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Solubility: Water: 11.2 mg/l (20°C) 1), 13 mg/ l (25°C)1)
Organic solvents: Freely soluble in alcohol, ether, benzene, acetone, etc.1).
Amount of production/import: 1998: 11.982 t (Production 11.766 t, Import 216 t)3)
Usage: Used as plasticizer for vinyl chloride, vinyl acetate, nitrocellulose and metacryl
resins1).
Applied laws and regulations: Law Concerning the Examination and Regulation of
Manufacture, etc. of Chemical Substances, Law on Industrial Safety and Hygiene,
Law Relating to Prevention of Marine Pollution and Maritime Disaster
1) HSDB 2001; 2) "Tsusansho Koho" (daily), 1975; 3) Ministry of Economy, Trade and Industry, 1999;
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1. Toxicity Data
1) Information on adverse effects on human health
A 23-year-old male worker who accidentally ingested about 10 g of DBP experienced
vomiting, dizziness, ocular pain, lacrimation and conjunctivitis. His urine was dark
yellow in color, and the urinary sediment contained numerous erythrocytes and leukocytes.
However, all these symptoms completely disappeared after 1 month (IPCS, 1997).
A 30-year-old woman who used an anti-perspirant containing DBP developed dermatitis,
and the results of patch testing was positive for DBP (IPCS, 1997).
A 32-year-old woman who used a DBP-containing deodorant spray developed itching
and redness, and the results of patch test were positive for DBP (IPCS, 1997).
A 44-year-old man who used a watch strap containing 5% of DBP developed eczema
(IPCS, 1997).
In a survey of 38 workers involved in manufacturing phthalate esters, the frequency of
dysesthesia of four extremities increased with increasing duration of the working hour in
the phthalate ester exposure group. Some workers complained of excessive perspiration
of feet and hands and vasomotor irregularity indicative of autonomic effects.
Polyneuritis was observed in 57% of the workers, and decreased sensitivity to pain,
decreased senses of hands and feet were noted in some workers. However, the authors
reported that they could not conclude whether the findings of polyneuropathy described in
this survey report were attributable to DBP or not, because the number of the subjects
included in the survey was small (IPCS, 1997).
Regarding the toxic effects of DBP on reproductive organs, there was a report of a
survey involving 189 female workers who underwent occupational exposure. However,
since the exposure levels were unknown and these workers were also exposed to other
nonspecific substances, the authors could not draw any conclusion (IPCS, 1997).
In Puerto Rican girls, the incidence of premature breast development (thelarche) was
high. In the analysis of serum samples from the girls with premature thelarche (6 months
- 8 years old), phthalate esters mainly in DBP and DEHP (di-(2-ethylhexyl) phthalate)
were detected in 28/41 samples, and, of these 28 samples, DBP and DEHP were detected
in 13 (15-276 µg/l) and 25 (187-2,098 µg/l) samples, respectively. The serum levels of
DBP and DEHP were significantly higher than those in 35 control serum samples from the
age-matched normal girls, suggesting the possible involvement of phthalate esters mainly
consisting of DBP and DEHP in the premature thelarche in these girls. However, the
Di-n-butyl phthalate
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authors concluded that further epidemiological studies and animal experiments would be
needed to substantiate the causal relationship of the endocrine-disrupting effect of
phthalate esters with premature thelarche (Colon et al., 2000).
2) Influence on endocrine system and reproductive system
(1) in vitro results related to receptor binding (Attachment-1)
The relative binding affinity of DBP for estrogen receptor was reported to be
(1/36,000 that of 17 β-estradiol (E2)) in a binding assay using uterine homogenate from
immature female SD rats (Zacharewski et al., 1998) and 1/28,000 that of E2 in a
binding assay using human estrogen receptors expressed in Sf9/Baculovirus (Nakai et
al., 1999). In an estrogen receptor binding assay using uterine homogenate from
ovariectomized female SD rats, DBP was reported not to bind to estrogen receptors up
to 1 mM (Blair et al., 2000). In a receptor binding assay, DBP was reported not to
bind to human estrogen receptors up to 10-4M (CERI, 2001).
In a reporter gene assay using human breast carcinoma cell line MCF-7, 10 µM of
DBP showed 37% of 10 nM E2 taken as 100% (Zacharewski et al., 1998). In cell
proliferation assay with yeast strain S. cerevisiae PL3 transfected with human estrogen
reporter gene which utilizes cell proliferation in response to ligand binding to human
estrogen receptor, DBP at 10 µM induced weak cell proliferation (Zacharewski et al.,
1998). In the assay with stable transformant of HeLa cells incorporated with the
same genes as those of the above MCF-7 cells and in the yeast two-hybrid assay, DBP
had no estrogen-like activity up to 10 and 0.3 µM, respectively (Nishihara et al., 2000).
In a reporter gene assay with cultured cells, DBP did not activate gene transcription
within the concentration range of 10-11 - 10-5M (CERI, 2001).
Thus, it was suggested that DBP may bind to estrogen receptor and induce
intracellular transcriptional activation, but several reports described that DBP does not
have any affinity for estrogen receptor or induce any gene transcriptional activation
(Zacharewski et al., 1998; Nakai et al., 1999; Blair et al., 2000; Nishihara et al., 2000;
CERI, 2001).
