n-Butylbenzene
Hazard assessment of n-Butylbenzene
[n-Butylbenzene, CAS No. 104-51-8]
Chemical name: n-Butylbenzene
Synonyms: 1-Phenylbutane, n-BB
Molecular formula: C10 C14
Molecular weight: 134.22
Structural formula:
CH2CH2CH2CH3
Appearance: No Report1)
Melting point: -87.9°C 2)
Boiling point: 183.3°C 2)
Specific gravity: No Report1)
Vapor pressure: 141 Pa (25°C) 2)
Partition coefficient: Log Pow = 4.38(observed value)2)
Degradability:
Hydrolyzability: No Report
Biodegradability: No Report
Solubility: Water: 11.8 mg/L (25°C)2)
Organic solvents: No Report 1).
Amount of production/import: No data are available on production/import3).
Usage:
Intermediate of synthesis of chemicals and raw material for liquid crystal
Applied law and regulations: Marine Pollution Prevention Law
1)
HSDB, 2001; 2)PHYSPROP, 2000; 3)Ministry of International Trade and Industry, 1999
37
n-Butylbenzene
1. Toxicity Data
1) Information on adverse effects on human health
Currently, no reports are available about n-butylbenzene-associated health impairment
in humans.
2) Information on endocrine system and reproductive system
(1) in vitro test results related to receptor binding (Attachment-1)
In estrogen receptor binding assay, n-BB did not bind to rat and human estrogen
receptors up to the concentration of 10-4M (Blair et al., 2000; CERI, 2001a). In reporter
gene assay, n-BB did not induce estrogen responsive element (ERE)-dependent gene
transcription activation mediated by human estrogen receptors within concentration ranges
of 10-11-10-5M (CERI, 2001a). In reporter gene assay by yeast two-hybrid assay, n-BB
did not induce gene transcription activation up to 3×10-3M (Nishihara et al., 2000).
(2) in vivo test results in mammals (Attachment-2)
In uterotrophic assay to detect estrogen or anti-estrogen activity (in accordance with the
OECD draft guidelines), n-BB caused no change in uterine weight in ovariectomized
female SD rats (8 weeks of age) when given subcutaneously at doses of 0, 4, 40 and 400
mg/kg/day for 7 days. In another experiment in which ovariectomized female SD rats (8
weeks of age) were treated subcutaneously with 0, 4, 40 or 400 mg/kg/day of n-BB in
combination with 0.3 µg/kg/day of 17α-ethinylestradiol for 7 days, uterine weight
remained unaffected (Attachment-2(1)) (CERI, 2001b).
In Hershberger assay to detect androgen or anti-androgen activity (in accordance with
the OECD draft guidelines), n-BB was administered to castrated male SD rats (7 weeks of
age) by oral gavage at doses of 0, 4, 40 and 400 mg/kg/day for 10 days, producing no
abnormal changes in male accessory reproductive organ weights in any groups. In order
to assess anti-androgen activity of n-BB, castrated male SD rats (7 weeks of age) were
given n-BB by oral gavage at 0, 4, 40 and 400 mg/kg/day plus testosterone propionate at
0.4 mg/kg/day, s.c., for 10 days. The male accessory reproductive organ weights
remained unchanged (Attachment-2(1)) (CERI, 2001b).
In male SD rats, intraperitoneal administration of n-BB at 5 mmol (671 mg)/kg/day for 4
days induced hepatic microsomal aminopyrine- and 7-ethoxycoumarin-metabolizing enzyme
38
n-Butylbenzene
activities, testosterone 16 β-hydroxylation activity and cytochrome P450 2B1 and 2B2. On
the other hand, n-BB inhibited testosterone hydroxylation at 2β-, 6β-, 15α-, 16α- and 16βpositions in liver microsomes (Attachment-2(2)) (Imaoka & Funae, 1991).
3) Information on general toxicity
(1) Acute toxicity (Table 1)
Table 1 Results of acute toxicity studies
Oral LD50
Inhalation LD 50
Percutaneous LD 50
Subcutaneous LD 50
* Tanii et al., 1995
Mouse
−
−
−
1994.5 mg/kg*
Rat
−
−
−
−
Rabbit
−
−
−
−
(2) Repeated-dose toxicity
At present, no data are available on repeated-dose toxicities.
