SVHC SUPPORT DOCUMENT
Substance name: Benzyl butyl phthalate
EC number: 201-622-7
CAS number: 85-68-7
MEMBER STATE COMMITTEE
SUPPORT DOCUMENT FOR IDENTIFICATION OF
Benzyl butyl phthalate (BBP)
AS A SUBSTANCE OF VERY HIGH CONCERN
Adopted on 1 October 2008
SVHC SUPPORT DOCUMENT
CONTENTS
JUSTIFICATION .........................................................................................................................................................3
1 IDENTITY OF THE SUBSTANCE AND PHYSICAL AND CHEMICAL PROPERTIES .................................3
1.1 Name and other identifiers of the substance ...................................................................................................3
1.2 Composition of the substance .........................................................................................................................3
1.3 Physico-chemical properties ...........................................................................................................................4
2 CLASSIFICATION AND LABELLING ...............................................................................................................5
2.1 Classification in Annex I of Directive 67/548/EEC........................................................................................5
2.2 Self classification(s) .......................................................................................................................................5
3 HUMAN HEALTH HAZARD ASSESSMENT.....................................................................................................6
3.1 Toxicity for reproduction................................................................................................................................6
3.1.1 Effects on fertility................................................................................................................................6
3.1.2 Developmental toxicity .......................................................................................................................6
3.1.3 Human data .........................................................................................................................................6
3.1.4 Other relevant information ..................................................................................................................6
3.1.5 Summary and discussion of reproductive toxicity...............................................................................8
4 ENVIRONMENTAL HAZARD ASSESSMENT ..................................................................................................9
OTHER INFORMATION ............................................................................................................................................11
REFERENCES .............................................................................................................................................................12
TABLES
Table 1: Summary of physico- chemical properties, from EU RAR 2007 ..................................................................4
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SVHC SUPPORT DOCUMENT
Substance Name: Benzyl butyl phthalate
EC Number: 201-622-7
CAS number: 85-68-7
The substance is identified as a CMR according to Article 57 (c) of Regulation (EC) 1907/2006
(REACH).
Summary of the evaluation:
According to Annex I to Directive 67/548/EEC, Benzyl butyl phthalate (BBP) is classified as a
substance toxic to reproduction Repr. Cat. 2; R 61 (May cause harm to the unborn child).
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JUSTIFICATION
1 IDENTITY OF THE SUBSTANCE AND PHYSICAL AND CHEMICAL
PROPERTIES
1.1 Name and other identifiers of the substance
Chemical Name: Benzyl butyl phthalate
EC Number: 201-622-7
CAS Number: 85-68-7
IUPAC Name: Benzyl butyl phthalate
1.2 Composition of the substance
From EU RAR (2007)
Chemical Name: Benzyl butyl phthalate
EC Number: 201-622-7
CAS Number: 85-68-7
IUPAC Name: Benzyl butyl phthalate
Molecular Formula: C19H20O4
Structural Formula:
Molecular Weight: 312,35 g/mol
Typical concentration (% w/w): Degree of purity > 98.5 % (w/w)
Concentration range (% w/w): -
< 1.0% dibenzyl phthalate (CAS No. 523-31-9)
Identity and percentage (w/w) of
impurities:
< 0.5% benzyl benzoate (CAS No. 120-51-4)
< 0.5% dibutyl phthalate (CAS No. 84-74-2)
< 2 ppm -clorotoluen (CAS No. 100-44-7)
< 2 ppm --diclorotoluen (CAS No. 98-87-3)
< 0.5 ppm pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-
Additives
hydoxyphenyl)propionate.
