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Butyl benzyl phthalate
CASRN 85-68-7
Contents
0293
Butyl benzyl phthalate; CASRN 85-68-7
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Butyl benzyl phthalate
File On-Line 08/22/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 02/01/1993
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 02/01/1993
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Butyl benzyl phthalate
CASRN -- 85-68-7
Last Revised -- 02/01/1993
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses UF MF RfD
-------------------- ----------------------- ----- --- ----------
Significantly NOAEL: 2800 ppm 1000 1 2E-1
increased liver- (159 mg/kg/day) mg/kg/day
to-body weight and
liver-to-brain LOAEL: 8300 ppm
weight ratios (470 mg/kg/day)
6-Month Rat Study
Oral Exposure (diet)
NTP, 1985
*Conversion Factors: approximately 300 g bw and 17 g of food consumption/day
from data presented in the report
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
NTP (National Toxicology Program). 1985. Twenty-six week subchronic study
and modified mating trial in F344 rats. Butyl benzyl phthalate. Final
Report. Project No. 12307-02, -03. Hazelton Laboratories America, Inc.
Unpublished study.
NTP (1985) conducted a toxicity study in F344 rats in which 15 males/group
were administered concentrations of either 0, 0.03, 0.09, 0.28, 0.83, or 2.5%
BBP in the diet for 26 weeks. Using body weight and food consumption data
presented in the report these dietary levels correspond to 0, 17, 51, 159,
470, and 1417 mg/kg/day, respectively. In this study powdered rodent meal was
provided in such a way that measured food consumption at the highest dose
level could include significant waste and spillage rather than true food
intake. For this reason a standard food consumption rate of 5% rat body
weight was used in the 2.5% dose conversion. Throughout the study body weight
gain was significantly depressed at the 2.5% BBP level when compared with the
controls. There were no deaths attributed to BBP toxicity. All the rats
given 2.5% BBP had small testes upon gross necropsy; 5/11 had soft testes and
1/11 had a small prostate and seminal vesicle. In the 0.03, 0.09, 0.28, and
0.83% dose groups there were no grossly observable effects on male
reproductive organs. Terminal mean organ weight values were significantly
decreased (p<0.05) for the heart, kidney, lungs, seminal vesicles and testes
in the 2.5% group. Hematological effects at 2.5% BBP included decreased red
cell mass (which the authors state is indicative of deficient hemoglobin
synthesis), reduced values for hemoglobin, total RBC and hematocrit. The
kidneys of six animals in the 2.5% group contained focal cortical areas of
infarct-like atrophy. In addition, testicular lesions were also observed at
the 2.5% dose level. Lesions were characterized by atrophy of seminiferous
tubules and aspermia. At 0.83% the effects noted were significantly (p<0.05)
increased absolute liver weight, increased liver-to-body weight and liver-to-
brain weight ratios and increases in mean corpuscular hemoglobin. The 0.03,
0.09, 0.28, and 0.83% treatment groups showed no evidence of abnormal
morphology in any organ. No adverse effects were observed at the 0.28%
treatment level or below.
The only other information on subchronic effects is reported by Krauskopf
(1973) from an unpublished study by Monsanto (1972). Rats fed diets
containing 0.25% (125 mg/kg/day) and 0.5% (250 mg/kg/day) for 90 days showed
no toxic effects. Liver weights were increased in animals fed diets
containing 1.0, 1.5, or 2.0% (500, 750, or 1000 mg/kg/day, respectively) for
90 days, and a mild decrease in growth rate was reported for the 1.5 and 2.0%
groups. No other hematologic, histopathologic or urinalysis effects were
observed. When dogs were administered gelatin capsules containing doses
equivalent to 1.0, 2.0, or 5.0% of the daily diet (10,000 20,000 and 50,000
ppm) for 90 days, no effect on hematological parameters, urinalysis or liver
and kidney functions were observed. No further details of this study were
available for review.
Similar LOAELs of 470 and 500 mg/kg/day for increased liver weight were
identified in both the NTP (1985) and Monsanto (1972) studies, respectively.
NOAELs differ slightly: 159 (NTP, 1985) versus 250 mg/kg/day (Monsanto, 1972).
It is recommended that the NOAEL of 159 mg/kg/day from the NTP (1985) study be
used to derive the RfD for two reasons: 1) the NTP (1985) study is of longer
duration, and 2) The Monsanto (1972) study provides an incomplete description
of methods comparing study design and clinical analysis. Treatment-related
effects across similar dose ranges including liver effects in both studies
support the use of 159 mg/kg/day as a NOAEL.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- 10 for intraspecies sensitivity, 10 for interspecies variability and 10
for extrapolating from subchronic to chronic NOAELs.
MF -- None
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Two 14-day studies support the selection of the NTP (1985) bioassay for
deriving the oral RfD. Agarwal et al. (1985) administered BBP to male F344
rats in the diet for 14 consecutive days at dose levels of 0.625, 1.25, 2.5,
and 5.0%. Significant increases in liver and kidney weights and kidney
pathology (proximal tubular regeneration) was observed at 0.625% (375
mg/kg/day), which represents a LOAEL.
