NTP Study Reports
Abstract for TR-452
Toxicology and Carcinogenesis Studies of 2,2-Bis(Bromomethyl)-1,3-Propanediol (FR-1138 ®) (CAS No. 3296-90-0) in F344 Rats and B6C3F1 Mice (Feed Studies)
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Chemical Formula: C5H10Br2 O2
2,2-Bis(bromomethyl)-1,3-propanediol is used as a fire retardant in unsaturated polyester resins, in molded products, and in rigid polyurethane foam. 2,2-Bis(bromomethyl)-1,3-propanediol was chosen for study because it is a widely used flame retardant and little toxicity and carcinogenicity data were available.
Groups of male and female F344/N
rats and B6C3F1 mice were exposed to technical grade 2,2-bis(bromomethyl)-1,3-propanediol
(78.6% pure) in feed for 13 weeks or 2 years. Genetic toxicology
studies were conducted in Salmonella typhimurium, cultured
Chinese hamster ovary cells, mouse bone marrow, and mouse peripheral
blood.
13-WEEK STUDY IN RATS
Groups of 10 male and 10 female
rats were fed diets containing 0, 1,250, 2,500, 5,000, 10,000,
or 20,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol for 13 weeks.
These levels corresponded to approximately 100, 200, 400, 800,
or 1,700 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight
(males) and 100, 200, 400, 800, or 1,600 mg/kg (females). No rats
died during the studies. The final mean body weights and weight
gains of 5,000, 10,000, and 20,000 ppm males and females were
significantly lower than those of the controls. Feed consumption
by exposed animals was lower than that by controls at week 1,
but was generally similar to or slightly higher than that by controls
at week 13. No chemical-related clinical findings were observed.
Chemical-related differences in clinical pathology parameters
included increased urine volumes accompanied by decreased urine
specific gravity and minimally increased protein excretion in
10,000 and 20,000 ppm males. In females, urine parameters were
less affected than males. Water deprivation tests demonstrated
that male and female rats were able to adequately concentrate
their urine in response to decreased water intake. Serum protein
and albumin concentrations in female rats exposed to 2,500 ppm
and higher were slightly lower than those of the controls. Renal
papillary degeneration was present in 5,000 and 10,000 ppm males,
and in 20,000 ppm males and females. Hyperplasia of the urinary
bladder was present in 20,000 ppm males.
13-WEEK STUDY IN MICE
Groups of 10 male and 10 female
mice were fed diets containing 0, 625, 1,250, 2,500, 5,000, or
10,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol for 13 weeks.
These levels corresponded to approximately 100, 200, 500, 1,300,
or 3,000 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight
(males) and 140, 300, 600, 1,200, or 2,900 mg/kg (females). One
control female, two males and one female receiving 625 ppm, one
female receiving 1,250 ppm, one female receiving 2,500 ppm, one
female receiving 5,000 ppm, and three males receiving 10,000 ppm
died during the study. The final mean body weights and body weight
gains of males and females receiving 1,250, 2,500, 5,000, or 10,000
ppm and of females receiving 625 ppm were significantly lower
than those of the controls. Feed consumption by exposed mice was
generally higher than that by controls throughout the study. Clinical
findings included abnormal posture and hypoactivity in 10,000
ppm male and female mice. Blood urea nitrogen concentrations of
5,000 ppm females and 10,000 ppm males and females were greater
than those of controls. Also, urine specific gravity was lower
in 10,000 ppm females. Differences in organ weights generally
followed those in body weights. Papillary necrosis, renal tubule
regeneration, and fibrosis were observed in the kidneys of 2,500
and 5,000 ppm males and 10,000 ppm males and females. Urinary
bladder hyperplasia was observed in 5,000 and 10,000 ppm males
and females.
2-YEAR STUDY IN RATS
Groups of 60 male and 60 female rats received 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol in feed for 104 to 105 weeks. Groups of 70 males and 60 females received 0 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. A stop-exposure group of 70 male rats received 20,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 3 months, after which animals received undosed feed for the remainder of the 2-year study. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 100, 200, or 430 mg/kg body weight for males and 115, 230, or 460 mg/kg for females. Stop-exposure males received an average daily dose of 800 mg/kg. Ten animals from the 0 ppm male group and the 20,000 ppm stop-exposure group were evaluated at 3 months; nine or 10 control animals and five to nine animals from each of the continuous-exposure groups were evaluated at 15 months.
Survival, Body Weights,
Feed Consumption, and Clinical Findings
Survival of 5,000 and 10,000 ppm
continuous-exposure study males and females and 20,000 ppm stop-exposure
males was significantly lower than that of the controls. Mean
body weights of exposed male and female rats receiving 10,000
ppm and stop-exposure males receiving 20,000 ppm were lower than
those of the controls throughout most of the study. In the continuous-exposure
study, feed consumption by exposed rats was generally similar
to that by controls throughout the study. In 20,000 ppm stop-exposure
males, the feed consumption was lower than that by controls. Clinical
findings included skin and/or subcutaneous masses on the face,
tail, and the ventral and dorsal surfaces of exposed rats.