(CAS No. 6683-19-8)
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1.3 Physico-chemical properties
Table 1: Summary of physico- chemical properties, from EU RAR 2007
Property Value Reference
REACH ref IUCLID
Annex section
VII, 7.1 3.1 liquid
Physical state at 20癈 and
101.3 kPa
VII, 7.2 Melting/freezing point 3.2 <-35癈 Monsanto internal
data
VII, 7.3 Boiling point 3.3 370癈 at 10.10 hPa Bayer AG MSDS
VII, 7.5 Vapour pressure 3.6 0.00112 Pa at 20癈 Hoyer and Peperle
(1957)
VII, 7.7 Water solubility 3.8 2.8 mg/l
VII, 7.8 Log Kow 4.84
Partition coefficient n- 3.7
octanol/water (log value) partition
coefficient
IX, 7.16 Dissociation constant 3.21
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2 CLASSIFICATION AND LABELLING
2.1 Classification in Annex I of Directive 67/548/EEC
Benzyl butyl phthalate (BBP) was inserted into Annex I of Directive 67/548/EEC with the 29. ATP
(2004/73/EC) and is classified as follows:
Index: Number: 607-430-00-3
Repr. Cat. 2; R 61 (May cause harm to the unborn child)
Repr. Cat. 3; R 62 (Possible risk of impaired fertility)
N; R 50-53 (Dangerous for the environment; Very toxic to aquatic organisms, may cause long term
effects in the aquatic environment)
Specific concentration limits: none
Labelling:
Symbols: T; N
R-Phrases: 61-62-50/53
S-Phrases: 53-45-60-61
2.2 Self classification(s)
Not relevant.
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3 HUMAN HEALTH HAZARD ASSESSMENT
3.1 Toxicity for reproduction
3.1.1 Effects on fertility
3.1.2 Developmental toxicity
3.1.3 Human data
3.1.4 Other relevant information
Endocrine effects of BBP
Endocrine activity has been assessed in various in vitro and in vivo studies on BBP and its most
important metabolites MBeP (mono-benzyl-phthalate) and MBuP (mono-n-butyl-phthalate) as
described in the EU RAR, 2007:
Estrogenicity
A potential estrogen activity of BBP and the major BBP metabolites MBuP and MBeP has been
investigated in both in vitro and in vivo studies. The in vitro studies include a recombinant yeast
screen assay, an estrogen-receptor (ER) competitive ligand binding assay, mammalian- and yeast-
based gene expression assays and an estrogen-dependent cell proliferation assay. In these assays
only a weak estrogen activity at high concentrations of BBP (10-100 礛) was reported. In the same
assays the positive control E2 (17?estradiol) was approximately 104 to 106 more potent than BBP.
The metabolites MBuP and MBeP did not exhibit estrogenic activity in a recombinant yeast screen
assay. The estrogenic activity of BBP and its major metabolites were studied in standard in vivo
uterotrophic assays. In these studies BBP and MBuP did not possess the potential to promote
uterine growth in immature female rats exposed orally to BBP (up to 2,240 mg/kg bw/day) or
subcutaneous to BBP (up to 5,000 mg/kg bw/day), whereas, MBeP caused a significant reduction in
absolute and relative uterine weight at 500 and 1,000 mg/kg bw/day, which was most probably due
to systemic toxicity. Furthermore only weak estrogenic activity of BBP was concluded in a study
that investigated the expression of estrogen regulated mRNAs in the hypothalamus, preoptic area
and pituitary.