In male Sprague-Dawley rats administered 160, 480, or 1600 mg/kg/day BBP for
14 days by gastric intubation, biochemical or morphological changes in the
liver as well as effects on testes weights were not observed in the 160
mg/kg/day dose group (Lake et al., 1978). However, at 480 mg/kg/day
activities of ethyl morphine N-demethylase and cytochrome oxidase were
significantly increased and testicular atrophy was observed in one-third
Sprague-Dawley rats in the first portion of this experiment. In the second
position, the 480 mg/kg/day dose induced testicular atrophy in one-sixth
Sprague-Dawley rats, whereas the Wistar albino strain revealed no such
effects. A NOAEL for this study would be 160 mg/kg/day based on the absence
of liver and testicular effects.
In an addendum to the NTP (1985) final report, evaluation of the data revealed
a significantly reduced total marrow cell count in the 2.5% dose group (NTP,
1986). The change in total cell count was comprised primarily of significant
decreases in neutrophil, metamyelocytes, bands, segmeters, lymphocytes and
leasophilic rubricytes. The total marrow cell counts, metamyelocyte, and
leasophilic rubricyte counts were also significantly decreased in the lowest
dose group, 0.03%. No statistically significant differences were noted in the
middle dose groups (0.09, 0.28, or 0.83%) when compared with controls. The
addendum states that decreased total marrow cell count in the 0.03 and 2.5%
dose group represent change of uncertain meaning in light of the systemic
effects noted in the middle dose groups. Trend analysis by the Terpstra-
Jonckheere test revealed significantly (p<0.05%) decreasing trends in all of
the previously mentioned parameters as well as an increasing trend for
monocytes at 0.03 and 2.5%.
NTP (1985) also conducted a male mating trial study concomitantly with the
toxicity study. Testicular atrophy was observed in male F344 rats after 10
weeks of exposure to 2.5% (2875 mg/kg/day) BBP. Throughout the study, body
weight gain was significantly depressed at the 2.5% BBP level when compared
with the controls.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Low
RfD -- Low
The critical study is of adequate quality and is given a medium confidence
rating. Since the critical study used only male rats and there are no
adequate supporting studies of chronic duration, the data base is given a low
confidence rating. Low confidence in the RfD follows.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- U.S. EPA, 1987a,b; 1988
U.S. EPA (1987a, 1988) have been both OHEA reviewed and Agency reviewed. U.S.
EPA (1987b) has been OHEA reviewed.
Other EPA Documentation -- None
Agency Work Group Review -- 06/15/1989
Verification Date -- 06/15/1989
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Butyl benzyl phthalate
CASRN -- 85-68-7
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Butyl benzyl phthalate
CASRN -- 85-68-7
Last Revised -- 02/01/1993
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- C; possible human carcinogen.
Basis -- Based on statistically significant increase in mononuclear cell
leukemia in female rats; the response in male rats was inconclusive and there
was no such response in mice.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Limited. A bioassay was performed by the NTP (1982) to evaluate the
carcinogenic potential of orally administered butyl benzyl phthalate (BBP) to
both rats and mice. Dietary levels of 0, 6000, and 12,000 ppm BBP were fed to
groups of 50 male and 50 female F344 rats and 50 male and 50 female B6C3F1
mice for 103 weeks. The male rats at both dose levels experienced high
mortality within the first 30 weeks of the study due to apparent internal
hemorrhaging; all male rats were, thus, terminated at 30 weeks. No chronic
toxicity or carcinogenic effects were observed in male or female mice. Among
female rats a statistically significant increase in mononuclear cell leukemia
(MCL) or lymphoma (p=0.007) was observed at the high dose level compared with
controls with an increasing trend at p=0.006. The time to first tumor was 83
weeks in control as well as in the high-dose group. NTP indicated that BBP
was "probably" carcinogenic in female rats. The tumor incidence was 7/49
(14%) for controls, 7/49 (14%) in low dose and 19/50 (38%) in the high dose as
compared with historical control incidence in the laboratory of 19% (12-24%
range).
Given the similarity of the MCL pathology in the control and the dosed
female rats as well as the absence of a reduction in time to first tumor, the
response is judged to be an acceleration of an old age tumor in the F344 rats.
This weakens somewhat the interpretive value of the MCL response. The NTP has
initiated a retest in the rats.