4) Information on mutagenicity/genotoxicity and carcinogenicity
(1) Mutagenicity/genotoxicity
At present, no data are available on mutagenicity/genotoxicity.
(2) Carcinogenicity (Table 2)
At present, no data are available on carcinogenicity.
Table 2
Carcinogenicity assessment by national and international organizations
Organization
Category
EPA
−
EU
−
NTP
−*
IARC
−
ACGIH
−
Japan Society for
−
Occupational Health
*: NTP does not provide the sign of classification.
Significance
No evaluation
No evaluation
No evaluation
No evaluation
No evaluation
No evaluation
5) Information on immune system
39
References
IRIS, 2002
ECB, 2000
NTP, 2000
IARC, 2001
ACGIH, 2001
Japan Society for
Occupational Health, 2001
n-Butylbenzene
At present, no data are available on the effects on immune system.
6) Fate and Metabolism
No data are aviable on metabolic pathway of n-BB.
2. Hazard assessment at present
No data are available on effects on human endocrine and reproductive systems.
The effects of n-BB on endocrine system were studied in the following in vitro assays:
i.e., in receptor binding assay, n-BB did not bind to human and rat estrogen receptors
(ERs), and, in the reporter gene assay, it did not induce estrogen response element (ERE)dependent gene transcriptional activation via human estrogen receptor. In yeast twohybrid assay, n-BB did not activate gene transcription, either. In in vivo test systems, nBB had no effect on uterine weight in uterotrophic assay in ovariectomized rats,
suggesting that n-BB has no estrogen or anti-estrogen effect. In Hershberger assay using
castrated rats, n-BB had no effect on male accessory reproductive organs, suggesting lack
of any androgen or anti-androgen effect. It is therefore considered that there is little
possibility for n-BB to have endocrine disrupting activity mediated by sex hormone
receptors.
At present there is no report related to effects on reproductive capability and
development of offspring.
3. Risk assessment and other necessary future measures
2-Generation reproductive toxicity study of n-BB is under way. n -BB is unlikely to
have endocrine disrupting activity mediated by sex hormone receptors and no report is
available concerning effects on fertility and development of offspring. The endocrine
disrupting effect of n-BB and associated toxicities will be comprehensively assessed by
incorporating the results of the above 2-generation reproductive study.
40
n-Butylbenzene
References
ACGIH (2001) Booklet of the threshold limit values and biological exposure indices.
Blair, R.M., Fang, H., Branham, W.S., Hass, B.S., Dial, S.L., Moland, C.L., Tong, W., Shi,
L., Perkins, R., and Sheehan, D.M. (2000) The estrogen receptor relative binding
affinities of 188 natural and xenochemicals: structural diversity of ligands.
Toxicol. Sci., 54, 138-153.
ECB (2000) Council Directive 67/548/EEC on the approximation of the laws, regulations
and administrative provisions relating to the classification, packaging and
labeling of dangerous substances : ANNEX I (http://ecb.jrc.it/).
HSDB (2001) Hazardous Substances Data Base Bank, National Library of Medicine,
(http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB).
IARC (2001) IARC Monograph on the Evaluation of Carcinogenic Risks to Humans.
Latest news in the homepage (http://www.iarc.fr)
Imaoka, S. and Funae, Y. (1991) Induction of cytochrome P450 isozyme in rat liver by
methyl n-alkyl ketones and n-alkylbenzenes. Effects of hydrophobicity of
inducers on inducibility of cytochrome P450. Biochem. Pharmacol., 42, Suppl.,
S143-S150.
IRIS (2002) Intergated Risk Information System. National Library of Medicine,
(http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?IRIS).
Jobling, S., Reynolds, T., White, R., Parker, M.G., and Sumpter, J.P. (1995) A variety of
environmentally persistent chemicals, including some phthalate plasticizers, are
weakly estrogenic. Environ. Health Persp., 103, 582-587.
Nishihara, T., Nishikawa, J., Kanayama, T., Dakeyama, F., Saito, K., Imagawa, M.,
Takatori, S., Kitagawa, Y., Hori, S., and Utsumi, H. (2000) Estrogenic activities
of 517 chemicals by yeast two-hybrid assay. J. Health Sci., 46, 282-298.
NTP (2000) U.S. Department of Health and Human Services Public Health Service,
National Toxicology Program, 9th Report on Carcinogens.
PHYSPROP (2000) Syracuse Research Corporation Physical Properties Database,
(http://esc.syrres.com/interkow/PhysProp.htm).
