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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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EXECUTIVE SUMMARY
Blsphenol A (80-05-7) 1s a white, flaky solid at room temperature having
a mild phenolic odor (Sax, 1984). It Is soluble In aqueous alkaline
solution and In many organic solvents, but Is almost Insoluble In water. It
Is produced by the reaction of phenol and acetone In the presence of an acid
catalyst (Thurman, 1982). Current domestic manufacturers are Dow Chemical
In Freeport, TX; General Electric 1n Mt. Vernon, IN; Shell Chemical 1n Deer
Park, TX; and U.S. Chemicals In Haverhlll, OH (SRI, 1986). Union Carbide
has a plant on stand-by 1n Penuelas, Puerto R1co (CMR, 1984). During 1985,
949.253 million pounds of blsphenol A was produced 1n the United States
(USITC, 1986). The most recent Import data available Indicate that 0.154
million pounds of this compound was Imported Into the United States through
the principal U.S. customs districts during 1983 (USITC, 1984). The use
pattern for blsphenol A Is as follows (CMR, 1984): epoxy resins, 4654;
polycarbonate resins, 45X; miscellaneous uses. Including polysulfone resins,
flame retardants, rubber chemicals and exports, 9%.
In the atmosphere, blsphenol A 1s expected to exist almost entirely In
the partlculate phase. The half-life for vapor phase reaction of blsphenol
A with photochemically produced HO radical 1s estimated as 3-4 hours (see
Section 2.1.2.); this reaction Is expected to be slower for partlculate
blsphenol (either free or sorbed). Removal of atmospheric blsphenol by dry
deposition 1s likely, but reaction with ozone Is not expected to be an
Important removal mechanism (U.S. EPA, 1987a). The compound also has poten-
tial for direct photolysis. In water, adsorption to suspended solids and
sediments may be significant. Blsphenol A may photolyze under neutral or
acidic conditions; under basic conditions the potential for photolysis may
1v
-------
be somewhat greater. Chemical hydrolysis, bloaccumulatlon and volatiliza-
tion are not expected to be Important fate processes. Data are Insufficient
for predicting the significance of blodegradatlon In aquatic media. In
soil, blsphenol A Is expected to adsorb strongly to most soils and will have
a low degree of mobility. Chemical hydrolysis and volatilization are not
expected to be Important fate processes In soil.
The U.S. EPA STORET Data Base reports four occurrences of blsphenol A In
whole water samples (U.S. EPA, 1987b). This compound has been Identified 1n
atmospheric fallout In Tokyo, Japan; however, no blsphenol A was detected In
soil samples taken from the same area (Matsumoto and Hanya, 1980). Perti-
nent data regarding exposure to this compound by Ingestlon of food or drink-
Ing water. Inhalation of air, or dermal contact could not be located In the
available literature as cited 1n Appendix A.
Blsphenol A acute toxldty data were available for four freshwater and
three saltwater species of fish and Invertebrates. Toxic concentrations for
these species ranged from 1.1-10.2 mg/i. The most sensitive species was
the mysld, Hysldopsls bahla. with a 96-hour LC5Q of 1.1 mg/l (Soc.
Plastics Ind. Inc., 1985b). Toxic concentrations for two algal species were
1.0-3.10 mg/l.
In the only study regarding the pharmacok1net1cs of blsphenol A found In
the literature, Knaak and Sullivan (1966) described the absorption, metabo-
lism and excretion of an oral dose of -800 mg/kg radlolabeled blsphenol A In
male rats. Estimates of gastrointestinal absorption ranged from 28-60.8%
based on metabolism and excretion data. Excretion was primarily through the
feces and urine. Blsphenol A was excreted In the feces as the free parent
compound, as an unidentified hydroxylated metabolite attributed to mlcroblal
action and probably as a conjugate. Excretion 1n the urine was primarily as
the glucuronlde.
-------
Three subchronlc oral toxldty studies of blsphenol A have been con-
ducted using dogs and rats (U.S. EPA, 1984b,c). The only toxic effect seen
1n beagle dogs fed 9000 ppm blsphenol A 1n the diet for 90 days was an
Increase 1n the group mean liver weight (U.S. EPA, 1984b). Two-generation
blsphenol A feeding studies conducted with Charles River rats were designed
to assess the effects of the compound on the fertility of the FQ
(parental) generation and to Investigate the in utero and toxic effects of
blsphenol A on the F, generation (U.S. EPA, 1984c). The only effect seen
1n both of these studies were decreases In body weight In members of the
FQ generation at 9000 ppm and FI generation at >1000 ppm. In subchronlc
NTP (1982) rat studies with diets containing 250-4000 ppm, reduced body
weight gain was noted at >1000 ppm. Hyaline masses 1n the bladder were
observed 1n all treated groups of males and cecal enlargement was observed
1n all treated groups except low-dose females. In subchronlc NTP (1982)
mice studies with diets containing 5000-25,000 ppm, reduced body weight gain
was noted 1n males at >15,000 ppm and 1n all treated groups of females.
Hultlnucleated giant cells were observed 1n the livers 1n all treated groups
of males.
Two acute Inhalation toxldty studies of blsphenol A conducted by the
U.S. EPA (1986b,c) using F344 rats have Indicated the presence of reversible
nasal lesions associated with the Inhalation of this compound. The signifi-
cance of these nasal lesions 1s currently unknown but are the Impetus for
the Initiation of a 90-day Inhalation toxldty study of blsphenol A (U.S.
EPA, 19865).
The results of a long-term (103-week) feeding study (NTP, 1982) designed
to evaluate the cardnogenlclty of blsphenol A have Indicated that there was
suggestive but not convincing evidence for the cardnogenlclty of this
compound 1n F344 rats or B6C3F1 mice.
v1
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The marginally significant Increase 1n leukemlas 1n male rats, along
with an Increase (not statistically significant) 1n leukemlas In female rats
and a marginally significant Increase In the combined Incidence of lymphomas
and leukemlas 1n male mice, suggests that exposure to blsphenol A may be
associated with Increased cancers of the hematopoletlc system. A statis-
tically significant Increase In Interstitial tumors of the testes 1n rats
was also suggestive of cardnogenesls, but was not considered to be convinc-
ing evidence of a compound-related effect; this lesion normally occurs at a
high Incidence In aging F344 rats. Under these circumstances, the U.S. EPA
has Judged the we1ght-of-ev1dence to be Group D, that 1s, Inadequate to
ascertain the human carcinogenic potential.
Blsphenol A was negative for mutagenldty In S. typhlmuMum (Ong, 1979),
D. melanogaster (Zavadsk11 and Khovanova, 1975) and In dominant lethal tests
(rats) and sperm abnormality tests (mice) (Bond et al., 1980). Occupa-
tional exposure to blsphenol A epoxy resins was not associated with chromo-
somal aberrations or sister chromatld exchange 1n human lymphocytes
(Mltelman et al., 1980).
Developmental tox1c1ty studies of blsphenol A are Inconclusive. Hardln
et al. (1981) reported fetotoxlclty 1n rats at >85 mg/kg/day and a
significant Increase 1n the Incidence of Imperforate anus and hydrocephaly
at 125 mg/kg/day by Intraperltoneal Injections; however, because of the
small size of the treatment group, this study was Inconclusive with respect
to the teratogenlc effects of blsphenol A. In contrast, two studies by NTP
(1985a,b) have Indicated that blsphenol A does not cause malformations 1n
the fetuses of rats and mice after IntragastMc administration of the
compound to the dams. This lack of fetal malformation was evident even at
dose levels of blsphenol A that produced significant maternal toxldty.
-------
In a continuous breeding study conducted by NTP (1985c), exposure of the
F. generation of CD-I mice to 0.5 or 1.0% BPA In the feed over an 18-week
period resulted 1n a significant reduction 1n the number of Utters per
pair, live pups per Utter, and 1n live pup weight. Body weights of F^
mice were not significantly different from controls Indicating normal growth
*
of surviving pups. However, continuous exposure of the F, mice to l.OX
BPA was lethal to 37.5% compared with 6.3, 3.8 and 13.9% lethality In 0,
0.25 and 0.5% BPA-treated F, mice, respectively. Blsphenol A was admin-
istered at 0, 160, 320 or 640 mg/kg/day (CD rats) or at 0, 500, 750, 1000 or
1250 mg/kg/day (CD-I mice) by gastric Intubation on gestatlonal days 6
through 15. Results of this study Indicated dose-related maternal toxldty
(decreased maternal body weight gain) In both mice and rats; fetotoxldty
was observed only 1n mice and morphological alterations were not observed 1n
either species (MorMssey et al., 1987).
Blsphenol A was negative for cardnogenldty 1n a dietary study using
rats and mice, and was assigned to EPA class E. An RfD for subchronlc oral
exposure of 0.6 mg/kg/day or 43 mg/day was derived from a NOAEL of 750 ppm
In the diet (61.9 mg/kg/day) of female rats In a reproductlon-subchronlc
toxldty study (U.S. EPA, 1984d). An RfD for chronic exposure was based on
the LOAEL of 1000 ppm 1n the diet (50 mg/kg/day) for reduced body weight In
rats (NTP, 1982). A toxldty based RQ of 1000 was based on fetotoxldty In
mice (NTP, 1985a).
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 2
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.1.1. Photolysis 5
2.1.2. Reaction with Hydroxyl Radicals 5
2.1.3. Reaction with Ozone 5
2.1.4. Physical Removal Processes 5
2.2. WATER 5
2.2.1. Hydrolysis 5
2.2.2. Photolysis 6
2.3.3. Mlcroblal Degradation 6
2.2.4. B1oconcentrat1on 6
2.2.5. Adsorption 6
2.2.6. Volatilization 7
2.3. SOIL 7
2.3.1. Hydrolysis 7
2.3.2. Adsorption 7
2.3.4. Volatilization 7
2.4. SUMMARY 7
3. EXPOSURE 9
3.1. HATER 9
3.2. FOOD 9
3.3. INHALATION 9
3.4. DERMAL 9
3.5. SUMMARY 10
4. AQUATIC TOXICITY 11
4.1. ACUTE TOXICITY 11
4.2. CHRONIC EFFECTS 11
4.3. PLANT EFFECTS 11
4.4. SUMMARY 11
1x
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TABLE OF CONTENTS (cont.)
5. PHARMACOKINETCS 14
5.1. ABSORPTION 14
5.2. DISTRIBUTION 15
5.3. METABOLISM 15
5.4. EXCRETION 15
5.5. SUMMARY 16
6. EFFECTS 17
6.1. SYSTEMIC TOXICITY 17
6.1.1. Inhalation Exposures 17
6.1.2. Oral Exposures 17
6.1.3. Other Relevant Information 21
6.2. CARCINOGENICITY 23
6.2.1. Inhalation 23
6.2.2. Oral 23
6.2.3. Other Relevant Information 26
6.3. MUTAGENICITY 26
6.4. TERATOGENICITY 26
6.5. OTHER REPRODUCTIVE EFFECTS 28
6.6. SUMMARY 30
7. EXISTING GUIDELINES AND STANDARDS 34
7.1. HUMAN 34
7.2. AQUATIC < 34
8. RISK ASSESSMENT 35
8.1. CARCINOGENICITY 35
8.1.1. Inhalation. . 35
8.1.2. Oral. . . 35
8.1.3. Other Routes 35
8.1.4. Weight of Evidence 35
8.1.5. Quantitative Risk Estimates 35
8.2. SYSTEMIC TOXICITY 35
8.2.1. Inhalation Exposure 35
8.2.2. Oral Exposure 36
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TABLE OF CONTENTS (cont.)