Anti-androgenicity
BBP was shown in one in vitro study to be a potent anti-androgen in yeast cells expressing the
androgen receptor. Nine in vivo studies are available which indicate an anti-androgen-like activity
of BBP or its major metabolites MBuP and MBeP in rats (Piersma et al., 2000; Gray et al., 2000;
Parks et al., 1999; Imajima et al., 1997; Shono et al., 2000; Nagao et al., 2000; Tyl et al., 2004; Ema
et al., 2002; Ema et al., 2003, all cited in EU RAR). Effects reported in the Piersma et al. (2000)
study included a reduction in testicular weight in offspring, and effects on testicular migration from
270 mg/kg bw/day and 580 mg/kg bw/day after in utero exposure to BBP from gestation day 6 to
20. In the Gray et al. (2000) study malformations in the reproductive organs in 84% of male
offspring (approximately 90 days of age) exposed to 750 mg/kg bw/day BBP from gestation day 14
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through postnatal day 2 were reported. Furthermore in the Gray et al. (2000) and Parks et al. (1999)
studies a reduced AGD and testis weight in males at day 2 of age, and males with areolas at day 13
of age were reported. In the Imajima et al. (1997) study and the Shono et al. (2000) study testicular
descendent was studied, which is under androgenic control. In this study the testis were located
significantly higher in the abdominal cavity on gd 20 offspring compared to control rats exposed in
utero to MBuP from gd 15-18. Furthermore, in the Imajima et al. (1997) study, on pnd 30-40
cryptorchidism was reported in 84.6% of the exposed offspring, compared to 0% in the control
group. In the study by Ema et al. (2002) in utero exposure to 500 and 1,000 mg/kg BBP on gd 15-
17 induced a significant decrease in the AGD and a significant increase in the incidence of
undescended testis. In the study by Ema et al. (2003) in utero exposure to MBeP on gd 15-17 was
shown to induce a significant decrease in AGD and a significant increase in the incidence of
undescended testis. In the study by Nagao et al. (2000) a decrease in the weight of the testis,
epididymis, and seminal vesicle, and tubular atrophy and decreased germinal epithelium was
reported in F1 male offspring exposed to 500 mg/kg bw/day BBP during gestation and lactation and
evaluated at weaning or after puberty. Furthermore, a decrease in AGD was reported in male
offspring in the 500 mg/kg bw/day dose group, which is a sensitive indicator of anti-androgen
activity. In the Tyl et al. (2004) study a dose-related decrease in absolute and adjusted AGD was
reported in F1 and F2 male pups from 250 mg/kg bw/day. Furthermore, at 750 mg/kg bw/day in F1
and F2 offspring a significant decrease in reproductive organ weights, and a significant increase in
the percentage of males with reproductive tract malformations were reported.
An association between prenatal and postnatal exposure to phthalates and whether the exposure had
any influence on reproductive organ development in newborn boys was studied in two
epidemiological studies. In the study by Swan et al. (2005, cited in EU RAR) an association
between maternal exposures to BBP as well as other phthalates and AGI in boys was reported.
When comparing boys with prenatal MBeP (monobenzyl phthalate, reflecting exposure to BBP)
exposure the odds ratio for a shorter AGI was 3.8. For the other monoester phthalates the odds ratio
were 10.2 for MBuP (reflecting exposure to DBP), 4.7 for MEP (reflecting exposure to DEP), and
9.1 for MiBP (reflecting exposure to DINP) (all p-values < 0.05).
In the study by Main et al. (2005, cited in EU RAR) no association was found between phthalate
monoester levels (MEP, MMP, MBuP, MBeP, MINP and MEHP) in breast milk and
cryptorchidism in newborn boys. However, a significant association was found between intake of
milk contaminated with phthalates (MEP, MBuP, MMP and MINP) and postnatal surge of
reproductive hormones (SHBG, LH, testosterone and inhibin B) in newborn boys. As regards the
monoester metabolite of BBP, MBeP the tendencies were similar, however, they were not
statistically significant. These data support the hypothesis that prenatal phthalate exposure at
environmental levels may affect male reproductive development in humans. However, due to the
small sample size, (85 boys in Swan et al., 2005 and 130 boys in Main et al., 2005) further studies
with larger sample size have to be performed before clear conclusions can be drawn from these
studies.
The following study was published after publication of the EU RAR:
Hauser et al. (2006) reported altered semen quality in relation to urinary concentrations of phthalate
monoester and oxidative metabolites in humans. Semen from 463 male partners of subfertile
couples was investigated and dichotomized according WHO reference values for sperm
concentration and motility as well as the Tygberg Kruger Strict criteria for morphology. Results
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were adjusted for age, abstinence time and smoking status. MBeP (mono-benzyl-phthalate) was
found in 94% of the samples. There was suggestive evidence of an association between the highest
MBeP quartile with low sperm concentration (Hauser et al., 2006).