(2) in vivo results in mammals (Attachments-2)
The effects of DBP and its metabolite mono-butyl phthalate (MBP) on endocrine
and reproductive systems in mammals are shown in Attachments-2.
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The results of the assays by each screening technique are summarized below.
In an uterotrophic assay, juvenile female SD rats (aged 20 days) were given DBP
subcutaneously at doses of 0, 40, 200 and 1,000 mg/kg/day for 3 days (in accordance
with the OECD draft guidelines), but uterine weight remained unchanged (Yamasaki et
al., 2001). In ovariectomized SD rats (aged 31-34 days), oral administration of DBP
at doses of 0, 20, 200 and 2,000 mg/kg/day for 4 days had no effect on uterine weight
(Zacharewski et al., 1998). Further, in ovariectomized SD rats (age, unspecified)
given DBP subcutaneously at 0, 200 and 400 mg/kg/day or orally at 1,000 mg/kg/day
for 2 days and then 0.5 mg/rat of progesterone once subcutaneously on the third day,
uterine weight remained unaffected (Gray et al., 1999).
In the Hershberger assay for detection of anti-androgenic activity (in accordance
with the OECD draft guidelines), castrated male Alpk:Apf SD rats (aged 7 weeks)
were given DBP by oral gavage at 0, 500 and 1,000 mg/kg/day in combination with
subcutaneous administration of testosterone propionate at 0.4 mg/kg/day for 10 days,
and 4 replicate assays were performed. The results suggested the anti-androgenic
activity of DBP, but the positive result was not definitely reproducible (Ashby &
Lefevre, 2000b). In peripubertal male rat assay, DBP was administered by gavage at
0 and 500 mg/kg/day to male Alpk:Apf SD rats for 14 days immediately after weaning
in accordance with the procedures proposed by EDSTAC (Endocrine Disruptor
Screening and Testing Advisory Committee), causing decrease in epididymal and
seminal vesicle weights. When administration was continued for 34 days, these
changes plus delayed preputial separation were observed (Ashby & Lefevre, 2000a).
The results of studies on the effects of DBP on male reproductive organs are shown
below.
In a male mouse assay (strain and age, unspecified) in which DBP was administered
orally at 0 and 2,000 mg/kg/day for 10 days, decrease in testis weight and testicular
tissue injuries (details, unknown) were reported in 2,000 mg/kg/day group (Gangolli,
1982).
In a 1-week feeding study in which male Wistar rats (aged 5 weeks) fed the diet
containing 0 and 2% (equivalent to 0 and 1,000 mg/kg/day) of DBP, testis showed
decrease in its weight, decrease in primary spermatocytes, marked increase in
testicular testosterone content and decrease in zinc content in the 1,000 mg/kg/day
group (Oishi & Hiraga, 1980a).
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In a male Wistar rat (aged 5 weeks) assay in which DBP was administered by
gavage at 0, 250, 500 and 1,000 mg/kg/day for 15 days, the testicular toxicities
included degeneration of seminiferous tubules and biochemical changes such as
decrease in acid phosphatase activity and increase in LDH, γ-GTP, β-glucuronidase (β-
G) and glucose-6-phosphate dehydrogenase (G6PDH) activities in 250 mg/kg/day or
higher groups and decrease in testicular weight, impaired spermatogenesis and
decrease in sorbitol dehydrogenase (SDH) activity in 500 mg/kg/day or higher groups
(Srivastava et al., 1990).
In a 13-week feeding study in male F344 rats (aged 5-6 weeks) fed the diets
containing DBP at 0, 2,500, 5,000, 10,000, 20,000 and 40,000 ppm (equivalent to 0,
176, 359, 720, 1,540 and 2,964 mg/kg/day), the abnormal changes included focal
atrophy of seminiferous tubules in 720 mg/kg/day or higher groups, decrease in testis
weight and decrease in testicular zinc and serum testosterone levels in the 1,540
mg/kg/day or higher groups and decrease in serum zinc level in 2,964 mg/kg/day
group (CERHR, 2000; Marsman, 1995).
In an inhalation toxicity study in which male Wistar rats (aged 4 weeks) were
exposed to 0, 0.5 and 50 mg/m3 (0, 0.044 and 4.4 ppm) of DBP mist for 6 hours/day
for 3 or 6 months, testis weight remained unaffected (Kawano, 1980).
In a 10-day oral administration study of DBP in male guinea pigs (strain and age,
unspecified) at 0 and 2,000 mg/kg/day, decrease in testis weight and degeneration of
Sertoli cells were observed in 2,000 mg/kg/day group (Gangolli, 1982).
In experiments in which DBP was administered orally at 0 and 2,000 mg/kg/day for
7-9 days, Gray et al. reported decrease in testis weight and toxic effects on
seminiferous tubules in TO mice, SD rats and Dunkin-Hartley guinea pigs receiving
2,000 mg/kg/day, but no testicular toxicities in Syrian hamsters (Gray et al., 1982).
The results of the reproductive/developmental toxicity studies are shown below.