Page
9. REPORTABLE QUANTITIES 40
9.1. BASED ON SYSTEHIC TOXICITY 40
9.2. BASED ON CARCINOGENICITY 44
10. REFERENCES 45
APPENDIX A: LITERATURE SEARCHED 53
APPENDIX B: SUMMARY TABLE FOR BISPHENOL A 56
x1
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LIST OF TABLES
No. Title Page
1-1 Current Domestic Manufacturers of Blsphenol A 3
4-1 Acute Toxldty of Blsphenol A to Aquatic Organisms 12
4-2 Acute Toxlclty of Blsphenol A to Aquatic Plants 13
9-1 Oral Toxlclty Summary for Blsphenol A 41
9-2 Oral Composite Scores for Blsphenol A 42
9-3 Blsphenol A: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 43
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LIST OF ABBREVIATIONS
BCF B1oconcentrat1on factor
BOOT Biological oxygen demand, theoretical
CAS Chemical Abstract Service
COD Chemical oxygen demand
CS Composite score
EC5Q Concentration effective to 50% of recipients
Koc Soil sorptlon coefficient
Kow Octanol/water partition coefficient
LCso Concentration lethal to 50% of recipients
1050 Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEC No-observed-effect concentration
ppm Parts per million
RfD Reference doses
RQ Reportable quantity
RVd Dose-rating value
RVe Effect-rating value
UV Ultraviolet
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Blsphenol A 1s also known as dlphenylolpropane; 4,4'-(l-methylethyl1-
dene)b1spheno1; and 4,4'-1sopropyl1dened1phenol (SANSS* 1987). The struc-
ture, molecular weight, empirical formula and CAS Registry number are as
follows:
Molecular weight: 228.31
Empirical formula: C^Mit0?
CAS Registry number: 80-05-7
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Blsphenol A Is a white, flaky solid at room temperature and has a mild
phenolic odor (Sax, 1984). When heated to decomposition It emits acrid
smoke and Irritating fumes (Sax, 1984). It Is soluble 1n aqueous alkaline
solutions, ethanol and acetone (Ulndholz, 1983). Selected physical prop-
erties are as follows:
Melting point, °C:
Boiling point, °C:
Vapor pressure, m Hg:
Water solubility, mg/l:
Log Kow:
Specific gravity:
Flashpoint, *C:
153
220 (4 mm Hg)
1.4xlO"» (25°C)
(estimated)
34.2 (20°C)
3.32
1.195 (25/25'C)
79.4
Reed, 1978
Reed, 1978
Singh et al., 1984
Singh et al.. 1984
Hansch and Leo, 1985
Reed, 1978
Hawley. 1981
0072d
-1-
08/13/87
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In general, alkylphenols (e.g., blsphenol A) are reactive compounds that
behave like phenol Itself, although alkyl substUuents 1n the o- or
p- position generally preclude further reaction at these sites (Reed, 1978).
Therefore, blsphenol A 1s expected to be susceptible to electrophlllc
substitution at Us vacant ortho positions.
1.3. PRODUCTION DATA
Blsphenol A Is produced by the reaction of phenol and acetone 1n the
presence of an acid catalyst (Thurman, 1982). Current domestic manufac-
turers of this compound are listed In Table 1-1.
During 1985, 949.253 million pounds of blsphenol A was produced 1n the
United States (USITC, 1986). The most recent Importation data available
Indicate that 0.154 million pounds of this compound was Imported Into the
United States through the principal U.S. customs districts during 1983
(USITC, 1984).
1.4. USE DATA
The use pattern for blsphenol A Is as follows (CHR, 1984): epoxy resins,
46X; polycarbonate resins, 45X; miscellaneous uses. Including polysulfone
resins, flame retardants, rubber chemicals and exports, 9%.
1.5. SUMMARY
Blsphenol A (80-05-7) Is a white, flaky solid at room temperature and
has a mild phenolic odor (Sax, 1984). It Is soluble 1n aqueous alkaline
solution and 1n many organic solvents, but 1s almost Insoluble 1n water. It
Is produced by the reaction of phenol and acetone 1n the presence of an acid
catalyst (Thurman, 1982). Current domestic manufacturers are Dow Chemical
In Freeport, TX; General Electric In Mt. Vernon', IN; Shell Chemical In Deer
Park, TX; and U.S.S Chemicals In Haverhlll. OH (SRI, 1986). Union Carbide
has a plant on stand-by 1n Penuelas, PR (CMR, 1984). During 1985, 949.253
0072d -2- 08/13/87
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TABLE 1-1
Current Domestic Manufacturers of Blsphenol Aa
Companyb
Dow Chemical
General Electric
Shell Chemical Co.
U.S.S. Chemicals
Location
Freeport, TX
Mt. Vernon, IN
Deer Park, TX
Haverhlll. OH
Capacity
(millions of pounds per year)
200
220
350
22QC
aSource: SRI, 1986
bUn1on Carbide has a 70 million pounds/year plant on standby at Penuelas,
Puerto Rico (CHR, 1984).
CReported by CHR (1984)
0072d -3- 06/26/87
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million pounds of blsphenol A was produced 1n the United States (USITC,.
1986). The most recent Importation data available Indicate that 0.154
million pounds of this compound was Imported Into the United States through
the principal U.S. customs districts during 1983 (USITC, 1984). The use
pattern for blsphenol A Is as follows (CMR, 1984): epoxy resins, 46X;
polycarbonate resins, 45X; miscellaneous uses, Including polysulfone resins,
flame retardants, rubber chemicals and exports, 9X.
0072d -4- 08/13/87
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based on an estimated vapor pressure of 1.4x10~9 mm Hg at 25°C (Singh
et al., 1984), blsphenol A 1s expected to exist almost entirely 1n the
participate phase In the atmosphere (E1senre1ch et al., 1981).
2.1.1. Photolysis. Blsphenol A In methanol exhibits some absorption of
solar UV light between wavelengths of 290 and 300 nm and no absorption of UV
light at wavelengths >300 nm (Sadtler, 1966). This Information suggests
that blsphenol A has very little potential to undergo direct photolysis In
the atmosphere; however, experimental data on direct photolysis could not be
located 1n the available literature as cited In Appendix A.
2.1.2. Reaction with Hydroxyl Radicals. The estimated rate constant for
the gas phase reaction of blsphenol A with HO radical at 25°C Is 6.0X10'11
cmVmolecule-sec (U.S. EPA, 1987a) or 7xlO~" cmVmolecule-sec (Singh
et al., 1984). Given these rate constants and an atmospheric concentration
of HO radical of 8x10' molecule/cm3 (U.S. EPA, 1987a), the half-life of
vapor phase blsphenol A In the atmosphere will be 3-4 hours. Since
blsphenol A Is expected to be present 1n the atmosphere 1n the partlculate
phase, this reaction will be slower than the gas phase reaction.
2.1.3. Reaction with Ozone. Blsphenol A 1s not susceptible to oxidation
by ozone In the atmosphere (U.S. EPA, 1987a).
2.1.4. Physical Removal Processes. Removal of blsphenol A from the
atmosphere by dry deposition Is likely; however, the rate of this process
cannot be estimated because of the lack of data on deposition velocity.
2.2. WATER
2.2.1. Hydrolysis. Based on the molecular structure of blsphenol A, this
compound 1s expected to be resistant to chemical hydrolysis In the environ-
ment (Lyman et al., 1982).
0072d -5- 08/13/87
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2.2.2. Photolysis. In neutral and acidic methanol solutions, blsphenol A
exhibits some absorption of UV light of wavelengths >290 nm, while 1n a
basic methanol solution blsphenol A exhibits significant absorption of UV
light of wavelengths >290 nm (Sadtler, 1966). These data Indicate that
blsphenol A may photolyze 1n water under neutral or acidic conditions, and
under basic conditions, the potential for photolysis may be somewhat greater.
2.2.3. M1crob1al Degradation. Results of the Japanese HITI test Indicate
that blsphenol A Is resistant to blodegradatlon by activated sludge.
Blsphenol A (100 ppm) Incubated at 25°C In a 30 ppm activated sludge Inocula
for 2 weeks consumed <30% of the oxygen that was predicted from Its BOOT
(Sasaki, 1978). In another screening study, Matsul et al. (1975) found
blsphenol A to be readily degraded by activated sludge; 105 ppm blsphenol A
Incubated In an activated sludge Inocula for 24 hours at 25°C underwent 72%
COO removal. Using standard BOD data, U.S. EPA (1984a) reported oxygen
consumption equivalent to 52% BOOT for blsphenol A 1n 5 days; however,
Munjko and Hegedla (1980) reported that the blodegradatlon rate for
blsphenol A was much lower than phenol.
2.2.4. B1oconcentrat1on. The BCF of blsphenol A 1n carp, Cyprlnus
carplo. was measured to be <100 (Kawasaki, 1980). BCFs of 196 and 84 were
estimated using a log K of 3.32 (Hansch and Leo, 1985), a water solubil-
ity of 34.2 mg/l at 20°C (Singh et al., 1984) and Equations 2-1 and 2-2:
log BCF = 0.76 log KQW - 0.23 (2-1)
log BCF = 2.791 - 0.564 log S (2-2)
These BCF values Indicate that blsphenol A should not bloaccumulate signifi-
cantly In aquatic organisms.
2.2.5. Adsorption. Estimated K values of 630 and 1520 (Section
2.3.2.) Indicate that adsorption of blsphenol A to suspended solids and
sediments In water may be significant.
0072d -6- 06/26/87
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2.2.6. Volatilization. Henry's Law constant for blsphenol A was
estimated to be -10"11 atm-mVmol at 20-25°C based on a vapor pressure
of 1.4xlO~» mm Hg at 25°C and a water solubility of 34.2 mg/i at 20°C
(Singh et al., 1984). This value of Henry's Law constant suggests that
volatilization of blsphenol A from water would be Insignificant (Lyman et
al., 1982).
2.3. SOIL
2.3.1. Hydrolysis. Blsphenol A 1s not expected to undergo chemical
hydrolysis under environmental conditions since 1t contains no hydrolyzable
functional groups (Lyman et al., 1982).
2.3.2. Adsorption. K values of 630 and 1520 were estimated using a
log KQw of 3.32 (Hansch and Leo, 1985), a water solubility of 34.2 mg/l
at 20°C (Singh et al., 1984) and Equations 2-3 and 2-4 (Lyman et al., 1982):
log KQC = -0.55 log S * 3.64 (2-3)
log KQC = 0.544 log KQW * 1.377 (2-4)
These K values suggest that blsphenol A will be sorbed strongly to most
soils and consequently will have a low degree of mobility In soil (Swann et
al., 1983).
2.3.3. Volatilization. Because of Us relatively low vapor pressure
(Singh et al., 1984) and Us tendency to adsorb to soil (see Section
2.3.2.), blsphenol A Is not expected to volatilize significantly from wet or
dry soil surfaces.