3.1.5 Summary and discussion of reproductive toxicity
BBP has been assessed for potential toxic effects on fertility, reproductive organs, development, and
endocrine activity. It is found to adversely affect the reproductive organs in experimental animal
studies which may affect fertility. Furthermore, the substance is found to be a developmental
toxicant. This is reflected in the classification as Repr.Cat. 3; R 62 and Repr.Cat. 2; R 61,
according to Directive 67/548/EEC.
BBP impairs the foetal development and causes malformations in rats and mice. A dose-related
significant reduction in absolute and adjusted anogenital distance index (AGI) in both F1 and F2
offspring from 250 mg/kg bw/day was observed in rats. At 750 mg/kg bw/day a significant increase
in F1 and F2 male pups with one or more nipples and/or areolae was reported. The NOAEL for
maternal toxicity was 750 mg/kg bw/day (Tyl et al., 2004, cited in EU RAR).
The results of several in vivo studies indicate an anti-androgen-like activity of BBP or its major
metabolites in rats following in utero exposure. Effects reported in the studies included a decreased
AGI, increases in male offspring with reproductive tract malformations, as well as effects on
testicular migration (EU RAR, 2007).
In studies commissioned by DG Environment of the European Commission a list of 146 substances
with endocrine disruption properties have been established (http://ec.europa.eu/environment/
docum/pdf/bkh_annex_13.pdf). BBP has been classified as Cat. 3 for wildlife, Cat. 1 for Humans and
Combined as Cat. 1 (Cat.1: Evidence for endocrine disruption in living organisms; Cat. 2: Evidence
of potential to cause endocrine disruption; Cat.3: No evident scientific basis). BBP is also listed in a
list of 66 potentially endocrine substances with classification of high exposure concern
(http://ec.europa.eu/ environment/docum/pdf/bkh_annex_15.pdf) (EUROPEAN COMMISSION DG ENV,
2000).
It is stated in the draft risk reduction strategy (April 2007) that BBP may be subjected to the
authorisation system. In the OSPAR convention BBP is put on the list of substances for priority
action. In the OSPAR Convention it is stated that BBP is a potential endocrine substance.
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4 ENVIRONMENTAL HAZARD ASSESSMENT
There have been suggestions of estrogenic and anti-androgenic effects caused by BBP in fish.
Following recent development of draft testing protocols for endocrine disruption in fish, more data
has become available.
Estrogenicity
In an early study BBP was found to be weakly estrogenic (Jobling et al., 1995, cited in EU RAR).
BBP at a concentration of approximately 0.01 ?10 mg/l reduced in vitro binding of natural
estrogen, 17-estradiol, to the rainbow trout estrogen receptor by about 40-60%. Furthermore, the
EU RAR (2007) refers to a study performed by Christiansen et al. (2000) who injected rainbow
trout intraperitoneally with different compounds. BBP was found to cause significant induction of
vitellogenin in vivo, but was a weaker inducer than e.g. bisphenol A. In further injection studies
with juvenile rainbow trout, no induction of the estrogen receptor was observed at an exposure
concentration of 50 mg/kg BBP, but both 5 and 50 mg/kg significantly lowered plasma levels of
eggshell proteins (Knudsen et al., 1998 cited in EU RAR), indicating an inhibition of synthesis of
these proteins. Similarly, Knudsen and Pottinger (1998, cited in EU RAR) found that BBP would
bind to the estrogen receptor, but only at high concentrations. There was no apparent binding of
BBP to corticosteroid or testosterone receptors in that study. Work performed by Gimeno (at this
time at TNO, The Netherlands) on the possible estrogenic effects of BBP on sexual differentiation
in all-male carp did not indicate any effects of BBP (Gimeno, pers.comm. cited in EU RAR).
Results for estrogenicity indicate that BBP may be estrogenic at high concentrations.