Tanii, H., Huang, J. and Hashimoto, K. (1995) Structure-acute toxicity relationship of
aromatic hydrocarbons in mice. Toxicol. Lett., 76, 27-31.
CERI (Chemicals Evaluation and Research Institute, Japan) (2001a): 2000 Contract
41
n-Butylbenzene
investigation/research on environment-compatible technology development on
behalf of the Ministry of Environment and Industry – Report on evaluation and
method development for hormone-like effects of exogenous substances.
CERI (Chemicals Evaluation and Research Institute, Japan) (2001b): 1999 Contract task
on behalf of the New Energy and Industrial Technology Development
Organization – Report on evaluation and method development for endocrinedisrupting effects of chemicals.
Japan Society for Occupational Health (2001): Advice on the tolerance limit. San Ei Shi,
43: 95-119.
42
n-Butylbenzene
Attachment-1 Results of in vitro studies on receptor binding
Item
ER binding
assay
Test methods and conditions
Results
Conclusion
References
-4
Methods: Human ER binding
IC50 value: >10 M
Does not bind to CERI, 2001a
ER
assay (recombinant ERα ligand) (E2: 1.1×10-9 M)
-4
Rat ER binding assay
Does not bind to Blair et al.,
IC50: >2.0×10 M
(cytoplasmic ER derived from rat (E2: 8.99×10-10 M )
ER
2000
uterus)
Yeast twoDoes not induce Nishihara et
Cells: Yeast, which carry a βREC10: >3×10-3 M
-10
hybrid assay
ER-mediated
al., 2000
galactosidase receptor gene,
(E2: 3×10 M)
gene
transfected with ERLBD (estroen
transcriptional
receptor ligard binding domain)
activation
and TLF2(coactivator) expression
plasmids.
Reporter gene Cells: HeLa cells transfected with Negative for agonist
Does not induce CERI, 2001a
assay with
human ER and ER response
activity within the
ER-mediated
recombinant
element expression plasmid.
concentration range of
gene
cell
Exposure concentration : 10-11 10-11-10-5M.
transcriptional
10-5 M
activation
(E2: PC50: <10−11 M)
ER: Estrogen receptor; E2: 17β-estradiol; IC50: 50% inhibition concentration; REC10: Concentration
equivalent to 10% of the activity of 10-7M E2; PC50: Concentration equivalent to 50% of the maximal
activity of E2.
43
n-Butylbenzene
Attachment-2
Results of studies on mammalian endocrine and reproductive systems
(1) Results of reproduction studies by biological screening tests
Animal
Administration
Administration
species
method
period
Rat
s.c.
n-BB was
(SD, female, (Uterotrophic administered for 7
6 rats/group)
assay)
days from the age
(Ovariectomized of 8 weeks, and
rats
uterus was removed
ovariectomized and weighed 8 days
at the age of 6 after initiation of
weeks)
dosing.
Rat
Oral gavage n-BB was
(SD, male, 6 (Hershberger administered for 10
rats/group)
assay)
days from the age
(Castrated rats, of 7 weeks, and
castrated at the accessory
age of 6 weeks) reproductive organs
were weighed 11
days after initiation
of dosing.
Dose
Results
References
0, 4, 40, 400 mg/kg/day No effect on the uterine weight. CERI, 2001b
n-BB at 0, 4, 40 and 400
mg/kg/day, s.c. +
ethinylestradiol at 0.3
µg/kg/day, s.c.
No effect on uterine weight.
0, 4, 40, 400 mg/kg/day No effect on male accessory
reproductive organs.
n-BB at 0, 4, 40 and 400 No effect on male accessory
mg/kg/day, p.o. +
reproductive organs.
testosterone propionate at
0.4 mg/kg/day, s.c.
CERI, 2001b
(2) Results of the studies for the effects of n-BB on cytochrome P450
Animal
Administration
Administration
species
method
period
Rat
i.p.
4 days
(SD, male)
(230-250 g)
Dose
0, 5 mmol (671 mg)/kg
44
Results
References
Induced aminopyrine- and 7Imaoka &
ethoxycoumarine-metabolizing
Funae, 1991
enzymes and testosterone 16βhydroxylation activity.
When incubated with hepatic
microsomes, n-BB inhibited
testosterone 2β-, 6β-, 15α-, 16αand 16β-site hydroxylation.