2.4. SUMMARY
In the atmosphere, blsphenol A 1s expected to exist almost entirely In
the partlculate phase. The half-life for vapor phase reaction of blsphenol
A with photochemically produced HO radical 1s estimated as 3-4 hours (see
Section 2.1.2.); this reaction Is expected to be slower for partlculate
0072d -r . -7- 08/13/87
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blsphenol (either free or sorbed). Removal of atmospheric blsphenol by dry
deposition Is likely, but reaction with ozone Is not expected to be an
Important removal mechanism (U.S. EPA, 1987a). The compound also has poten-
tial for direct photolysis. In water, adsorption to suspended solids and
sediments may be significant. Blsphenol A may photolyze under neutral or
acidic conditions; under basic conditions the potential for photolysis may
be somewhat greater. Chemical hydrolysis, bloaccumulatlon and volatiliza-
tion are not expected to be Important fate processes. Data are Insufficient
for predicting the significance of blodegradatlon 1n aquatic media. In
soil, blsphenol A 1s expected to adsorb strongly to most soils and will have
a low degree of mobility. Chemical hydrolysis and volatilization are not
expected to be Important fate processes 1n soil.
0072d -8- 06/26/87
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3. EXPOSURE
3.1. WATER
The U.S. EPA STORET Data Base reports four occurrences of blsphenol A In
whole water samples (U.S. EPA, 1987b). The maximum, minimum and mean con-
centrations detected were 9.5, 1.4 and 2.22 mg/l, respectively; however,
caution should be exercised when Interpreting this value since some of the
earlier data In the STORET data base are of questionable quality. Blsphenol
A has been found 1n water samples from Japanese rivers at concentrations
ranging from 0.01-1.9 yg/i. The origin of blsphenol A In these river
waters was mainly Industrial effluents from Industries manufacturing epoxy
and polycarbonate resins (Hatsumoto et al., 1977; Hatsumoto, 1982).
Blsphenol A was also reported 1n the effluent of a chemical Industry at Mt.
Vernon, IN (Shackelford and Keith, 1976).
3.2. FOOD
Pertinent data regarding the detection of blsphenol A In food could not
be located In the available literature as dted In Appendix A.
3.3. INHALATION
Matsumoto and Hanya (1980) detected 0.04-0.2 yg/m'/day of blsphenol
A In atmospheric fallout (both wet and dry deposition) 1n a residential area
of Tokyo, Japan during 1976-78; however, no blsphenol A was detected In soil
samples taken from the same area.
3., 4. DERMAL
Pertinent data regarding dermal exposure to blsphenol A could not be
located In the available literature as cited 1n Appendix A.
0072d -9- 06/26/87
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3.5. SUMMARY
The U.S. EPA STORET Data Base reports four occurrences of blsphenol A In
whole water samples {U.S. EPA, 1987b). This compound has been Identified In
Tokyo, Japan; however, no blsphenol A was detected 1n soil samples taken
from the same area (Hatsumoto and Hanya, 1980). Pertinent data regarding
exposure to this compound by Ingestlon of food or drinking water, Inhalation
of air, or dermal contact could not be located 1n the available literature
as cited In Appendix A.
0072d -10- 06/26/87
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
The available Information concerning toxklty of blsphenol A to fish and
aquatic Invertebrates Is presented 1n Table 4-1. LC5Q values were 3-6
mg/i for three freshwater fish species, the most sensitive of which was
rainbow trout, Salmo galrdnerl. The only freshwater Invertebrate for which
there were data was Daphnla maqna. with 48-hour EC5Q values of 3.9 and
10.2 mg/8. (Soc. Plastics Ind., Inc., 1984, 1985a). LC5Q values for two
marine fishes were 7.5 and 9.4 mg/l (see Table 4-1), which were slightly
higher than those reported for freshwater fishes. The lowest reported toxic
concentration for any species was 1.1 mg/l, a 96-hour LC5Q for Hysldop-
s_1s_ bahla. the only marine Invertebrate for which data were available (Soc.
Plastics Ind. Inc., 1985b).
4.2. CHRONIC EFFECTS
Pertinent data regarding chronic tox1c1ty of blsphenol A to aquatic
organisms could not be located In the available literature as cited In
Appendix A.
4.3. PLANT EFFECTS
Data concerning effects of blsphenol A on two species of algae, one
freshwater and one marine, are presented In Table 4-2. Toxic concentrations
In these studies range from 1.0-3.10 mg/l.
4.4. SUMMARY
Blsphenol A acute toxlclty data were available for four freshwater and
three saltwater species of fish and Invertebrates. Toxic concentrations for
these species ranged from 1.1-10.2 mg/l. The most sensitive species was
the mysld, Hvsldopsls bahla. with a 96-hour LC5Q of 1.1 mg/l (Soc.
Plastics Ind. Inc., 1985b). Toxic concentrations for two algal species were
1.0-3.10 mg/l.
0072d -11- 08/13/87
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TABLE 4-1
Acute Toxlclty of Blsphenol A to Aquatic OrganlsMS
1
1
o
CO
ca
CO
*"'
Species
FISH
Rainbow trout
Sal MO aalrdnerl
EMerald shiner
Notropls athertnoldes
Fathead Minnow
PlMephales proMelas
INVERTEBRATES
Water flea
Daphnla Maona
FISH
Sheepshead Minnow
Cyprlnodon varleaatus
Atlantic sllverslde
Henldla Menldla
INVERTEBRATES
Hysld shrimp
Hvsldopsls bah la
Concentration
(•g/O
3-3. S
4-6
2
4.7
2.29
4.6
2.29
3.9
10.2
6.97
7.5
9.4
<4.8
1.1
0.51
Exposure
Conditions
FRESHWATER
static.. aerated
NR
NR
static. Measured
concentrations
continuous flow.
Measured concen-
trations
static
static. Measured
concentrations
SALTWATER
NR
continuous flow.
Measured concen-
trations.
continuous flow.
Measured concen-
trations ^^
Effect
SPECIES
96 -hour LCso
72-hour LCso
MaxlMUM safe concentration
96-hour LCso
96-hour NOEC
96-hour LCso
96-hour NOEC
48-hour ECso. iMMblllzatlon
48-hour ECKn, tanoblllzatlon
48-hour NOEC
SPECIES
96-hour LCso
96-hour LCso
96-hour NOEC
96-hour LCso
96 -hour NOEC
Reference
Soc. Plastics Ind.. Inc..
Alexander. 1984
Soc. Plastics Ind.. Inc..
1985a
Soc. Plastics Ind.. Inc..
Soc. Plastics Ind.. Inc..
1985a
Soc. Plastics Ind.. Inc..
Soc. Plastics Ind.. Inc..
1985b
Soc. Plastics Ind.. Inc..
1985b
•
1984
1984
1984
= Not'reported
-------
rsj
o.
TABLE 4-2
Acute ToxIcUy of Btsphenol A to Aquatic Plants
Species
.
Green alga
Selenastrua caprlcornutum
Concentration . Exposure
(mg/t) Conditions
FRESHWATER SPECIES
2.5 static
2.73 static. Measured
concentrations
Effect
growth reduction.
96 hours
96-hour ECso.
cell count
Reference
Soc. Plastics
Ind.. Inc.. 1984
Soc. Plastics
Ind., Inc.,
3.10
1.99
96-hour EC5Q,
chlorophyll a
growth Inhibition.
96 hours
1985a
Soc. Plastics
Ind. Inc.. 1985a
Soc. Plastics
Ind. Inc.. 1985a
Green alga
Skeletonena costatun
1.0
1.8
SALTWATER SPECIES
static, measured
concentrations
96-hour EC5Q.
cell count
96-hour ECcQ,
chlorophyll a
Soc. Plastics
Ind.. Inc..
1985b
Soc. Plastics
Ind., Inc..
1985b
OJ
CO
-------
5. PHARHACOKINETICS
5.1. ABSORPTION
Knaak and Sullivan (1966) administered single gavage doses of -800 mg/kg
ring labeled l4C-b1sphenol A to three groups of four young adult male
Carworth Farm rats and collected urine and feces separately for 8 days.
Some of the treated rats were placed 1n an apparatus to collect expired
14COp for 4 hours Immediately after treatment. Radlolabeled C02 was
not Identified 1n the expired air of treated rats. Substantial radio-
activity was excreted through the urine and feces within the first 48 hours
after treatment. Excretion by both routes appeared to be nearly complete by
48 hours. At the end of the 8-day collection period, 28% of the dose of
administered radioactivity was recovered In the urine and 56% In the feces.
These data suggest a minimal estimate of gastrointestinal absorption of 28%.
If, however, as suggested by the Investigators (Section 5.3.), 30% of the
fecal radioactivity or 16.8% of the administered dose represented a conju-
gate, presumably formed following absorption, a more realistic estimate of
gastrointestinal absorption may be -44.8% of the dose. The Investigators
also noted that -35% of the fecal radioactivity, which 1s equivalent to
-19.6% of the administered dose, represented unmetabollzed parent compound
and another 35% (19.6% of the dose) represented a hydroxylate formed by
mlcroblal action In the Intestine. If It 1s assumed that unmetabollzed
material and the hydroxylate represent unabsorbed material, gastrointestinal
absorption may be estimated at -60.8%. Little can be Inferred from these
data regarding the rate of gastrointestinal absorption.
0072d . -14- 08/13/87
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5.2. DISTRIBUTION
Knaak and Sullivan (1966) detected no radioactive residues In the
carcasses or gastrointestinal tracts of male rats 8 days after receiving
single gavage doses of -800 mg/kg ring labeled 14C-b1sphenol A (see
Section 5.1.).
5.3. METABOLISM
Knaak and Sullivan (1966) Identified the metabolites In the urine and
feces1 of male rats treated with single gavage doses of -800 mg/kg ring
labeled l4C-b1sphenol A. Urinary excretion of radioactivity, which
constituted -28X of the administered dose, consisted almost entirely of the
glucuronlde conjugate. Fecal excretion of radioactivity accounted for ~56X
of the administered dose. About 35X of the fecal radioactivity was Iden-
tified as unchanged parent compound. Another 35% was Identified as a
hydroxylatlon product, believed to be the result of m1crob1al metabolism In
the Intestine. The remainder.of the fecal radioactivity was presumed to be
present as a conjugate of blsphenol A.
5.4. EXCRETION
The major excretory pathway In the rat for an oral dose of blsphenol A
appears to be the feces (Knaak and Sullivan, 1966), although It Is unclear
what proportion of an oral dose Is absorbed. Measurement of the excretion
of radioactivity over an 8-day period Indicated that 56X of the administered
dose was excreted In the feces, 28X of the dose was excreted 1n the urine,
and no radioactivity In the form of 14C02 was found In the exhaled air.
Nearly as much excretion occurred during the second 24-hour period as during
the first. Excretion by both routes was essentially complete by 48 hours.
0072d -15- 08/13/87
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5.5. SUMMARY
In the only study regarding the pharmacoklnetlcs of blsphenol A found In
the literature, Knaak and Sullivan (1966) described the absorption, metabo-
lism and excretion of an oral dose of ~800 mg/kg radlolabeled blsphenol A In
male rats. Estimates of gastrointestinal absorption ranged from 28-60.8%
based on metabolism and excretion data. Excretion was primarily through the
feces and urine. Blsphenol A was excreted In the feces as the free parent
compound, as an unidentified hydroxylated metabolite attributed to mlcroblal
action and probably as a conjugate. Excretion 1n the urine was primarily as
the glucuronlde.