Harries et al. (2000, cited in EU RAR) exposed fish to BBP (100 礸/l) and nonylphenol (1, 10 and
100 礸/l). Breeding pairs were exposed for 3 weeks during which reproductive performance was
monitored. Endpoints were number of spawnings, number of eggs and size of eggs. At the end of
the exposure period plasma vitellogenin and gonadosomatic index was determined. In addition,
secondary sexual characteristics in male were quantified (growth of tubercles and thickness of
dorsal fat pad). While nonylphenol caused dose-dependent estrogenic effects down to 10 礸/l, no
effects were seen following BBP exposure.
Anti-androgenicity
The EU RAR (2007) furthermore refers to studies suggesting that BBP may be anti-androgenic.
These observations have been derived from mammalian studies (e.g. Zacharewski et al., 1998) as
well as an in vitro study conducted by Sohoni and Sumpter (1998). BBP has been found to be an as
potent anti-androgen as the model substance used for that purpose, flutamide. Unfortunately there is
no established model to ascertain anti-androgenicity in fish. The Harries et al. (2000) study was not
specifically designed to detect anti-androgenicity (e.g. through concomitant exposure to anti-
androgens). Therefore, the lack of response following BBP exposure in this study does not disprove
earlier suggestions that this phthalate may be anti-androgenic to wildlife. Recently, Ankley et al.
(2004) provided in vitro support for using fathead minnow to identify anti-androgenic effects, but it
is still necessary to establish such effects in vivo.
There is work ongoing within the OECD to establish appropriate test systems for endocrine
disrupting effects. The test systems are expected to include a study in fish that will include
endpoints relevant to estrogenic, androgenic, anti-estrogenic and anti-androgenic effects. The tests
performed with BBP referred to above have not incorporated the aspect of transfer from parent to
offspring included in the current test requirements for BBP. An agreement was reached with
Industry to perform a partial life cycle study that was a combination of the two OECD
recommended "tier 2 tests" for assessing possible endocrine disruption effects of chemicals in fish.
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The test is a combination of the so-called pair-breeding test in which egg production and
hatchability of eggs from a breeding pair of Fathead minnow is assessed and an enhanced early life
stage test in which exposure of the eggs from the pair breeding test is continued for sufficient time
to enable sexual differentiation of the offspring. Exposure concentrations should be 25 and 100 礸/l.
After some pre-dosing trials a definite study with the pair breeding phase was attempted in March
2002. This study was aborted on day 47 because measured BBP concentrations in the exposure
vessels were always below the nominal concentrations and appeared to decline throughout the
study. In the nominal 25 礸/l exposure tanks mean concentration on day 32 was 20 礸/l and by day
47 the mean concentration had declined to 14 礸/l (56% of nominal). In the nominal 100 礸/l
exposure tanks mean concentration on day 32 was 72 礸/l and by day 47 the mean concentration
had declined to 59 礸/l (59% of nominal). Industry has performed a number of additional trials in
order to investigate the optimal conditions for performing a chronic fish test. The trials included
variable use of solvent, variable delivery systems and variable flow rates. These trials have
indicated that it will not be possible to obtain a stable test concentration > 80% of the nominal BBP
concentration as required according to the test guidelines. Apparently a plateau level could not be
obtained either. Very high flow rates were also tested (residence time 1-1.15 hour) without attaining
the required concentration level, although it seemed that a fairly stable level was achieved at about
50% of nominal. The industry report concluded that the reason for these problems was the
biodegradation of BBP to its primary biodegradation products (monobutyl-phthalate and
monobenzyl-phtalate) and that these metabolites were also rapidly degraded within this test system.
It should however be pointed out that other factors cannot be excluded like adsorption to the test
system and that some solubility problems as reported may also be part of the problem. The technical
difficulties described above have been reported to the Technical Meeting. However, the TM (cf.
minutes of TM II `03) "generally supported the request to industry to perform the endocrine effect
test. The TM realised that the results would not meet the ideal test requirements, but would accept
that in this particular case.