Pathology Findings
In the 2-year continuous and stop-exposure
studies in male rats, exposure to 2,2-bis(bromomethyl)-1,3-propanediol
was associated with neoplastic effects in the skin, mammary gland,
Zymbal's gland, oral cavity, esophagus, forestomach, small and
large intestines, mesothelium, urinary bladder, lung, thyroid
gland, hematopoietic system, and seminal vesicle. Nonneoplastic
effects in the kidney, lung, thyroid gland, seminal vesicle, pancreas,
urinary bladder, and forestomach were also observed. In females,
2-year exposure to 2,2-bis(bromomethyl)-1,3-propanediol was associated
with neoplastic effects in the oral cavity, esophagus, mammary
gland, and thyroid gland. Nonneoplastic effects in the kidney
were also observed. These findings are outlined in the two summary
tables.
2-YEAR STUDY IN MICE
Groups of 60 male and 60 female mice received 0, 312, 625, or 1,250 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 35, 70, or 140 mg/kg (males) and 40, 80, or 170 mg/kg (females). Eight to 10 animals from each group were evaluated at 15 months.
Survival, Body Weights,
Feed Consumption, and Clinical Findings
Survival of 1,250 ppm males and
females was significantly lower than that of the controls. Mean
body weights of exposed male and female mice were similar to controls
throughout the study. Final mean body weights were also generally
similar to those of controls. Feed consumption by exposed male
and female mice was similar to that by controls. Clinical findings
included tissue masses involving the eye in exposed mice.
Pathology Findings
Exposure of male mice to 2,2-bis(bromomethyl)-1,3-propanediol
for 2 years was associated with neoplastic effects in the harderian
gland, lung, and kidney. Exposure of female mice to 2,2-bis(bromomethyl)-1,3-propanediol
was associated with increased incidences of neoplasms of the harderian
gland, lung, and skin. Nonneoplastic effects in the lung were
also observed in exposed females. These findings are outlined
in the two summary tables.
GENETIC TOXICOLOGY
2,2-Bis(bromomethyl)-1,3-propanediol
was mutagenic in Salmonella typhimurium strain TA100 when
tested in the presence of induced 30% hamster liver S9; all other
strain/activation combinations gave negative results. In cultured
Chinese hamster ovary cells, 2,2-bis(bromomethyl)-1,3-propanediol
induced chromosomal aberrations only in the presence of S9; no
induction of sister chromatid exchanges was observed in cultured
Chinese hamster ovary cells after treatment with 2,2-bis(bromomethyl)-1,3-propanediol,
with or without S9. In vivo, 2,2-bis(bromomethyl)-1,3-propanediol
induced significant increases in the frequencies of micronucleated
erythrocytes in male and female mice. Significant increases in
micronuclei were observed in peripheral blood samples from male
and female mice exposed to 2,2-bis(bromomethyl)-1,3-propanediol
for 13 weeks via dosed feed. Results of a bone marrow micronucleus
test in male mice, where 2,2-bis(bromomethyl)-1,3-propanediol
was administered by gavage, were considered to be equivocal due
to inconsistent results obtained in two trials. An additional
bone marrow micronucleus test was performed with male and female
mice and 2,2-bis(bromomethyl)-1,3-propanediol was administered
as a single intraperitoneal injection; results of this test were
positive in females and negative in males.
CONCLUSIONS
Under the conditions of these
2-year feed studies, there was clear evidence of carcinogenic
activity of 2,2-bis-(bromomethyl)-1,3-propanediol (FR-1138)
in male F344/N rats based on increased incidences of neoplasms
of the skin, subcutaneous tissue, mammary gland, Zymbal's gland,
oral cavity, esophagus, forestomach, small and large intestines,
mesothelium, urinary bladder, lung, thyroid gland, and seminal
vesicle, and the increased incidence of mononuclear cell leukemia.
There was clear evidence of
carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol
in female F344/N rats based on increased incidences of neoplasms
of the oral cavity, esophagus, mammary gland, and thyroid gland.
There was clear evidence of
carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol
in male B6C3F1 mice based on increased incidences of neoplasms
of the harderian gland, lung, and kidney.
There was clear evidence of
carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol
in female B6C3F1 mice based on increased incidences of neoplasms
of the harderian gland, lung, and subcutaneous tissue.
Slight increases in the incidences
of neoplasms of the pancreas and kidney in male rats; forestomach
in male mice; and forestomach, mammary gland, and circulatory
system in female mice may have also been related to treatment.
Exposure of male and female rats
to 2,2-bis(bromomethyl)-1,3-propanediol was associated with alveolar/bronchiolar
hyperplasia in the lung (males only); focal atrophy, papillary
degeneration, transitional epithelial hyperplasia (pelvis), and
papillary epithelial hyperplasia in the kidney; follicular cell
hyperplasia in the thyroid gland (males only); hyperplasia in
the seminal vesicle and pancreas (males only); mucosal hyperplasia
in the forestomach (males only); and urinary bladder hyperplasia
(males only). Exposure of mice to 2,2-bis(bromomethyl)-1,3-propanediol
was associated with hyperplasia of the alveolar epithelium in
females.
Synonyms: 2,2-Bis(2-bromomethyl)-1,3-propanediol;
1,3-dibromo-2,2-dihydroxymethylpropane; 1,3-dibromo-2,2-dimethylolpropane;
2,2-dibromomethyl-1,3-propanediol; dibromopentaerythritol; dibromoneopentyl
glycol; pentaerythritol dibromide; pentaerythritol dibromohydrin
Report Date: May 1996
Pathology Tables, Survival and Growth Curves from NTP 2-year Studies
Target Organs & Incidences from 2-year Studies
Web page last updated on March 16, 2009