0072d -16- 06/26/87
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures. Pertinent data regarding either subchronlc
or chronic Inhalation exposure to blsphenol A could not be located In the
available literature as cited In Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONK — Four male and four female beagle dogs were fed
blsphenol A In the diet at dosage levels of 1000, 3000 and 9000 ppm for 90
days (U.S. EPA, 1984b). Four males and four females were used as controls.
Physical and ophthalmoscoplc examinations, hematologlcal and biochemical
studies, and urlnalysls were conducted during the treatment period and at
sacrifice selected tissues were collected for hlstopathology from the
control and 9000 ppm group. At the end of the treatment period, there were
no gross or microscopic pathological lesions 1n any of the tissues examined
and there were no compound-related changes In any of the other parameters
examined. The only effect considered to be treatment-related was an Increase
In group mean relative liver weight 1n the dogs fed 9000 ppm blsphenol A for
90 days.
A dietary study of the toxlclty and reproductive effects of blsphenol A
was conducted 1n two generations of Charles River CD rats (U.S. EPA, 1984c).
The parent or FQ generation (10 males and 10 females) was fed blsphenol A
In the diet at dosage levels of 1000, 3000 and 9000 ppm for 17 weeks. At
100 days of age, the males and females within the same treatment group were
mated one to one. After weaning, the pups produced by this mating (F,
generation) were started on a 90-day feeding study at the same dosage levels
as the parental generation (I.e., 1000, 3000 and 9000 ppm blsphenol A).
0072d -17- 06/26/87
-------
There were 15 male and 15 female FI rats at each dose level. The rats 1n
the FQ generation were monitored for body weight gain during the course of
the study and their reproductive capacity 1n terms of number of pups per
litter and pup survival was also measured. Parameters measured 1n the F,
generation Included ophthalmoscopy, hematologlcal and urlnalysls studies.
Gross pathological and hlstopathologlcal examinations were also conducted on
a variety of tissues from the control and 9000 ppm treatment groups of the
F, generation. Blsphenol A treatment-related effects seen 1n the FQ
generation were limited to a dose-related decrease 1n mean body weight that
exceeded 10% 1n rats of both sexes at the 9000 ppm dosage level. Food
consumption was similar 1n treated and control groups. There was no effect
on the reproductive capacity of the F_ generation. Similarly, In the F..
generation treatment-related effects associated with blsphenol A .were
limited to reductions 1n body weight gain. Weaning weights of offspring of
3000 and 9000 ppm parents were significantly (p<0.05) less than controls.
Terminal mean group body weights were moderately decreased (>10X) 1n female
rats at >1000 ppm and 1n male rats at X3000 ppm. Food consumption was
decreased In males at 9000 ppm and In all treated groups of females. All
other parameters examined 1n the F, generation rats (I.e., ophthalmoscopy,
hematology and urlnalysls) were unremarkable, and there were no gross or
microscopic lesions 1n any of the organs examined from rats at the 9000 ppm
dosage level. ;
In a similar 2-generat1on oral toxldty study of blsphenol A (U.S. EPA,
(1984c), 10 male and 10 female CD rats (F. generation) were fed 100, 250,
500, 750 and 1000 ppm blsphenol A 1n the diet for 18 weeks. At 100 days of
age, these rats were mated to produce the F. generation. After weaning.
the F, generation (15/sex/concentratlon group) was then fed blsphenol A 1n
0072d -18- 01/14/88
-------
the diet at the same concentrations used for the FQ generation for a
period of 90 days. The FQ generation was monitored for body weight gain
and male and female fertility. Ophthalmoscope examinations and hematologl-
cal and urlnalysls studies were conducted on the rats of the F, generation
during and after the 90-day feeding study had ended. Hlstopathologlcal
examinations were also conducted on various tissues of rats In the F,
generation at the highest dose level (1000 ppm). The results of this study
were similar to the results of the previously described study that used
higher concentrations of blsphenol A In the feed (U.S. EPA, 1984c). The
only effects attributable to blsphenol A treatment were reductions In body
weight gain In members of the FQ and F, generation. FQ males fed a
diet containing 1000 ppm blsphenol A had a slightly (6X) lower body weight
than males In the control group and males 1n the F, generation fed 750 ppm
blsphenol A had a slightly lower body weight gain (~6X) than males In the
control group. Body weight gain of F, males at 1000 ppm, however, was
similar to controls. There were no treatment-related effects on the fertil-
ity of the FQ generation and the results of ophthalmoscoplc examinations
and hematologlcal and urlnalysls examinations on the F, generation
Indicated that there was no effect associated with blsphenol A treatment on
these parameters.
NTP (1982) performed 13-week dietary feeding experiments In groups of 10
male and 10 female F344 rats and the same numbers of B6C3F1 mice. Rats were
fed diets containing 0, 250, 500, 1000, 2000 or 4000 ppm and mice were fed
diets containing 0, 5000, 10,000, 15,000, 20,000 or 25,000 ppm blsphenol A.
Parameters of toxldty evaluated Include general appearance, behavior,
survival, food consumption (rats only), body weight gain and hlstopathologlc
appearance of a large number of organs and tissues. A reduction of body
0072d -19- 08/13/87
-------
weight gain exceeding 10% was observed In male rats at >1000 ppm and In
female rats at 250 ppm and at >1000 ppm, but not at 500 ppm. There were.no
effects on food consumption at any level 1n rats. Hyaline masses were found
1n the bladders of >3/10 male rats 1n all treatment groups, but not 1n
controls. A 60-100% enlargement of the cecum was observed 1n all treated
groups of rats except low-dose females. The Incidence of these alterations
did not appear to occur In a dose-related manner. Both of these pathologic
findings were attributed to treatment with blsphenol A, although microscopic
examination of the walls of the ceca revealed no mucosal lesions or Inflam-
matory changes.
Hale mice at >15,000 ppm and all treated groups of female mice experi-
enced a reduction In body weight gain exceeding 10%. Multlnucleated giant
hepatocytes were observed In all treated groups of male mice, with the Inci-
dence and severity both Increasing In a dose-related fashion. No les.lons
were observed In female mice.
6.1.2.2. CHRONIC — NTP (1982) conducted a chronic feeding study
using B6C3F1 mice that was designed to examine the carclnogenlcHy of
blsphenol A. In this study, male mice were fed blsphenol A 1n the diet for
103 weeks at concentrations of 0, 1000 or 5000 ppm and female mice were fed
dietary blsphenol A concentrations of 0, 5000 or 10,000 ppm. There were 50
male and 50 female mice at each dosage level. At necropsy, a large number
of tissues were examined microscopically and the only significant effect
related to blsphenol A consumption was an Increase In the number of multi-
nucleated giant hepatocytes In male mice at both 1000 and 5000 ppm. Hale
mice at 5000 ppm and female mice at 5000 and 10,000 ppm also had a reduction
1n body weight compared with control animals. There were no effects on food
consumption.
0072d -20- 08/13/87
-------
In this same study .{NTP, 1982), male and female F344 rats (50/sex/dose
level) were also fed 0, 1000 and 2000 ppm blsphenol A In the diet for 103
weeks. The only clinical sign of toxldty associated with blsphenol A
treatment was a decrease 1n body weight for both male and female rats at
1000 ppm and 2000 ppm, which was more apparent 1n the females. Food con-
sumption appeared to be slightly depressed In both sexes of rats after 12
weeks of exposure; treated males ate ~90X as much food as controls and
treated females ate ~70-80X as much food as controls.
6.1.3. Other Relevant Information. In a range finding study (U.S. EPA,
1984d) associated with the 90-day studies of blsphenol A toxldty 1n the CO
rat (U.S. EPA, 1984c) (see Section 6.1.2.), blsphenol A was administered 1n
the diet to CD rats (flve/sex/dose level) at 2000, 4000, 8000 and 12,000 ppm
for 14 days. The rats were monitored for body weight gain, and general
appearance and behavior. At the end of the treatment period, the rats were
sacrificed and necropsled. There were no treatment-related gross patho-
logical lesions, and the only compound-related effect was a dose-related
decrease 1n body weight gain for male rats at the 4000, 8000 and 12,000 ppm
dosage levels.
A similar 14-day dose range finding study was conducted In beagle dogs
(U.S. EPA, 1984e) and this was associated with the 90-day subchronlc toxlc-
Ity study of blsphenol A described previously (U.S. EPA, 1984b). One male
and one female dog/dose level were fed blsphenol A 1n the diet at dosage
levels of 2000, 4000, 8000 and 12,000 ppm. There were no changes 1n the
general appearance or behavior of the treated dogs and there were no
differences In body weights between control and blsphenol A treated dogs.
No pathological lesions were observed at necropsy and 1t was unknown If the
focal lesions of congestion and hemorrhage observed In the gastrointestinal
tract of a number of dogs had any relation to blsphenol A treatment.
0072d -21- 01/14/88
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NTP (1982) conducted 14-day dietary studies 1n rats and mice. Dietary
concentrations In both species ranged from 500-10,000 ppm. There were no
effects on survival. Body weight gain depression 1n rats exceeded 60X In
males at >2500 ppm and exceeded 40% 1n females at >5000 ppm. Frank weight
loss occurred In both sexes of rats at 10,000 ppm. Body weights of treated
mice were similar to controls.
Acute Inhalation toxlclty studies of blsphenol A have been conducted In
rats. Gage (1970) exposed four male rats, 6 hours/day for 5 days to a
saturated atmosphere (concentration not specified). At the end of the
exposure period, blood samples were taken by cardiac puncture and the lungs,
liver, kidneys, spleen and adrenals were examined microscopically. Gage
(1970) reported that there were no toxic signs associated with exposure to
blsphenol A and at necropsy all organs were normal.
Two acute Inhalation toxlclty studies of blsphenol A, one a single
exposure for 6 hours (U.S. EPA, 1986b) and the other a 2-week study (U.S.
EPA, 1986c), have been conducted using the F344 rat. In the single exposure
study, groups of 10 male and 10 female rats were exposed to either 0.0 or
170 mg blsphenol A/m3 for 6 hours. Half of the rats were necropsled the
day after exposure and the other half were sacrificed after a recovery
period of 14 days. Only minor treatment-related effects were found In these
rats. There was a slight decrease 1n body weight gain In male rats exposed
to blsphenol A (170 mg/m3) and male and female rats had microscopic
changes In the nasal cavity Immediately following exposure. Both of these
treatment-related changes, decrease 1n body weight gain and changes In the
nasal cavity, were reversible after the 2-week period and there was no
evidence of systemic toxlclty observed. In the 2-week study, 20 rats/sex/
exposure level were exposed to blsphenol A concentrations of 0, 10, 50 and
0072d -22- 08/13/87
-------
150 mg/m3 for 6 hours/day for 9 total exposures. There was a slight
decrease 1n body weight gain 1n male rats exposed to 150 mg/m3 and micro-
scopic changes 1n the nasal cavities of male and female rats exposed to
either 50 or 150 mg/m3. These treatment-related changes were reversible
after a 29-day recovery period and there was no evidence of systemic
toxlclty.
The appearance of microscopic lesions 1n the nasal cavity after acute
Inhalation exposure to blsphenol A In F344 rats (U.S. EPA, 1986b,c) has
served as an Impetus for the Initiation of a subchronlc 90-day Inhalation
toxldty study of blsphenol A (U.S. EPA, 1986b). Results are not yet
available.