In an NTP protocol study in which male and female CD-1 mice (aged 11 weeks)
were fed the diets containing DBP at 0, 0.03, 0.3 and 1.0% (equivalent to 0, 52.5, 525
and 1,750 mg/kg/day) for 105 days (7 days before and 98 days during co-housing),
there was a significant decrease in the percentage of pregnant rat pairs, the number of
live pups per litter, propotion of pups born alive and live pups in 1,750 mg/kg/day
group. In the cross-over mating, the percentage of pregnant rat, litter size, percentage
of pups born alive and body weight of live fetuses decreased in females in high-dose
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group mated with the control males (Lamb et al., 1987).
In a teratogenicity study in which female ICR mice (mated at the age of 8-16 weeks)
were fed the diets containing DBP at 0, 0.05, 0.1, 0.2, 0.4 and 1.0% (equivalent to 0,
80, 180, 350, 600 and 2,100 mg/kg/day) on gestation days 0-18, increase in embryonic
death, exencephaly, spina bifida and decrease in maternal body weight were observed
in 2,100 mg/kg/day group (Shiota et al., 1982).
In feeding studies in which female B6C3F1 mice (age, unspecified) were fed the
diets containing DBP at 0 and 20,000 ppm (equivalent to 0 and 2,600 mg/kg/day)
during the gestation period, complete resorption of all embryos occurred in 2,600
mg/kg/day group (ATSDR, 1990; Killinger et al., 1988a).
In a developmental toxicity study in which female Wistar rats (mated at the age of
10-14 weeks) were given DBP by oral gavage at 0, 750, 1,000 and 1,250 mg/kg/day on
gestation days 7-9, 10-12 or 13-15, post-implantation losses increased in all dams
treated on these gestation days in 750 mg/kg/day or higher groups. When DBP was
given on gestation days 7-9, increase in incidence of skeletal malformation and
decreases in number of live fetuses and in fetal body weight were observed in 750
mg/kg/day or higher groups. When given on gestation days 10-12, DBP caused
decrease in number of live fetuses in 750 mg/kg/day or higher groups and decrease in
fetal body weight in 750 and 1,250 mg/kg/day groups, but no fetal malformations were
observed. Administration on gestation days 13-15 resulted in increase in incidences
of cleft palate and abnormal fusion of sternebrae in 750 mg/kg/day or higher groups
and decrease in number of live fetuses in 1,000 mg/kg/day or higher groups (Ema et al.,
1995a). In this experiment, malformation of fetuses were observed when DBP was
given on gestation days 7-9 and 13-15, but not on gestation days 10-12, and the same
results are reported in a similar experiment using 1,500 mg/kg/day as the high dose
(Ema et al., 1994). In another developmental toxicity study in which female Wistar
rats (mated at the age of 14 weeks) were given single oral administration of DBP at 0
and 1,500 mg/kg/day on one day during gestation days 6-16, DBP induced obvious
skeletal malformations (cervical and thoracic vertebrae and ribs) when given on
gestation days 8, 9 or 15, exencephaly and dilatation of renal pelvis when given on
gestation day 9 and cleft palate when given on gestation day 15, and these findings
supported the results in the above study (Ema et al., 1997).
In a feeding study in which female Wistar rats (mated at the age of 14 weeks) were
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fed the diets containing DBP at 0, 0.5, 1.0 and 2.0% (equivalent to 0, 331, 555 and 661
mg/kg/day) on gestation days 11-21, maternal body weight gain was suppressed in 555
mg/kg/day or higher groups. Undescended testis and reduced anogenital distance
(AGD) were observed in 555 mg/kg/day or higher groups, and decrease in fetal body
weight, cleft palate and abnormal sternal fusion in 661 mg/kg/day group. However,
DBP had no effect on development of female reproductive organs (Ema et al., 1998).
Based on the results of oral administration study in female Wistar rats (mated at the
age of 14 weeks) given DBP at 0, 500 (only on gestation days 15-17), 1,000 and
1,500 mg/kg/day on gestation days 12-14, 15-17 and 18-20, the authors concluded that
the critical period for induction of undescended testis and reduced AGD by DBP was
gestation days 15-17 (Ema et al., 2000a).
In an oral administration study in which female SD rats (mated at the age of 8
weeks) were give DBP at 0, 100, 250 and 500 mg/kg/day or at 0, 0.5, 5, 50, 100 and
500 mg/kg/day on gestation days 12-21, abnormal findings in offsprings included
nipple retention in male offsprings in 100 mg/kg/day or higher groups, reduced AGD
in 250 mg/kg/day or higher groups and hypospadias, cryptorchidism, hypoplasia of
prostate, epididymis, seminal vesicle and ductus deferens, epithelial degeneration of
seminiferous tubules, interstitial cell hyperplasia in testis, atrophy of vas deferens and
decreased weights of testis, seminal vesicle, epididymis, prostate and levator ani-
balbocarvernosus in male offspring in 500 mg/kg/day group. Based on these, the
authors concluded that the NOAEL and LOAEL of DBP for male reproductive
malformations are 50 and 100 mg/kg/day, respectively, under the conditions of 10-day
exposure during pregnancy (Mylchreest et al., 1999; Mylchreest et al., 2000).