In the risk assessment report (EU-RAR, 2007) BBP is considered as a suspected endocrine
disruptor. It was concluded that further information is needed concerning reproductive toxicity and
endocrine effects in fish. A long term fish study on reproductive and endocrine effects has to be
performed and therefore the PNECaquatic (7.5 礸/l wwt) has to be seen provisional. From informal
contacts with the rapporteur (Norway) information was received that the long term fish study has
been conducted, but still needs to be reviewed in detail.
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OTHER INFORMATION
Benzyl butyl phthalate (BBP) is on the 3rd priority list under Council Regulation (EEC) No 793/93
on the Control and Evaluation of the Risks of Existing Substances with Norway as Rapporteur. The
final risk assessment report was published in 2007. The risk reduction strategy was endorsed at the
13th RRS Meeting, publication in the Official Journal is foreseen for 2008.
Note that no re-evaluation was conducted of those references which are cited in this Annex XV
dossier and which were taken from the Risk Assessment Report for benzyl butyl phthalate (EU
RAR, 2007). The last full literature survey for the RAR was carried out in 2003 with subsequently
conducted targeted searches. For the present dossier no comprehensive literature survey was carried
out, but focus was given to exposure related data (especially monitoring data) and endocrine effects.
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REFERENCES
Ankley GT, DeFoe DL, Kahl MD, Jensen KM, Makynen EA, Miracle A, Hartig P, Gray E, Cardon
M and Wilson V (2004). Evaluation of the Model Anti-androgen Flutamide for Assessing the
Mechanistic Basis of Responses to an Androgen in the Fathead Minnow (Pimephales promelas).
Environmental Science and Technology. 38 (23), (December 2004). 6322-6327.
Bayer MSDS Extract concerning physico chemical properties of BBP.
Christiansen LB, Pedersen KL, Pedersen SN, Korsgaard B and Bjerregaard P (2000). In vivo
comparison of xenoestrogens using rainbow trout vitellogenin induction as a screening system.
Environ. Toxicol. Chem. 19, 1867-1874.
Council Directive 67/548/EEC of 27 June 1967 on the approximation of laws, regulations and
administrative provisions relating to the classification, packaging and labelling of dangerous
substances. OJ 196, 16.8.1967, p.1-98;
Ema M and Miyawaki E (2002) Effects on development of the reproductive system in male
offspring of rats given butyl benzyl phthalate during late pregnancy. Reprod. Toxicol. 16, 71-76.
Ema M, Miyawaki E, Hirose A and Kamata E (2003) Decreased anogenital distance and increased
incidence of undescended testes in fetuses of rats given monobenzyl phthalate, a major metabolite
of butyl benzyl phthalate. Reprod. Toxicol. 17, 407-412.
EUROPEAN COMMISSION DG ENV (2000) Towards the establishment of a priority list of
substances for further evaluation of their role in endocrine disruption - preparation of a candidate
list of substances as a basis for priority setting. FINAL REPORT. BKH Consulting Engineers,
Delft, The Netherlands in association with TNO Nutrition and Food Research, Zeist, The
Netherlands. Project No M0355008/1786Q/10/11/00
EU RAR, 2007: European Union Risk assessment report, Benzyl butyl phthalate (BBP); Volume:
76 (ISSN 1018-5593)
Gray Jr LE, Ostby J, Furr J, Price M, Veermachaneni DNR and Parks L (2000) Perinatal exposure
to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation
of the male rat. Toxicol. Science 58, 350-365.
Harries CE, Runnalls T, Hill E, Harris CA, Maddix S, Sumpter JP and Tyler CR (2000)
Development of a reproductive performance test for endocrine disrupting chemicals using pair-
breeding fat-head minnows (Pimephales promelas). Environ Sci Technol. 34:3003?011
Hauser R, Meeker JD, Duty S, Silva MJ, Calafat AM (2006) Altered semen quality in relation to
urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiolog, 17(6):682-
91.