Skin rashes have been reported 1n workers exposed occupatlonally to
blsphenol A. Freeman and Warln (1984) reported a severe rash In a worker
exposed to a wax composed of 15-30% blsphenol A. Allen and Kaldbey (1979)
reported that eight workers exposed occupatlonally to hot epoxy resin fumes
developed photosensltlvlty and that this photosens1t1v1ty was probably due
to an allergic reaction to blsphenol A.
The oral LD5Q values for rats, mice and rabbits are 4040, 2500 and
2230 mg/kg, respectively (Sax, 1984). NTP (1982) determined oral LD5Q
values for rats of 4100 and 3300 mg/kg for males and females and 5200 and
4100 mg/kg for male and female mice, respectively.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent: data regarding the cardnogenldty of
blsphenol A following Inhalation exposure could not be located In the
available literature as cited In Appendix A.
6.2.2. Oral. The National Toxicology Program (NTP, 1982) conducted a
long-term study on the carcinogenic effects of blsphenol A 1n F344 rats and
0072d -23- 08/13/87
-------
B6C3F1 mice. Groups of 50 male and 50 female rats were fed either 1000 or
2000 ppm blsphenol A 1n the diet for 103 weeks. Fifty male mice were fed
either 1000 or 5000 ppm blsphenol A 1n the diet for 103 weeks, while 50
female B6C3F1 mice were fed either 5000 or 10,000 ppm blsphenol A 1n the
diet for 103 weeks. Tissues examined microscopically following necropsy
were lymph nodes, skin, mammary gland, salivary gland, thigh muscle, sciatic
nerve, bone marrow, costochondral junction, thymus, larynx, trachea, lungs
and bronchi, heart, thyroid, parathyroid, esophagus, stomach, duodenum,
jejunum, 1leum, colon, liver, gallbladder (mice), pancreas, spleen, kidneys,
adrenals, bladder, seminal veslcles/prostate/testes, ovaries/uterus, nasal
cavity, brain, pituitary, eyes and spinal cord.
Mean body weights of rats of either sex and of high- and low-dose female
mice and high-dose male mice were lower than those of the controls. Since
feed consumption by dosed female rats was only 70-80% that of the controls
throughout most of the study, reduced mean body weight gain 1n these groups
may have been due to reduced feed consumption. The compound-related weight
gain depression In rats and mice Indicates that the high doses used 1n this
study approximated maximum tolerated dose levels.
Leukemlas 1n male rats occurred at an Incidence that showed a statis-
tically significant positive association with the dose of blsphenol A.
Although the Incidence 1n high-dose male rats appeared to be statistically
significant (p=0.030), H did not meet the Bonferronl Inequality criterion
of p=0.025 for comparing the dosed groups with a common control. The
Incidence of leukemlas was also Increased 1n female rats, but the observed
Increases were not statistically significant. Life table analyses, adjusted
for Intercurrent mortality, were also carried out for the leukemia data. It
was found that, for male rats, neither the high-dose effect nor the
dose-response trend was statistically significant (p=0.141 and p=0.074).
0072d -24- 01/14/88
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The female rats likewise showed no significant effects. The Increased
Incidence of leukemia In rats was therefore not considered to be convincing
evidence of cardnogenldty 1n rats.
Interstitial-cell tumors In the testes 1n the low- and high-dose rats
occurred at Incidences significantly higher (p=0.001 and p=0.003), than
those In the controls; however, since this type of lesion normally occurs at
a high Incidence In aging F344 rats (Goodman et al., 1979), the Increased
Incidence 1s not clearly compound related.
In male mice, the combined Incidence of leukemlas and lymphomas appeared
to be statistically significant (p=0.028) In the low-dose group, but did not
meet the Bonferronl Inequality criterion of p=0.025. In the high-dose
group, the combined Incidence of leukemlas and lymphomas was Increased
(relative to controls) but was not statistically significant. Since the
combined Incidence of leukemlas and lymphomas was not significant 1n the
high-dose group and did not meet the Bonferronl Inequality criterion 1n the
low-dose group, 1t was not considered convincing evidence of cardnogenldty
1n male mice.
Multlnucleated giant hepatocytes observed 1n dosed male mice In sub-
chronic studies were Increased 1n dosed male mice 1n the chronic studies
(control, 1/49; low-dose, 41/49; and high-dose 41/50); the Incidence of
hepatocellular carcinomas or adenomas was not any higher 1n dosed male mice
than In the controls.
When the marginally significant Increase of leukemlas 1n male rats and
the combined Incidence of lymphomas and leukemlas In male mice are consid-
ered along with the Increase 1n leukemia Incidence (not significant) 1n
female rats, the evidence Is suggestive of a carcinogenic effect on the
hematopoletlc system.
0072d -25- 01/14/88
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6.2.3. Other Relevant Information. Other relevant Information regarding
the cardnogenldty of blsphenol A could not be located 1n the available
literature as dted 1n Appendix A.
6.3. MUTAGENICITY
Results of mutagenldty testing with blsphenol A have been negative.
Blsphenol A was not mutagenlc to Salmonella typhlmurlum strains TA1535,
TA1537, TA98 and TA100 either with or without metabolic activation (Ong,
1979) and blsphenol A had no mutagenlc effect on the somatic cells of
Drosophlla melanoqaster (Zavadskll and Khovanova, 1975). In an abstract,
Bond et al. (1985) reported that dally l.p. Injections of 85 mg/kg for 5
days did not Increase the Incidence of dominant lethals In male Sprague-
Dawley rats or sperm abnormalities 1n C3H/He mice. Mltelman et al. (1980)
determined that occupational exposure to low and high molecular weight
blsphenol A epoxy resins had no effect on chromosomal aberrations and sister
chromatld exchanges 1n lymphocytes.
6.4. TERATOGENICITY
A preliminary study of the teratogenlclty of blsphenol A was conducted
by Hardln et al. (1981) and Bond et al. (1980) 1n groups of 10-15 mated
Sprague-Dawley rats. Blsphenol A was administered to these rats by 1ntra-
perltoneal Injection at dose levels of 0, 85 or 125 mg/kg on days 1-15 of
gestation. The dams were killed on day 21 and a hlstopathologlc examination
was conducted on the brain, heart, lungs, liver, spleen, kidneys, adrenals
and ovaries. The Individual fetuses were examined for externally visible
malformations and crown-rump length was measured. Both dose levels of
blsphenol A caused a significant reduction In the number of live fetuses per
Utter and It was concluded that blsphenol A significantly Interfered with
establishment of pregnancy. There were also dose-related reductions of
0072d -26- 01/14/88
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fetal body weight and crown-rump length. At the 125 nig/kg dose level, the
lungs of the dams showed hlstocytosls and Intra-alveolar plgmented macro-
phages; the fetuses at this dose level had a significant Incidence of Imper-
forate anus and hydrocephaly. It was not possible, however, to conclude 1f
there was a definite teratogenlc effect of blsphenol A because of the small
size of the treatment groups (I.e., three pregnant females at the 125 mg/kg
dose level and four pregnant females at the 85 mg/kg dose level). Further-
more Intraperltoneal administration may not adequately represent results
anticipated by natural routes of exposure such as oral or Inhalation.
Evidence that blsphenol A does not cause malformations 1n the fetuses of
rats and mice 1s provided by two studies (NTP, 1985a,b). In one study (NTP,
1985a), mated CD-I mice were administered blsphenol A In corn oil by gavage
on days 6-15 of gestation. The dose levels of blsphenol A used and the
number of pregnant mice at each dose level (1n parenthesis) were 0 mg/kg/day
(vehicle control) (26), 500 mg/kg/day (23), 750 mg/kg/day (21), 1000
mg/kg/day (23) and 1250 mg/kg/day (21). The mice were sacrificed on day 17
and blsphenol A-treated mice exhibited clinical signs of toxldty Including
arched back, lethargy, plloerectlon, rough coat, vaginal bleeding, alopecia,
weight loss and wheezing. Maternal mortality was apparent at all dose
levels and ranged from 7.IX at the 500 mg/kg/day level to 18.2X at the 1250
mg/kg/day level. There were no deaths 1n the vehicle control group.
Maternal liver weight was significantly elevated at the 500, 750 and 1000
mg/kg/day levels, and at the highest dose level (1250 mg/kg/day) there was a
significant decrease 1n maternal body weight and gravid uterine weight.
Blsphenol A at the highest dose level (1250 mg/kg/day) significantly
Increased the percent of resorbed and dead Implants but did not cause a
significant Increase 1n the Incidence of malformations at any dose level.
0072d -27- 01/14/88
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In a similar study using CD rats, blsphenol A was administered orally on
days 6-15 of gestation and the rats were sacrificed on day 20 (NTP, 1985b).
The dose levels of blsphenol A used and the number of rats at each dose
level (In parenthesis) were 0.0 mg/kg/day (23), 160 mg/kg/day (26), 320
mg/kg/day (vehicle control) (24), 640 mg/kg/day (29) and 1280 mg/kg/day
(18). In the highest dose group (1280 mg/kg/day), 26% of dams died, but
there were no dose-related deaths observed at the other dose levels. Signs
of toxldty, which Included plloerectlon, weight loss, lethargy, rough coat
and alopecia, occurred 1n the blsphenol A-treated dams. Maternal body
weight gain was significantly reduced at <640 mg/kg/day. Data from the 1280
mg/kg/day group were not Included 1n the analysis of maternal body weight or
fetal parameters because of the high mortality at that dosage level (which
also occurred 1n one of two replicates of this experiment). Blsphenol A
treatment at dose levels of 0, 160, 320 or 640 mg/kg/day had no effect on
the percent of resorptlons, dead fetuses or dead Implants/Utter, and bls-
phenol A had no effect on the Incidence of Utters with malformed fetuses.
When data from the highest dose of blsphenol A (1280 mg/kg/day) were con-
sidered, only a marginal Increase In fetotoxldty (percent of dead Implants)
and no Increase In the Incidence of malformations were observed despite the
high Incidence of maternal mortality (26X) observed at this dosage. NTP
(1985b) concluded that blsphenol A does not represent a selective risk to
the fetus. ' ;
6.5. OTHER REPRODUCTIVE EFFECTS
Continuous exposure of female CD-I mice to blsphenol A for 2 weeks by
means of a subcutaneous Implant containing 100 mg of the compound caused an
Increase 1n the weight of the reproductive tract (NTP, 1984).
0072d -28- 01/14/88
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Using a continuous breeding protocol, NTP (1985c) evaluated the repro-
duction and fertility effects of blsphenol A administered In the feed of
CD-I mice. Twenty animals/sex/dose were fed 0.25, 0.5 and 1.0% blsphenol A
for 7 days before pairing, for 98 days of cohabitation and for 21 days after
separation. Under the conditions of this reproductive toxlclty study,
exposure of the F. generation of mice to 0.5 or 1.0% BPA 1n the feed over
an 18-week period resulted In a significant reduction 1n the number of
litters per pair, live pups per Utter, and In live pup weight, and In the
1.0% BPA group only, a slight but statistically significant decrease 1n the
proportion of pups born alive when compared with controls. Since F_
maternal postpartum body weights tended to decrease at doses of 0.5% BPA,
and were significantly less than controls 1n the 1.0% BPA group, the
observed toxldty to the conceptus may be all or In part due to generalized
maternal toxldty. Body weights of F. mice were not significantly dif-
ferent from controls at 21 days of age or at 74±10 days of age. Indicating
normal growth of pups surviving to the lactatloal and postweanlng periods.