In an oral administration study in which female LE rats (age, unspecified) were
given DBP at 0 and 500 mg/kg/day on gestation days 16-19, increase in resorptions
and abnormalities in male offsprings such as reduced AGD, decreased weights of
seminal vesicle, prostate and levator ani-balbocavernosus and retained nipple (areolas)
in 500 mg/kg/day group. In a similar experiment, female SD rats (age, unspecified)
were given DBP by oral gavage at 0 and 500 mg/kg/day from gestation day 14 to day
3 postpartum. In 500 mg/kg/day group, the number of pups delivered decreased, and
male offsprings showed reduced AGD, hypospadias, atrophy or hypoplasia of the testis
and epididymis, decreased weights of seminal vesicle, prostate, epididymis, testis,
levator ani-balbocavernosus and penis and retained nipple (Gray et al., 1999).
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In another study, male and female LE or SD rat weanlings were given DBP by
gavage at 0, 250, 500 and 1,000 (only to males) mg/kg/day from weaning through the
subsequent periods of growth, mating and lactation of F1 animals, and then the F1
animals from the treated groups were mated with untreated animals. In F0 animals,
the abnormal findings included delayed sexual maturation in both sexes in 250
mg/kg/day or higher groups, reduced fertility in 500 mg/kg/day group, testicular
atrophy and hypospermatogenesis in males in 500 mg/kg/day or higher groups and
infertility in males in 1,000 mg/kg/day group. In the F1 animals, malformations,
reduced conception rate and reduced epididymal sperm count were observed in 250
mg/kg/day or higher groups (Gray et al., 1999).
In a continuous breeding study in male and female SD rats (aged 10 weeks), the
diets containing DBP at 0, 0.1, 0.5 and 1.0% (equivalent to 0, 52, 256 and
509 mg/kg/day in males and to 0, 80, 385 and 794 mg/kg/day in females) were
administered to F0 animals. Dietary administration of DBP caused decreased total
number of live F1 pups in 0.1% (equivalent to 52-80 mg/kg/day) or higher groups,
decreased body weight of live F1 pups in 0.5% (equivalent to 256-385 mg/kg/day) or
higher groups and suppressed maternal body weight gain in 1.0% (equivalent to 509-
794 mg/kg/day) group. In the cross-over mating trial of parental F0 animals, the body
weight of the pups from the high-dose females paired with the control males decreased.
When the control females were paired with the high-dose males (reversed pairing),
however, the offspring body weight was not changed. In F0 animals, liver and kidney
weights increased in both sexes in 1.0% (equivalent to 509-794 mg/kg/day) group.
However, male and female reproductive organs were grossly intact, nor were there any
abnormalities in sperm count, sperm motility and estrus cycle. In F1 animals, DBP
caused decreased body weight of live F2 pups in 0.1% (equivalent to 52-80 mg/kg/day)
or higher groups and marked decrease in copulation and pregnancy indexes and
decrease in body weight in male and female F1 parental animals in 1.0% (equivalent to
509-794 mg/kg/day) group. In F1 generation, increased kidney weight was also
observed in males in 0.5% (equivalent to 256-385 mg/kg/day) or higher groups, and
increased liver weight, decreased weights of prostate, seminal vesicle and testis,
decrease in epididymal sperm count and testicular spermatid head counts, degeneration
of seminiferous tubules, interstitial cell hyperplasia and epididymal hypoplasia in
males in 1.0% (equivalent to 509-794 mg/kg/day) group. The authors therefore
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concluded that reproductive/developmental effects of DBP on offspring generation
was greater than those on the parental generation (Wine et al., 1997).
In male SD rats (aged 4-6 weeks), oral administration of MBP, a metabolite of DBP,
at 0 and 2,000 mg/kg/day resulted in decrease in testis weight and diffuse atrophy of
seminiferous tubules in 2,000 mg/kg/day group (Gray et al., 1982). When MBP was
administered orally to pregnant Wistar rats, the offspring showed skeletal
malformation, cleft palate, dilatation of renal pelvis and undescended testis
(Attachment-3) (CERHR, 2000; Ema et al., 1995b, 1996a, 1996b; Imajima et al.,
1997).
In the NTP-CERHR (Center for Evaluation of Risks to Human Reproduction)
Expert Panel Report on DBP, it was described that various malformations seen in male
F1 animals from the pregnant rats given DBP orally were not mediated by androgen
receptors but were due to inhibition of testosterone biosynthesis. However, the
literature that constitutes the basis of this speculation was not given, and the
mechanistic details remained unknown (CERHR, 2000).
3) Information on general toxicity
(1) Acute toxicity (Table 1)
The LD50 values for each administration route in mice, rats and rabbits are shown in
Table 1 (ACGIH, 1991; ATSDR, 1990; German Chemical Society, 1987). In the
inhalation exposure experiment in mice, the symptoms of acute toxicity such as
labored breathing, motor ataxia, local paralysis, convulsion and coma were observed,
with some deaths due to respiratory failure. In rats, weight loss and decrease in blood
components were reported (ACGIH, 1991). In an inhalation experiment in cats,
salivation, unrest and hypoactivity were reported (German Chemical Society, 1987).
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Table 1 Results of acute toxicity studies
Mouse Rat Rabbit
Oral LD50 More than 20,000 mg/kg 3,000 – 8,000 mg/kg* -
Inhalation LD50 - - -
Percutaneous LD50 - - More than 20,000 mg/kg
Intraperitoneal LD50 4,000 mg/kg 3,050 mg/kg -
*: Variable depending on the studies.
