNA alkaline elution assay

	43180201 (1994)

Acceptable/non-guideline

Dose range:  0, 75, 150 or 250 ppm (0, 291, 581 or 969 mg/m3) for 6
hr/day over 5 consecutive days	The test was positive.

870.7485

Metabolism and pharmacokinetics	International Agency for Research on
Cancer (IARC) Monographs Vol 41, p198	Rats received a single gavage dose
(preparation of test solution was unspecified) of 24 mg/kg/b.w.
14C-MeBr.  Over a 3-day period, the radioactivity recovered  were as
follows:  carcass (14-17%), expired carbon dioxide (32%), urine (43%),
and feces (less than 3%). 

 During a 6-hour exposure of rats to 4.75-9874 mg/cu.m 14C-MeBr vapor,
approximately 27-50% of the compound inhaled was absorbed.

870.6300

Developmental Neurotoxicity Study	46665001 (2004)

Acceptable/non-guideline

Dose Range: 0, 5, 25, or 50 ppm	Maternal NOAEL = 50 ppm; LOAEL = not
identified

Developmental NOAEL =5 ppm; LOAEL = 25 ppm based on decreased motor
activity on PND21

(*)   A new 90-day inhalation study in rodents is not required for
reregistration of MeBr.  Acceptable rat chronic inhalation toxicity
(MRIDs 41213301, 42418301; reviewed in HED doc. nos. 007017, 007845,
009843 and 14130) and rat 90-day inhalation neurotoxicity (MRIDs
42933901 and 43077401; reviewed in HED doc. no. 010820) studies have
been received.  These studies provide adequate descriptions of systemic
toxicity to rodents from inhalation exposures of intermediate duration.

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