However, continuous exposue of the F, generation mice to 1.0% BPA was
lethal to 37.5% of a sample of mice, compared with 6.3, 3.8 and 13.9%
lethality observed 1n samples of 0, 0.25 and 0.5% BPA-treated FI mice,
respectively. A crossover mating trial with control and 1.0% BPA FQ pairs
revealed no significant effect of 1.0% BPA on mating and fertility, but a
significant reduction 1n the number of live pups per Utter 1n both the 1.0%
BPA males x Control females and the Control males x 1.0% BPA female groups
compared with controls, with Utters from pairs with treated dams more
severely affected. At necropsy, body weights for treated FQ females were
significantly below the combined control group, and both male and female
treated (1.0% BPA) FQ mice exhibited significantly Increased adjusted
0072d -29- 01/14/88
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liver and kidney weight and hlstopathologlc evidence of treatment-related
hepatic and renal toxldty. Treated FQ males also had significantly
reduced adjusted seminal vesicle weight and significantly reduced sperm
motlllty, but no evidence of pathological lesions of the tissues of the
reproductive system. No significant difference was observed 1n the repro-
ductive performance of F, breeding pairs exposed to 0.25, 0.5 or 1.0% BPA
compared with control F, breeding pairs. However, at necropsy, adjusted
liver and kidney/adrenal weight of BPA-treated F, male and female mice
were significantly higher than control mice, and both organs exhibited an
Increase 1n treatment-related lesions. Treated F, male mice also
exhibited significantly reduced adjusted weight of the reproductive organs
at all three dose levels Indicating BPA toxlclty, although there was no
hlstopathologlc evidence of tissue lesions. Thus, BPA was a reproductive
toxicant that caused a reduction 1n the number of live pups born 1n the F_
generation, and reduced sperm motlllty and weight of some male reproductive
organs 1n both the F_ and F, generation, and reduced postnatal survival
of the FI generation. These effects were accompanied by significant
hepatic and renal toxlclty 1n the parental F. and F, animals. It 1s
possible, therefore, that some or all of the adverse effects on reproductive
performance observed 1n the present study may be secondary to the general-
ized toxlclty of BPA.
No effects on reproduction were observed 1n Charles River rats 1n sub-
chronic 2-generatlon dietary studies conducted with dietary levels ranging
from 100-9000 ppm (U.S. EPA, 1984c).
6.6. SUMMARY
Three subchronlc oral toxlclty studies (dogs and rats) of blsphenol A
have been conducted (U.S. EPA, 1984b,c). The only toxic effect seen 1n
0072d -30- 01/14/88
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beagle dogs fed 9000 ppm blsphenol A 1n the diet for 90 days was an Increase
1n the group mean liver weight (U.S. EPA, 1984b). Two-generation blsphenol
A feeding studies conducted using Charles River rats were designed to assess
the effects of the compound on the fertility of the FQ (parental) genera-
tion and to Investigate the in utero and toxic effects of blsphenol A on the
F, generation (U.S. EPA, 1984c). The only effect seen In both of these
studies were decreases In body weight 1n members of the F_ generation at
9000 ppm and F, generation at >1000 ppm. In subchronlc rat studies (NTP,
1982), diets containing 250-4000 ppm caused reduced body weight gain at
>1000 ppm. Hyaline masses In the bladder were observed 1n all treated
groups of males and cecal enlargement was observed In all treated groups
except low-dose females. In subchronlc NTP (1982) studies using mice with
diets containing 5000-25,000 ppm, reduced body weight gain was noted In
males at >15,000 ppm and 1n all treated groups of females. Hultlnucleated
gHant cells were observed 1n the livers 1n all treated groups of males.
Two acute Inhalation toxldty studies of blsphenol A conducted by the
U.S. EPA (1986b,c) using F344 rats have Indicated the presence of reversible
nasal lesions associated with the Inhalation of this compound. The signifi-
cance of these nasal lesions 1s currently unknown but are the Impetus for
the Initiation of a 90-day Inhalation toxldty study of blsphenol A (U.S.
EPA, 19865).
The results of a long-term (103-week) feeding study (NTP, 1982) designed
to evaluate the carclnogenlcUy of blsphenol A have Indicated that there was
no convincing evidence for the cardnogen1c1ty of this compound 1n F344 rats
or B6C3F1 mice; however, the evidence was suggestive of carclnogenesls of
the hematopoletlc system. A statistically significant Increase 1n Inter-
stitial cell tumors of the rat testes was also suggestive of carclnogenesls.
0072d -31- 01/14/88
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MuH1 nucleated .giant hepatocytes were observed In both treated groups of
male mice (5000 and 10,000 ppm) and reduced body weights were observed In
both groups of female mice (5000 and 10,000 ppm). Reduced body weights were
observed 1n both treated groups of male and female rats (1000 and 2000 ppm).
Blsphenol A was negative for mutagenldty 1n S. typhlmurlum (Ong, 1979),
|). melanoqaster (Zavadskll and Khovanova, 1975) and 1n dominant lethal tests
using rats and sperm abnormality tests using mice (Bond et al., 1980).
Occupational exposure to blsphenol A epoxy resins was not associated with
chromosomal aberrations or sister chromatld exchange 1n human lymphocytes
(MHelman et al., 1980).
Developmental toxlclty studies of blsphenol A are Inconclusive. Hardln
et al. (1981) reported fetotoxiclty at >85 mg/kg/day and a significant
Increase In the Incidence of Imperforate anus and hydrocephaly at 125
mg/kg/day by 1ntraper1toneal Injections; however, because of the small size
of the treatment group, this study was Inconclusive with respect to the
teratogenlc effects of blsphenol A. In contrast, two studies by NTP
(1985a,b) have Indicated that blsphenol A does not cause malformations 1n
the fetuses of rats and mice after IntragastMc administration of the
compound to the dams. This lack of fetal malformation was evident even at
dose levels of blsphenol A that produced significant maternal toxlclty.
In a continuous breeding study conducted by NTP (1985c), exposure of the
FQ generation of CD-I mice to 0.5 or l.OX BPA 1n the feed over an 18-week
period resulted 1n a significant reduction In the number of Utters per
pair, live pups per Utter, and In live pup weight. Body weights of F,
mice were not significantly different from controls Indicating normal growth
of surviving pups. However, continuous exposure of the F, mice to 1.0%
BPA was lethal to 37.5% compared with 6.3, 3.8 and 13.9% lethality In 0,
0072d -32- 01/14/88
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0.25 and 0.554 BPA-treated F, mice, respectively. Blsphenol A was admin-
istered at 0, 160, 320 or 640 mg/kg/day (CD rats) or at 0, 500, 750, 1000 or
1250 mg/kg/day (CD-I mice) by gastric Intubation on gestatlonal days 6
through 15. In rats, maternal weight gain during gestation was signifi-
cantly reduced at all BPA doses. Gravid uterine weight and average fetal
body weight per Utter were not affected by BPA. No Increase 1n percentage
of resorptlons per litter or percentage of fetuses malformed per litter was
detected. In mice, maternal mortality occurred at all BPA doses, reaching
18% at the high dose, which also produced a significant decrease In maternal
weight gain during gestation. Reductions 1n gravid uterine weight and
average fetal body weight per litter were observed with the high dose.
Relative maternal liver weight was Increased at doses of BPA. There was a
significant Increase 1n the percentage of resorptlons per litter with the
high dose; morphological alterations were unaffected. Thus, BPA treatment
at maternally toxic dose levels during organogenesls produced fetal toxIcHy
1n mice but not 1n rats and did not alter fetal morphologic development In
either species (MorMssey et al., 1987).
0072d -33- 01/14/88
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
Pertinent guidelines and standards, Including EPA ambient water and air
quality criteria, drinking water standards, FAO/HHO ADIs, EPA or FDA toler-
ances for raw agricultural commodities or foods, and ACGIH, NIOSH or OSHA
occupational exposure limits could not be located 1n the available litera-
ture as cited 1n Appendix A.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of blsphenol A could not be located In the available literature
as cited 1n Appendix A.
0072d -34- 01/14/88
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenldty of
blsphenol A after Inhalation exposure could not be located In the available
literature as cited In Appendix A.
8.1.2. Oral. The results of a long-term (103-week) feeding study (NTP,
1982) designed to evaluate the cardnogenldty of blsphenol A have Indicated
that there 1s no convincing evidence for the cardnogenldty of this
compound 1n F344 rats or B6C3F1 mice.
8,1.3. Other Routes. Pertinent data regarding the cardnogenldty of
blsphenol A after exposure by routes other than the oral or Inhalation
routes of exposure could not be located 1n the available literature as cited
1n Appendix A.
8.1.4. Height of Evidence. Because blsphenol A has suggestive but not
convincing evidence of cardnogenldty In two species of animals (I.e., F344
rats and B6C3F1 mice) In an adequate long-term feeding study (NTP, 1982),
and In the absence of data regarding Us cardnogenldty 1n humans, It Is
assigned to EPA Group D, Inadequate evidence to assess carcinogenic activity
1n humans.
8.1.5. Quantitative Risk Estimates. There 1s no convincing evidence that
blsphenol A 1s a carcinogen based on the results of a long-term feeding
study using rats and mice (NTP, 1982). It Is, therefore, not appropriate to
derive a q * for blsphenol A for exposure either by the Inhalation or the
oral routes.
8.,2. SYSTEHIC TOXICITY
8.2.1. Inhalation Exposure. Pertinent data regarding the systemic
toxldty of blsphenol A following either subchronlc or chronic Inhalation
<
0072d -35- 01/14/88
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exposure could not be located In the available literature as cited In
Appendix A; hence, derivation of RfDs for Inhalation exposure to blsphenol A
1s not possible.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — Subchronlc oral
studies have been performed using dogs (U.S. EPA, 1984a), rats (U.S. EPA,
1984c; NTP, 1982) and mice (NTP, 1982). The only effect In dogs was
elevated relative liver weights without hlstopathologlc alteration at 9000
ppm of the diet (the highest level tested) but not at 3000 ppm (the next
highest level tested). In the absence of hlstopathologlc alteration, the
elevated liver weights observed at 9000 ppm are not considered adverse and
this dietary concentration constitutes a NOAEL In dogs. Based on food
consumption and body weight data provided by the Investigators, this dietary
concentration corresponds to a dosage of 259 mg/kg/day 1n the males and 291
mg/kg/day 1n the females.
In the subchronlc study, dietary levels of 5000, 10,000, 15,000, 20,000
and 25,000 ppm were fed to mice for 13 weeks (NTP, 1982). Multlnucleated
giant hepatocytes were observed In all treated groups of males. Males at
>15,000 ppm and all treated groups of females had reductions 1n rate of body
weight gain of >10X compared with controls. In mice, the lowest dietary
level tested, 5000 ppm, represents a LOAEL associated with reduced rate of
body weight gain 1n the females. The biological significance, 1f any, asso-
ciated with the multlnucleated giant hepatocytes 1n the males 1s unclear.
Multlnucleated giant hepatocytes were observed In the livers of male mice 1n
the chronic portion of this study, but the Incidence of Hver tumors In male
mice was not significantly Increased and there appeared to be no effect on
longevity. The dietary level of 5000 ppm Is equivalent to a dosage of 650
mg/kg/day, assuming a food factor for mice of 0.13 (U.S. EPA, 1985).