Hoyer H and Peperle W (1975) Dampfdruckmessungen an organischen Substanzen und ihre
Sublimationsw鋜me. Zeitschrift f黵 Elektrochemie Bd. 62, Nr 1.
Imajima T, Shono T, Zakaria O and Sulta S (1997) Prenatal phthalate exposure causes
cryptorchidism postnatally by inducing transabdominal ascent of testis in fetal rats. J. Pediatric
Surgery 32 (1), 18-21.
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Jobling S, Reynolds T, White R, Parker MG and Sumpter JP (1995) A variety of environmentally
persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Environ. Health
Perspect. 103, 582-587.
Knudsen FR, Arukwe A and Pottinger TG (1998) The in vivo effect of combinations of octylphenol,
butylbenzylphthalate and estradiol on liver estradiol receptor modulation and induction of zona
radiata proteins in rainbow trout: no evidence of synergy. Env. Poll. 103, 75-80.
Knudsen FR and Pottinger TG (1998) Interaction of endocrine disrupting chemicals, singly and in
combination, with estrogen-, androgen- and corticosteroid-binding sites in rainbow trout
(Oncorhynchus mykiss). Aquat. Toxicol. 44, 159-170.
Main KM, Mortensen GK, Kaleva MM, Boisen KA, Damgaard IN, Chellakooty M, Schmidt IM,
Suomi AM, Virtanen HE, Petersen JH, Andersson AM, Toppari J and Skakkeb鎘 NE (2005)
Human breast milk contamination with phthalates and alterations of endogenous reproductive
hormones in three month old infants. Environ. Health Perspect., online 7 September 2005
(http://dx.doi.org).
Monsanto Internal data (1988) Santicizer 160 bulletin. Monsanto Europe S.A., 8th edition.
Nagao T, Ohta R, Marumo H, Shindo T, Yoshimura S and Ono H (2000) Effect of butyl benzyl
phthalate in Sprague-Dawley rats after gavage administration: a two-generation reproductive study.
Reproductive Toxicology 14, 513-532.
Parks LG, Ostby JS, Lambright CR, Abbott BD and Gray LE Jr (1999). Perinatal butyl benzyl
phthalate (BBP) and di-(2ethylhexyl) phthalate (DEHP) exposures induce antiandrogenic effects in
Sprague-Dawley (SD) rats. Biol. Reprod. 60 (1), 153.
Piersma AH, Verhoef A, te Biesebeek JD, Pieters MN and Slob W (2000) Developmental toxicity
of butyl benzyl phthalate in the rat using a multiple dose study design. Reprod. Toxicol. 14, 417-
425. From the report: Piersma AH, Verhoef A, Dormans JAMA, Elvers LH, de Valk F, te
Biesebeek JD, Pieters MN and Slob W (1999). Developmental and testicular toxicity of butyl
benzyl phthalate in the rat and the impact of study design. RIVM report No. 650040 001.
Shono T, Kai H, Suita S and Nawata H (2000) Time-specific effects of mono-n-butyl phthalate on
the transabdominal descent of the testis in rat fetuses. BJU International 86, 121-125.
Sohoni P and Sumpter JP (1998) Several environmental oestrogens are also anti-androgens. J.
Endocrinol. 158, 327-339.
Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, Mao CS, Redmon JB, Ternand
CL, Sullivan S, Teague JL and the Study for Future Families Research team (2005) Decrease in
anogenital distance among male infants with prenatal phthalate exposure. Environ. Health Perspect.
113, 1056-1061.
Tyl RW, Myers CB, Marr MC, Fail PA, Seely JC, Brine DR, Barter RA and Butala JH (2004).
Reproductive toxicity evaluation of dietary Butyl Benzyl Phthalate (BBP) in rats. Reprod. Toxicol.
18, 241-264.
Zacharewski TR, Meek MD, Clemons JH, Wu ZF, Fielden MR and Matthews JB (1998)
Examination of the in vitro and in vivo estrogenic activities of eight commercial phthalate esters.
Toxicol. Science. 46, 282-293
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