(2) Repeated-dose toxicity (Attachment-3)
In a 7-day feeding study in male ICR mice (age, unspecified) fed the diets
containing DBP at 0 and 20,000 ppm (equivalent to 0 and 2,600 mg/kg/day), mice in
2,600 mg/kg/day group showed decrease in body weight, increase in liver weight,
decrease in kidney weight and decreased zinc concentrations in testis and liver
(ATSDR, 1990; Oishi & Hiraga, 1980b). In another feeding study in mice (strain and
age, unspecified) in which DBP was administered in diet at 0, 628 and 1,248
mg/kg/day for 21 days, body weight decreased in 1,248 mg/kg/day group (ATSDR,
1990). In a 13-week feeding study in which B6C3F1 mice (aged 6 weeks) were fed
the diets containing DBP at 0, 1,250, 2,500, 5,000, 10,000 and 20,000 ppm (equivalent
to 163, 353, 812, 1,601 and 3,689 mg/kg/day in males and to 238, 486, 971, 2,137 and
4,278 mg/kg/day in females), the abnormal changes included suppressed body weight
gain and increase in liver weight in males in 812 mg/kg/day or higher groups, increase
in kidney weight in females in 238 mg/kg/day or higher groups and eosinophilic
granules, increased staining intensity of cytoplasm and increased lipofuscin granules
in hepatocytes in males in 1,601 mg/kg/day or higher groups and females in 4,278
mg/kg/day group (CERHR, 2000; Marsman DS, NTP, 1995). In a long-term study in
which CD-1 mice (aged 11 weeks) were fed the diets containing DBP at 0, 0.03, 0.3
and 1.0% (equivalent to 0, 52.5, 525 and 1,750 mg/kg/day) for 126 days, decrease in
body weight and increase in liver weight were observed in 1,750 mg/kg/day group
(CERHR, 2000; Reel et al., 1984).
In a 21-day feeding study in rats (strain and age, unspecified) in which DBP was
administered at doses of 0 and 348 mg/kg/day, decrease in blood cholesterol and
increase in liver weight were observed in 348 mg/kg/day group (ATSDR, 1990; Bell,
1982). In another 21-day feeding study in rats (strain and age, unspecified) in which
DBP was administered at doses of 0, 628 and 1,248 mg/kg/day, liver and kidney
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weight increased in 628 mg/kg/day or higher groups and in 1,248 mg/kg/day group,
respectively (ATSDR, 1990; BIBRA). In a feeding study in male and female Wistar
rats (age, unspecified) in which DBP was administered in diet at doses equivalent to 0
and 250 mg/kg/day for 34-36 days, decrease in body weight and hepatocellular
necrosis were observed in 250 mg/kg/day group, and inhibition of hepatic
mitochondrial energy metabolism was also reported (ATSDR, 1990; Murakami et al.,
1986a). In another feeding study in which male and female Wistar rats (age,
unspecified) received DBP in diet at doses equivalent to 0 and 2,500 mg/kg/day for
35-45 days, hepatic mitochondrial oxidation decreased, and spleen weight increased
(ATSDR, 1990; Murakami et al., 1986b). When male and female Wistar rats (aged 6
weeks) were fed the diets containing DBP at 0, 400, 2,000 and 10,000 ppm (equivalent
to 0, 27, 142 and 688 mg/kg/day in males and to 0, 33, 161 and 816 mg/kg/day in
females) for 3 months, males in 688 mg/kg/day group showed peroxisome
proliferation and histopathological changes in liver, decrease in thyroid hormone (T3)
levels and anemia, and females in 816 mg/kg/day group showed increases in liver and
kidney weight, decrease in thyroid hormone (T3) levels with no histopathological
changes. And also, to evaluate neurological toxicity neurologic functional (behavior,
reflex, audition, vision, ordor detection sense, nociception, etc.) and histopathological
examinations were conducted and no effects were observed at all dose levels.
Therefore, considering these parameters NOAEL was determined as 142 mg/kg/day in
male and 161 mg/kg/day in female. (CERHR, 2000; BASF, 1992). In a 13-week
study in which male and female F344 rats (aged 5-6 weeks) were fed the diets
containing DBP at 0, 2,500, 5,000, 10,000, 20,000 and 40,000 ppm (equivalent to 0,
176, 359, 720, 1,540 and 2,964 mg/kg/day in males and to 0, 177, 356, 712, 1,413 and
2,943 mg/kg/day in females), the abnormal changes in males included decrease in
hemoglobin and red blood cell count, increase in platelet count and serum albumin,
increase in hepatic palmitoyl CoA oxidase (PCAO) activity and increase in liver and
kidney weights in 359 mg/kg/day or higher groups, suppressed body weight gain and
histopathological changes in liver in 720 mg/kg/day or higher groups and peroxisome
proliferation in liver in 2,964 mg/kg/day group, and those in females included increase
in hepatic PCAO activity in 356 mg/kg/day or higher groups, increase in liver and
kidney weight in 712 mg/kg/day or higher groups, suppressed body weight gain in the
1,413 mg/kg/day or higher groups and peroxisome proliferation in liver in 2,943
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mg/kg/day group (CERHR, 2000; Marsman DS, NTP, 1995).