0072d -36- 01/14/88
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Subchronlc rat studies Include two dietary reproduction and 90-day
studies at levels of 1000, 3000 and 9000 ppm, and 250, 500, 750 and 1000 ppm
(U.S. EPA, 1984c) and a 13-week dietary study at 250, 500, 1000, 2000 and
4000 ppm (NTP, 1982). The effect most consistently observed In these
studies 1s depression of body weight gain. In the NTP (1982) experiment,
the rate of body weight gain was depressed >10% In both sexes of rats at the
1000 ppm dietary level. Food consumption was not affected. In the U.S. EPA
(1984c) study, a depression of mean body weights was observed 1n the
parental (FQ) generation at 9000 ppm but not at 1000 or 3000 ppm. Group
mean body weights of F, females were reduced >10X, however, at 1000 ppm.
In the U.S. EPA (1984c) study at lower dosage levels, a slight depression
(~6X) was observed 1n group mean body weights of FQ males at 1000 ppm and
1n F, males at 750 ppm but not at 1000 ppm. It 1s doubtful that a depres-
sion of mean group body weights <10% constitutes a genuinely adverse effect.
When data from all the subchronlc studies 1n rats are considered collec-
tively, 1t appears that the dietary concentration of 1000 ppm In the rat 1s
a LOAEL and 750 ppm 1s a NOAEL for reduced body weights or reduced rate of
body weight gain, a potentially adverse effect.
The NTP (1982) study also observed hyaline masses In the urinary
bladders of male rats 1n all treated groups and cecal enlargement In all
treated groups of males and 1n females 1n all but the lowest group. The
Investigators reported no hlstopathologlc alteration of the bladder,
however, and stated that there were no Inflammatory or other mucosal
alterations of the wall of the cecum. Furthermore, In the chronic rat study
(NTP, 1982), although grossly observed necropsy findings were not reported,
there were no significant lesions In the wall of the urinary bladder or 1n
the cecum at dietary levels of 1000 or 2000 ppm and survival In treated rats
0072d -37- 01/14/88
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was comparable with control rats. The observation of hyaline masses 1n the
urinary bladder and cecal enlargement, therefore, although apparently
compound-related, may not represent adverse effects. The biological
significance of these observations 1n rats to human health, however, 1s
unclear. The dietary level of 1000 ppm, therefore, 1s considered a
subchronlc LOAEL associated with reduced body weights and the next lower
dietary level, 750 ppm In the U.S. EPA (1984c) rat study Is considered a
NOAEL.
An RfD for subchronlc oral exposure to blsphenol A can be derived from
the NOAEL of 750 ppm In the U.S. EPA (1984c) study. Based on food consump-
tion data for F, rats provided by U.S. EPA (1984c), 750 ppm corresponds to
dosages of 55.0 mg/kg/day In the males and 61.9 mg/kg/day 1n the females.
Application of an uncertainty factor of 100, 10 to exptrapolate from rats to
humans and 10 to protect unusually sensitive humans, to the NOAEL 1n female
rats of 61.9 mg/kg/day (the higher NOAEL) results In an RfD of 0.6 mg/kg/day
or 43 mg/day for a 70 kg human. This RfD may not protect against the
development of multlnucleated giant cells 1n the liver, an effect of unknown
biological significance.
8.2.2.2. CHRONIC EXPOSURES — Chronic oral toxlclty data for bls-
phenol A consist of the 103-week NTP (1982) dietary studies using rats at
1000 and 2000 ppm, male mice at 1000 and 5000 ppm, and female mice at 5000
and 10,000 ppm. Adverse effects reported In rats were restricted to reduced
body weights 1n both sexes at :both dietary levels. Food consumption was
also reduced, -10% 1n males and 20-30% 1n females. Reduced body weights
were also observed 1n mice, In males at.5000 ppm and 1n females at 5000 and
10,000 ppm. Food consumption was comparable between treated groups and
controls. Multlnucleated giant hepatocytes were also observed In both
treated groups of male mice.
0072d -38- 01/14/88
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Interpretation of the biological significance of the reduced body
weights observed 1n treated rats 1s complicated by the observation that food
consumption was also reduced. Examination of the growth curves shows that
the effects on body weight became apparent by the 5th week of exposure and
persisted throughout the experiment. The reduction 1n food consumption, on
the other hand, did not become apparent until the 12th week of treatment.
Reduced rate of body weight gain, therefore, appears to be a potentially
adverse effect that Is directly due to Ingestlon of blsphenol A. The 1000
ppm dietary concentration, corresponding to a dosage of 50 mg/kg/day,
assuming a food factor for rats of 0.05, 1s considered a LOAEL 1n rats for
this effect.
In mice, the only effect observed at 1000 ppm was the presence of mutll-
nucleated giant hepatocytes. As discussed 1n Section 8.2.2.1., this effect
does not appear to be adverse and this level 1s considered a NOAEL In mice.
Assuming a food factor for mice of 0.13, this dietary concentration corre-
sponds to a dosage of 130 mg/kg/day.
Because the LOAEL of 50 mg/kg/day 1n rats Is less than the NOAEL of 130
mg/kg/day In mice, the NOAEL 1n mice cannot be chosen as a basis for the
RfD. The LOAEL of 50 mg/kg/day 1n rats, the lowest dosage used In either
species In the chronic studies, Is chosen as the basis for a chronic oral
RfO. Because the chronic oral RfD 1s based on a LOAEL and not a NOAEL the
transformed animal dose must be divided by an uncertainty factor of 1000, 10
for Interspecles extrapolation, 10 to protect the most sensitive Individuals
and 10 to estimate a NOAEL from a LOAEL. The chronic oral RfD Is therefore
0.05 mg/kg/day and multiplication of this value by 70 kg (the reference
human body weight) gives an RfD of 3.5 mg/day. The chronic study used more
than one species and more than adequate number of animals, however, because
of the free standing LOAEL the confidence In the RFD 1s medium.
0072d -39- 01/14/88
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxldty of blsphenol A has been discussed 1n Chapter 6 and the data
pertinent to toxldty-based CSs are summarized 1n Table 9-1. Table 9-1 does
not contain data from two reproductive subchronlc oral toxldty rat studies
(U.S. EPA, 1984c) because there are adequate chronic toxldty data available
from the NTP (1982) study regarding the critical effect, reduction 1n body
weights. When reduced body weights were observed In males and females of
the same species at the same dietary level, only data from the females were
entered, because their lower body weight would result 1n the higher RV .
CSs for these effects are calculated and presented 1n Table 9-2. The most
severe effect associated with chronic exposure to blsphenol A was signs of
fetotoxlclty observed 1n the teratogenldty study of blsphenol A (NTP,
1985a). This effect occurred at a human equivalent dose of 94.2 mg/kg/day.
Multiplication of this dose by 70 kg gives a MED of 6594 mg/day; the loga-
rithm of this MED 1s 3.8, resulting 1n an RV, of 1. The RVg associated
with this effect (fetotoxlclty) Is 8 and multiplication of this RV by the
RV. gives a CS of 8, which 1s associated with an RQ of 1000.
The second most severe effect associated with chronic administration of
blsphenol A 1s a reduction 1n body weight 1n the F344 rat, which occurred at
a human equivalent dose of 7.1 mg/kg/day or 497 mg/day.
The chronic toxldty RQ 1s therefore obtained from the blsphenol A
teratogenldty study conducted by NTP (1985a). The CS calculated from the
effect In this study (8) was the highest CS and corresponds to an RQ of
1000. The effects seen In the cardnogenldty study of blsphenol A (NTP,
1982) also yielded an RQ of 1000, but the CS In this case was 6. The RQ
associated with fetotoxlclty Is presented 1n Table 9-3.
0072d -40- 01/14/88
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o
o
ro
TABLE 9-1
Oral Toxlclty Suanary for Blsphenol A
Species/
Strain
Dog/
beagle
House/
B6C3F1
House/
B6C3F1
House/
B6C3F1
Rat/F344
House/
CD-I
Average
Sex/ Body
Nuaber Height
(kg)
F/4 8.4b
H/50 0.035«
H/50 0.035d
F/50 0.025e
F/50 0.200*
F/21 0.030'
Purity/
Vehicle
NR/dlet
NR/dlet
NR/dlet
NR/dlet
NR/dlet
95V
corn oil
Transformed
Exposure Anlaal Dose
(ag/kg/day)
9000 ppa for 225C
90 days
1000 ppa for 130*
103 weeks
5000 ppa for 650<>
103 weeks
5000 ppa for 650C
103 weeks
1000 ppa for 50C
103 weeks
1250 ag/kg/day 1250
on ges tat tonal
days 6-15
Equivalent
Human Dosea Response
(ag/kg/day)
11. 111 Increase In aean relative
liver weight
10.3 Increase In aultlnucleated
giant hepatocytes
51.6 Reduction In body weight
46.1 Reduction In body weight
7.1 Reduction In body weight
94.2 Increase In percent of resorp-
tlons and dead laplants
Reference
U.S. EPA.
1984b
NTP. 1982
NTP. 1982
NTP. 1982
NTP. 1982
NTP. 1985a
'Calculated by Multiplying the transformed anlaal dose by the cube root of the ratio of the antaal body weight to the reference human body
weight of 70 kg.
Height at week 6 of treatment
Calculated using food factors given In U.S. EPA (1985) (0.025 for dogs. 0.13 for alee. 0.05 for rats)
dAn uncertainty factor of 10 was applied to expand froa subchronlc to chronic exposure
eUelght at week 50 of treatment, estlaated froa graphic data
fHeight at gestatlonal day 0
NR - Not reported
CO
CO
-------
o
o
•~4
0.
TABLE 9-2
Oral Composite Scores for Blsphenol A
Species Animal Dose
(mg/kg/day)
Dog 225
i. Mouse 130
i
Mouse 650
Rat 50
Mouse 1250
Chronic
Human MED*
(rag/day)
777
721
3227
497
6594
RVd Effect
1.1 Increased mean relative
liver weight
1.2 Increased multlnucleate
giant hepatocyte
1.0 Reduced body weights
1.5 Reduction In body weight
1 Fetotoxlclty
RVe CS RQ Reference
4 4.4 5000 U.S. EPA.
1984b
3 3.6 5000 NTP. 1982
4 4 5000 NTP. 1982
4 6 1000 NTP. 1982
8 8 1000 NTP. 1985a
'Derived by multiplying the Equivalent Human Dose expressed as mg/kg/day In Table 9-1 by 70 kg to express
the MED In terms of mg/day for a 70 kg human.
CO
00
-------
TABLE 9-3
BISPHENOL A
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 6594 mg/day
Effect: fetotoxldty 1n mice
Reference: NTP, 1985a
RVd: 1
RVe: 8
Composite Score: 8
RQ: 1000
*Equ1valent human dose
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9.2. BASED ON CARCINOGENICITY
There 1s no convincing evidence that blsphenol A 1s carcinogenic either
In B6C3F1 mice or F344 rats (NTP, 1982) and the compound was assigned to EPA
Group E. Therefore, an RQ based on cardnogenldty was not calculated.
0072d -44- 01/14/88
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10. REFERENCES
Alexander, H.M. 1984. Blsphenol A biochemical oxygen demand (BOD) and fish
toxldty data. Internal letter to L.M. Thomka, Dow Chemical Co. TSCA 4(A)
submission, F1che No. OTS0509952, Doc. No. 40-8486010, U.S. EPA, Washington,
DC.