BBP did not induce lung adenomas in strain A mice administered 24
intraperitoneal injections of 160, 400 or 800 mg/kg (Theiss et al., 1977).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Studies indicate that BBP is not a direct acting mutagen in the reverse
mutation assay in Salmonella typhimurium (Rubin et al., 1979; Kozumbo et al.,
1982; Zeiger et al., 1982) or in E. coli (NTP, 1982). Mammalian cytogenicity
studies using chinese hamster ovary cells were also negative (NTP, 1982). NTP
(1982) noted that additional studies on metabolites, benzyl alcohol and
n-butanol was important.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available. The qualitative weaknesses of the MCL response does not
provide a compelling basis to model the dose-response data.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1987
The 1987 Draft Drinking Water Quality Criteria Document received Agency
review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 08/26/1987
Verification Date -- 08/26/1987
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Butyl benzyl phthalate
CASRN -- 85-68-7
Last Revised -- 09/01/1989
__VI.A. ORAL RfD REFERENCES
Agarwal, D.K., R.R. Maronpot, J.C. Lamb, IV and W.M. Kluwe. 1985. Adverse
effects of butylbenzyl phthalate on the reproductive and hematopoietic systems
of male rats. Toxicology. 35: 189-206.
Krauskopf, L.G. 1973. Studies on the toxicity of phthalates via ingestion.
Environ. Health Perspect. 3: 61-72.
Lake, B.G., R.A. Harris, P. Grasso and S.D. Gangollia. 1978. Studies on the
metabolism and biological effects of n-butyl benzyl phthalate in the rat.
Prepared by British Industrial Biological Research Association for Monsanto,
Report No. 232/78, June.
Monsanto Chemical Company. 1972. Unpublished work. (Cited in Krauskopf,
1973)
NTP (National Toxicology Program). 1985. Twenty-six week subchronic study
and modified mating trial in F344 rats. Butyl benzyl phthalate. Final
Report. Project No. 12307-02, -03. Hazelton Laboratories America, Inc.
Unpublished study.
NTP (National Toxicology Program). 1986. Addendum to Final Report. Bone
marrow differential results - 26 Week study. LBI/HLA Project No. 12307-02.
Hazelton Laboratories America, Inc. Unpublished report.
U.S. EPA. 1987a. Health and Environmental Profile for Phthalic Acid Alkyl,
Aryl and Alkyl/Aryl Esters. 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. 1987b. Health Effects Assessment for Selected Phthalic Acid
Esters. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1988. Drinking Water Criteria Document for Phthalic Acid Esters
(PAEs). Prepared by the Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Drinking Water, Washington, DC. Final Draft.
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Kozumbo, W.J., R. Kroll and R.J. Rubin. 1982. Assessment of the mutagenicity
of phthalate esters. Environ. Health Perspect. 45: 103-109.
NTP (National Toxicology Program). 1982. Carcinogenesis Bioassay of Butyl
Benzyl Phthalate (CAS No. 85-68-7) in F344 Rats and B6C3F1 Mice (Feed Study).
NTP Tech. Rep. Ser. TR No. 213, NTP, Research Triangle Park, NC. p. 98
Rubin, R.J., W. Kozumbo and R. Kroll. 1979. Ames mutagenic assay of a series
of phthalic acid esters: Positive response of the dimethyl and diethyl esters
in TA100. Soc. Toxicol. Ann. Meet., New Orleans, March 11-15. p. 11.
(Abstract)
Theiss, J.C., G.D. Stoner, M.B. Shimkin and E.K. Weisburger. 1977. Test for
carcinogenicity of organic contaminants of United States drinking waters by
pulmonary tumor response in strain A mice. Cancer Res. 37: 2717-2720.
U.S. EPA. 1987. Drinking Water Criteria Document for Phthalic Acid Esters.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking
Water, Washington, DC. External Review Draft.
Zeiger, E., S. Haworth, W. Speck and V. Mortlemans. 1982. Phthalate ester
testing in the National Toxicology Program's environmental mutagenesis test
development program. Environ. Health Perspect. 45: 99-101.
_VII. REVISION HISTORY
Substance Name -- Butyl benzyl phthalate
CASRN -- 85-68-7
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
08/22/1988 II.A. Carcinogen summary on-line
02/01/1989 II.D.3. Primary contact's phone number corrected
07/01/1989 I.A. Oral RfD now under review
09/01/1989 I.A. Oral RfD summary on-line
09/01/1989 VI. Bibliography on-line
08/01/1991 I.A.7. Primary and secondary contacts changed
08/01/1991 II.D.3. Primary and secondary contacts changed
01/01/1992 IV. Regulatory Action section on-line
02/01/1993 I.A.7. Primary contact changed
02/01/1993 II.D.3. Primary contact changed
VIII. SYNONYMS
Substance Name -- Butyl benzyl phthalate
CASRN -- 85-68-7
Last Revised -- 08/22/1988
85-68-7
BBP
1,2-BENZENEDICARBOXYLIC ACID, BUTYL PHENYLMETHYL ESTER
BENZYL-BUTYLESTER KYSELINY FTALOVE
BENZYL BUTYL PHTHALATE
BENZYL n-BUTYL PHTHALATE
Butyl benzyl phthalate
n-BUTYL BENZYL PHTHALATE
BUTYL PHENYLMETHYL 1,2-BENZENEDICARBOXYLATE
NCI-C54375
PALATINOL BB
PHTHALIC ACID, BENZYL BUTYL ESTER
SANTICIZER 160
SICOL 160
UNIMOLL BB
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0293.HTM
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