In an inhalation study in which male Wistar rats (aged 4 weeks) were exposed to 0,
0.5 and 50 mg/m3 (0, 0.044 and 4.4 ppm) of DBP mist for 6 hours/day, 5 days/week,
for 3-6 months, decreased body weight and increased relative weight of lung were
observed in 50 mg/m3 (4.4 ppm) group (ATSDR, 1990; Kawano, 1980a; Kawano,
1980b). In another inhalation study in which rats (strain and age, unspecified) were
exposed to DBP at 0 and 2.5 ppm for 6 hours/day for 5 days, pulmonary cytochrome
P-450 content decreased in 2.5 ppm group (ATSDR, 1990; Walseth & Nilsen, 1984).
In rabbits (strain and age, unspecified), the topical application of DBP at 0 and
4,200 mg/kg/day for 90 days caused renal toxicities (details unknown) (ATSDR, 1990;
Lehman, 1955).
4) Information on mutagenicity/genotoxicity and carcinogenicity
(1) Mutagenicity/genotoxicity (Table 2)
DBP was reported to be negative in many of the reverse mutation tests using
Salmonella typhimurium strains, but positive results were also reported in some studies.
The positive results were reported in the absence of metabolic activation, but increase
in the number of revertant colonies was about twice the solvent control value and
showed no dose-response relationship (IPCS, 1997). Two gene mutation tests with
mouse lymphoma cells were reported, and DBP was positive in one assay without
metabolic activation system but only at the dose which was cytotoxic (IPCS, 1997).
In another assay, DBP was positive in the presence of exogenous metabolic activation
system (Barbar, 2000). DBP was reported to be negative in all chromosomal
aberration tests (IPCS, 1997). DBP was also negative in BALB/3T3 cell
transformation assay (Barbar et al., 2000). In a DNA repair test using human
mucosal cells of upper respiratory tract, however, DBP was positive for DNA-
damaging potential (Kleinsasser, 2000). No reports are available about the in vivo
assays on DBP.
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Table 2 Results of mutagenicity/genotoxicity studies
Test method Cells/animal species used Results* ReferencesS. typhimurium strain TA100, S9(+/-), 13 - 50µg/m l(DBP induces significant increases in thenumber of revertant colonies under the S9(-)condition, but the increases are not 2-fold orgreater than that in the control group.)
DNA repair test Human mucosal cells of the upper respiratorytract, 354 µmol/m l
+ Kleinsasser, 2000
*-: Negative +: Positive +w: Weakly positive
(2) Carcinogenicity (Table 3)
In a one-year study, Wistar rats given to 0 and 55 mg/kg/day of DBP in diet showed
no DBP-related tumor development. In rats (strain and age, unspecified) given DBP
at 0 and 100-500 mg/kg/day for 15-21 months and those fed the diet containing DBP
at 2,500 ppm for 18 months or more, no DBP-related tumor development was
observed (ATSDR, 1990; German Chemical Society, 1987).
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Table 3 Carcinogenicity assessment by national and international organizations.
Organization Category Significance ReferencesEPA Group D Not classifiable as a human carcinogen. IRIS, 2002EU - No evaluation. ECB, 2000NTP - No evaluation NTP, 2000IARC – No evaluation IARC, 2001ACGIH - No evaluation ACGIH, 2001
Japan Society forOccupational Health - No evaluation
Japan Society forOccupational Health,
2001
5) Information on immune system
At present, no reports are available on the effects on the immune system.
6) Fate and Metabolism
DBP was slowly absorbed from skin, but was rapidly absorbed from gastrointestinal
tracts (IPCS, 1997). In a single oral administration study in which rats were given
60 mg/kg of 14C-DBP (the position of radiolabel, unspecified), radioactivity was detected
in liver, kidney, blood, muscle, adipose tissues, stomach and small intestine 24 hours after
administration (IPCS, 1997; Keys et al., 2000). In a 12-week study, however, the
radioactivity was not accumulated in rats fed the 0.1% DBP diet (IPCS, 1997). In rats
given single oral administration of 7-14C-DBP at 0.27 or 2.31 g/kg, 92% and 83% of the
dose, respectively, were excreted into urine by 48 hours after administration. In the urine,
CERI (Chemicals Evaluation and Research Institute, Japan) (2001): Report on evaluation
and method development for hormone-like effects of exogenous substances. 2000
Contract investigation/research on environment-compatible technology development
on behalf of the Ministry of Environment and Industry.
"Tsusansho Koho" (daily) (1975)
Ministry of Economy, Trade and Industry (1999): Survey on the production/import of
existing chemical substances in 1998
Japan Society for Occupational Health (2001): Advice on the tolerance limit. San Ei Shi,
43: 95-119.
Di-n-butyl phthalate
263
Di-n-butyl phthalate
264
Attachment-1 Results of in vitro studies on receptor binding
Item Test methods and conditions Results Conclusion ReferencesMethods: Competitive binding assaywith [3H]-E2 as a ligand. Receptor:Human ER expressed inSf9/Baculovirus. Temperature: 25°C,pH: 7.4
Four replicate assays wereperformed. In the second assay,weights of bulbospongiosus muscle+ levator ani muscle, bulbourethralgland, seminal vesicle and prostatedecreased significantly in 500mg/kg/day or higher groups ascompared with the control group(treated with TP). In other 2assays, however, no significantdecrease was observed in seminalvesicle and prostate weights in1,000 mg/kg/day group, and,moreover, no significant decreasewas observed in bulbourethral glandweight in one of these two assays.It is thought that DBP may have ananti-androgenic effect, but theresults were not definitelyreproducible in four replicateassays.