Allen, H. and K. Kaldbey. 1979. Persistent photosensUlvlty following
occupational exposure to epoxy resin. Arch. Dermatol. 115(11): 1307-1310.=
Bond, G.P., P.M. HcG1nn1s, K.L. Cheever et al. 1980. Reproductive effects
of blsphenol A. Paper presented at the 19th annual meeting of the Society
of Toxicology, Washington, DC. (Abstract only) (CHed In U.S. EPA, 1981)
CHR (Chemical Marketing Reporter). 1984. Chemical Profile. Blsphenol - A
(July 16, 1984). Schnell Publishing Co. NY.
E1senre1ch, S.J., B.B. Looney and J.D. Thornton. 1981. Airborne organic
contaminants of the Great Lakes ecosystem. Environ. Scl. Technol. 15(1):
30-38.
Freeman, K. and A.P. Warln. 1984. Contact dermatitis due to blsphenol A In
semi-synthetic waxes. Contact Derm. 11: 259-260.
Gage, J.C. 1970. Subacute Inhalation toxldty of 109 Industrial chemicals.
Br. J. Ind. Med. 27(1): 1-18.
0072d -45- 01/14/88
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Hansch, C. and A.J. Leo. 1985. Medchem Project Issue No. 26. Pomona
College, Claremont, CA.
Hardln, B.D., G.P. Bond, M.R. S1kov, P.O. Andrew, R.P. Bellies and R.M.
Nlemeler. 1981. Testing of selected workplace chemicals for teratogenlc
potential. Scand. J. Work Environ. Health. 7: 66-75.
Hawley, G.G. 1981. The Condensed Chemical Dictionary, 10th ed. Van
Nostrand Relnhold Co., New York. p. 137.
Kawasaki, M. 1980. Experiences with the test scheme under the chemical
control law of Japan: An approach to structure-activity correlations.
Ecotoxlcol. Environ. Saf. 4: 444-454.
Knaak, J.B. and L.J. Sullivan. 1966. Metabolism of blsphenol A In the rat.
Toxlcol. Appl. Pharmacol. 8: 175-184.
Lyman, W.J., W.F. Reehl and O.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw Hill Book Co., New York. p. 4-9, 5-5,
7-4, 15-27.
Matsul, S., T. Murakami, T. Sasaki, Y. Hlrose and Y. Iguma. 1975. Acti-
vated sludge degradabllUy of organic substances 1n the waste water of the
Kashlma petroleum and petrochemical Industrial complex 1n Japan. Prog.
Water Technol. 7: 645-659.
0072d -46- 01/14/88
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Matsumoto, G. 1982. Comparative study on organic constituents 1n polluted
and unpolluted Inland aquatic environments-Ill. Phenols and aromatic acids
1n polluted and unpolluted waters. Water Res. 16: 551-557.
Matsumoto, G. and T. Hanya. 1980. Organic constituents 1n atmospheric
fallout 1n the Tokyo area. Atmos. Environ. 14: 1409-1419.
Matsumoto, G., R. Ish1watar1 and T. Hanya. 1977. Gas chromatographlc-mass
spectrometHc Identification of phenols and aromatic adds In river waters.
Water Res. 11: 693-698.
MHelman, P., S. Fregert, K. Hedner, et al. 1980. Occupational exposure to
epoxy resins has no cytogenetlc effect. Mutat. Res. 77: 345-348. (Cited
In U.S. EPA, 1981)
MorMssey, R.E., J.G. George, C.J. Price, R.W. Tyl, M.C. Marr and C.A.
Klmmel. 1987. The developmental toxiclty of blsphenol A In rats and mice.
Fund. Appl. Toxlcol. 8: 001-0012.
Munjko, T. and D. Hegedla. 1980. Preliminary tests of blsphenol A bio-
degradation 1n wastewater. Vodaprlvreda. 12: 167-170. (CA 94:89541p)
NTP (National Toxicology Program). 1982. Cardnogenesls bloassay of
blsphenol A In F344 rats and B6C3F1 mice (feed study). NTP Tech. Rep. Ser.
No. 80-35. NTIS PB84-155308. 192 p.
0072d -47- 01/14/88
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NTP (National Toxicology Program). 1984. Blsphenol A: Reproduction and
fertility assessment In CD-I mice when administered via subcutaneous
Sllastlc Implants. Report NTP-84-015.
NTP (National Toxicology Program). 1985a. Teratologlc evaluation of
blsphenol A (CAS No. 80-05-7) administered to CD-I mice on gestatlonal days
6-15. NTP, NIEHS, RTP, NC.
NTP (National Toxicology Program). 1985b. Teratologlc evaluation of
blsphenol A (CAS No. 80-05-7) administered to CD(R) rats on gestatlonal days
6-15. NTP, NIEHS, RTP, NC.
Ong, T. 1979. Mutagen1c1ty testing. Memorandum to Office/Division
Directors. NIOSH, Members MutagenlcUy Task Force. November 26, 1979.
(CHed 1n U.S. EPA, 1981)
Reed, H.W.B. 1978. Alkylphenols. In: Klrk-Othmer Encyclopedia of Chemical
Technology, Vol. 2, 3rd ed., M. Grayson and D. Eckroth, Ed. John Wiley and
Sons, New York. p. 75, 88, 90.
Sadtler. 1966. Sadtler Standard UV Spectra. Sadtler Research Laboratory,
Philadelphia, PA.
SANSS (Structure and Nomenclature Search System). 1987. Chemical Informa-
tion System (CIS) computer data base. Online: February, 1987.
0072d -48- 01/14/88
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Sasaki, S. 1978. The scientific aspects of the chemical substance control
law In Japan. I_n: Aquatic Pollutants: Transformation and Biological
Effects, 0. Hutzlnger, L.H. Von Letyoeld and B.C.J. Zoeteman, Ed. Pergamon
Press, Oxford, p. 283-298.
Sax, N.I. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van
Nostrand Relnhold Co., New York. p. 500.
Shackelford, W.M. and L.H. Keith. 1976. Frequency of organic compounds
Identified In water. Environmental Research Laboratory, Office of Research
and Development, U.S. EPA, Athens, GA. EPA 600/4-76-062. p. 88.
Singh, H.B., H.H. Jaber and J.E. Davenport. 1984. Reactivity/volatility
classification of selected organic chemicals: Existing data. EPA
600/3-84-0821.
Soc. Plastics Ind., Inc. 1984. Appendix D. Environmental Effects [of b1s-
phenol A]. TSCA 4(A) submission, Flche No. OTS0509967, Doc. No. 40-8486028.
U.S. EPA, OTS, Washington, DC.
Soc. Plastics Ind., Inc. 1985a. Toxldty of blsphenol A to freshwater
aquatic species and to Fischer 344 rats (Executive Summary). TSCA 4(0)
submission, Flche No. OTS0510007, Doc. No. 40-8586071. U.S. EPA, OTS,
Washington, DC.
Soc. Plastics Ind., Inc. 1985b. Toxlclty of blsphenol A to saltwater
aquatic species. TSCA 4(D) submission, Flche No. OTS0510008, Doc. No.
40-8586072. U.S. EPA, OTS, Washington, DC.
0072d -49- 01/14/88
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SRI (Stanford Research Institute). 1986. 1986 Directory of Chemical
Producers: United States of America. SRI International, MenTo Park, CA.
Swann, R.L., D.A. Laskowskl, P.J. McCall, K. Vander Kuy and H.J. Olshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
Thurman, C. 1982. Phenol. in: K1rk-0thmer Encyclopedia of Chemical
Technology, 3rd ed., Vol. 17, M. Grayson and D. Eckroth, Ed. John Wiley and
Sons, New York. p. 382.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45:(231): 49347-49357.
U.S. EPA. 1981. Chemical Hazard Information Profile. Blsphenol A. SRI
International.
U.S. EPA 1983. Methodology and Guidelines for Reportable Quantity
Determinations Based on Chronic Toxldty Data. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1984a. Draft Technical Support Document: Blsphenol A. U.S. EPA,
Test Rules Development Branch, Assessment Division, Office of Pesticides and
Toxic Substances, Washington, DC.
0072d -50- 01/14/88
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U.S. EPA. 1984b. Ninety-day oral toxlclty study In dogs. U.S. EPA/OPTS
Public Files. F1che #0150509954.
U.S. EPA. 1984c. Reproduction and ninety-day oral toxlclty study 1n rats.
U.S. EPA/OPTS Public Files. Flche No. OTS0509954.
U.S. EPA. 1984d. Fourteen-day range finding study 1n rats. U.S. EPA/OPTS
Public Files. Flche No. OTS0509954.
U.S. EPA. 1984e. Fourteen-day range finding study 1n dogs. U.S. EPA/OPTS
Public Files. Flche No. OTS0509954.
U.S. EPA. 1985. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Haste, Washington,
DC.
U.S. EPA. 1986a. Methodology for Evaluating Potential Cardnogenlclty In
Support of Reportable Quantity Adjustments Pursuant to CERCLA Section 102.
Prepared by the Office of Health and Environmental Assessment, Carcinogen
Assessment Group, for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986b. Blsphenol A: Final Test Rule. Federal Register. 51:
33047-33054.
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U.S. EPA. 1986c. Blsphenol A: 2-week aerosol toxldty study with Fischer
344 rats. U.S. EPA/OPTS Public Files. F1che # OTS0510007.
U.S. EPA. 1987a. Graphical Exposure Modeling System (GEMS). Fate of
Atmospheric Pollutants (FAP). Office of Toxic Substances, U.S. EPA,
Washington, DC.
U.S. EPA. 1987b. STORE! Water Quality Database. Online: February, 1987.
USITC (U.S. International Trade Commission). 1984. Imports of benzenold
chemicals and products. 1983. USITC Publ. 1548, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic Organic
Chemicals United States Production and Sales, 1985. USITC Publ. 1745,
Washington, DC.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Inc.,
Rahway, NJ. p. 181.
Zavadsk11, V.N. and E.M. Khovanova. 1975. Morphogenetlc properties of
certain phenols Inducing vltlllgo phenocopy. Genetlka. 11: 132-139.
(Cited In U.S. EPA, 1981)
0072d -52- 01/14/88
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APPENDIX A
LITERATURE SEARCHED
This HEED 1s based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted 1n February, 1987. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances In
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
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Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1986. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M.. Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to F1sh and .Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0072d -55- 01/14/88
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o
o
ro
o.
APPENDIX B
Summary Table for Blsphenol A
Species
Inhalation Exposure
Subchronlc ID
Chronic ID
Carclnogenlclty ID
Oral Exposure
in
°* Subchronlc rat
Chronic * rat
Carclnogenlclty NA
REPORTABLE QUANTITIES
Based on Chronic Toxlclty:
0 Based on Carclnogenlclty:
>>- —
Exposure
ID
ID
ID
750 ppm In diet
(61.9 mg/kg/day)
for 90 days
1000 ppm In diet
for 103 weeks
NA
1000
NA
Effect RfD or qi* Reference
ID ID ID
ID ID ID
ID ID ID
NOAEL: reduced 0.6 mg/kg/day U.S. EPA.
body weight at or 43 ing/day 1984d
1000 ppm
LOAEL: reduction 0.05 mg/kg/day NTP, 1982
In body weight
NA NA NA
NTP. 1985a
NA
CD
00
ID = Insufficient data; NA = not applicable
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