Ashby &Lefevre,2000b
22-23 days of age14 days
0, 500 mg/kg/day Decreased testis and seminal vesicleweights at 500 mg/kg/day.
22-23 days of age14 days of dosingperiod + 20 daysof recovery period
0, 500 mg/kg/day Decreased testis and epididymalweights at 500 mg/kg/day.
35-36 days of age14 days
0, 500 mg/kg/day No abnormal changes in testis andaccessory reproductive organs.
Rat(Alpk:ApfSD,male)
Oral gavage
22-23 days of age34 days
0, 500 mg/kg/day Decreased testis and seminal vesicleweights and delay in prepuceseparation at 500 mg/kg/day.
Ashby &Lefevre,2000a
Di-n-butyl phthalate
266
(2) Results of reproductive/developmental toxicity studies
Animal species Administrationmethod
Administrationperiod
Dose Results References
Mouse (TO,male)
Oral gavage 4-6 weeks of age7-9 days
0, 2000 mg/kg/day Decreased testis weight and slightatrophy of seminiferous tubules at2,000 mg/kg/day.
Rat (SD, male) Oral gavage 4-6 weeks of age7-9 days
0, 2000 mg/kg/day Decreased testis weight and diffuseatrophy of vas deference at 2,000mg/kg/day.
Gray et al.,1982
Rat (Wistar,male)
By feeding 5 weeks of age1 week
0, 2%(Corresponding to 0and 1,000mg/kg/day)
Decreased testis weight and primaryspermatocytes and increasedconcentration of testosterone anddecreased concentration of zinc intestis at 1,000 mg/kg/day.
Oishi &Hiraga,1980a
Rat (Wistar,male)
Oral gavage 5 weeks of age15 days
0, 250, 500, 1,000mg/kg/day
Degeneration of seminiferoustubules, interstitial edema,decreased acid phosphatase (AP)activity and increased activities ofLDH, γ-GTP, β-glucuronidase (β-G)and glucose-6-phosphatedehydrogenase (G6PDH) in testis at250 mg/kg/day or above.Decreased testis weight, impairedspermatogenesis and decreasedsorbitol dehydrogenase (SDH)activity in testis at 500 mg/kg/dayor above.(The decreased SDH and increasedLDH are thought to indicatedestruction of germinal epithelium.β-G and γ-GTP are the markers forSertoli cells, and the increases inthese marker enzymes are thoughtto be associated with decrease ingerminal epithelium. AP exists inlysosomes of Sertoli cells andgerminal epithelium and is knownto increase during development ofprimary spermatocytes andtesticular maturation. Thedecrease in AP seems to implyinhibition of spermatogenicprocesses. The G6PDH activity isreported to increase at the time oftesticular injuries.)
Focal atrophy of seminiferoustubules in testis at 720 mg/kg/day orabove, decreases in testis weight,testicular concentration of zinc andserum concentration of testosteroneat 1,540 mg/kg/day or above anddecrease in serum concentration ofzinc at 2,964 mg/kg/day.
CERHR,2000,
Marsman,1995
Rat (Wistar,male)
Inhalation 4 weeks of age3-6 months(6 hr/day)
0, 0.5, 50 mg/m3
(0, 0.044, 4.4 ppm)No effect on the relative testisweight.
Kawano,1980
Guinea pig(Dunkin-Hartley, male)
Oral gavage 4-6 weeks of age7 days
0, 2,000 mg/kg/day Decreased testis weight and diffuseatrophy of seminiferous tubules at2,000 mg/kg/day.
Decrease in fertility, number ofpups delivered and number of livepups at 1,750 mg/kg/day.In cross-over mating, decrease infertility, number of pups delivered,number of live pups and bodyweight of live fetuses in females inthe high dose group mated withcontrol males.
Lamb etal., 1987
Mouse (ICR,female)
By Feeding Mated at the ageof 8-16 weeksOn gestation days0-18
Decreased maternal body weight,increased embryonic deaths andexencephaly/spina bifida at2,100 mg/kg/day.
Shiota,1982
Mouse(B6C3F1,female)
By Feeding Age, unspecifiedGestation day 0-lactation day 28(48 days)
0, 20,000 ppm(Corresponding to 0and 2,600mg/kg/day)
Complete resorptions of all embryosat 2,600 mg/kg/day.
ATSDR,1990,
Killinger etal., 1988a
Di-n-butyl phthalate
268
Animal species Administrationmethod
Administrationperiod
Dose Results References
Rat (Wistar,female)
Oral gavage Mated at the ageof 14 weeksOn one dayduring gestationdays 6-16
0, 1,500 mg/kg/day Suppressed maternal body weightgain immediately afteradministration in all DBP groups.Increased post-implantation lossesupon exposure upon gestation days6, 8-10 and 12-16.A decrease in number of live fetusesupon exposure on gestation days 9and 13-15.
Skeletal malformations uponexposure on gestation day 8.Skeletal malformations,exencephaly, dilatation of renalpelvis, etc. upon exposure ongestation day 9.Skeletal malformations and cleftpalate upon exposure on gestationday 15.
Ema et al.,1997
Rat (SD,female)
Oral gavage Age, unspecifiedGestation day 14
0, 500, 1,000, 1,500,2,000 mg/kg/day
Increased resorptions, decreasedfetal body weight and skeletalabnormalities at 1,500 mg/kg/day orabove.The transplacentral transfer of DBPinto fetuses was 0.12-0.15% or lessof the dose.DBP is metabolized into MBP andthen transferred to fetal tissues.
Saillenfaitet al., 1998
Mated at the ageof 10-14 weeksGestation days 7-9
0, 750, 1,000, 1,500mg/kg/day
Maternal deaths and completeresorptions of all embryos at 1,500mg/kg/day.Skeletal malformations, increasedpost-implantation losses, decreasednumber of live fetuses anddecreased fetal body weight at 750and 1,000 mg/kg/day.
Mated at the ageof 10-14 weeksGestation days10-12
0, 750, 1,000, 1,500mg/kg/day
Complete resorptions of all embryosat 1,500 mg/kg/day.Increased post-implantation lossesand decreased number of livefetuses.No malformed fetuses.
Rat (Wistar,female)
Oral gavage
Mated at the ageof 10-14 weeksGestation days13-15
0, 750, 1,000 ,1,500mg/kg/day
Maternal deaths and completeresorptions of all embryos at 1,500mg/kg/day. Cleft palate, skeletalmalformations and increased post-implantation losses at 750 and 1,000mg/kg/day. Decreased number oflive fetuses and decreased fetalbody weight at 1,000 mg/kg/day.
Ema et al.,1994
Di-n-butyl phthalate
269
Animal species Administrationmethod
Administrationperiod
Dose Results References
Mated at the ageof 10-14 weeks,Gestation days 7-9
0, 750, 1,000 ,1,250mg/kg/day
Increases in the number ofmalformed fetuses (skeletalmalformations) and post-implantation losses and decreases inthe number of live fetuses and fetalbody weight at 750 mg/kg/day orabove.
Mated at the ageof 10-14 weeks,Gestation days10-12
0, 750, 1,000 ,1,250mg/kg/day
Increase in post-implantation lossesand decrease in number of livefetuses at 750 mg/kg/day or above.decrease in fetal body weight at 750and 1,250 mg/kg/day.No increase in the number ofmalformed fetuses.
Rat (Wistar,female)
Oral gavage
Mated at the ageof 10-14 weeks,Gestation days13-15
0, 750, 1,000 ,1,250mg/kg/day
Increases in number of malformedfetuses (cleft palate, abnormalsternal fusion) and post-implantation losses at 750mg/kg/day or above. Decreasednumber of live fetuses at 1,000mg/kg/day or above.
Ema et al.,1995a
Rat (Wistar,female)
By feeding Mated at the ageof 10-14 weeks,Gestation days11-21
0, 0.5, 1.0, 2.0%(Corresponding to0, 331, 555 and 661mg/kg/day)
Suppressed maternal body weightgain at 555 mg/kg/day or above.Undescended testis and reducedano-genital distance (AGD) at 555mg/kg/day or above. Decreasedfetal body weight, cleft palate andabnormal sternal fusion at 661mg/kg/day.No effect on female reproductiveorgans.
Ema et al.,1998
Mated at the ageof 10-14 weeks,Gestation days12-14
0, 1,000, 1,500mg/kg/day
Suppressed maternal body weightgain and decreased fetal bodyweight at 1,000 mg/kg/day orabove. Increased resorptions,decreased number of live fetusesand undescended testis at 1,500mg/kg/day
Mated at the ageof 10-14 weeks,Gestation days15-17
0, 500, 1,000, 1,500mg/kg/day
Suppressed maternal body weightgain at 1,000 mg/kg/day or above.Undescended testis and reducedAGD at 500 mg/kg/day or above.Increased resorptions, decreasednumber of live fetuses anddecreased fetal body weight at1,500 mg/kg/day.
Rat (Wistar,female)
Oral gavage
Mated at the ageof 10-14 weeks,Gestation days18-20
0, 1,000, 1,500mg/kg/day
Suppressed maternal body weightgain and decreased fetal bodyweight at 1,000 mg/kg/day orabove.
Ema et al.,2000
Di-n-butyl phthalate
270
Animal species Administrationmethod
Administrationperiod
Dose Results References
Rat (SD,female)
Oral gavage Age, unspecifiedGestation days 3-21Days 1-20 afterbirth
0, 250, 500, 750mg/kg/day
Effects on F1 animals:Hypospadias, absent or hypoplasticepididymis, degeneration andatrophy of seminiferous tubules andabsence of germinal cells in maleoffspring at 250 mg/kg/day orabove. Reduced AGD, testicularatrophy and absence or atrophy ofthe prostate and seminal vesicle at500 mg/kg/day or above.Decreased offspring viability at750 mg/kg/day.No effect on female reproductiveorgans.
Mylchreestet al., 1998
Rat (SD,female)
Oral gavage Mated at the age of8 weeksGestation days 12-21
0, 100, 250, 500mg/kg/day
Effects on dams:Decreased maternal body weight onthe day of delivery at 500mg/kg/day.Effects on F1 animals:Delayed prepuce separation in maleoffspring at 100 mg/kg/day orabove. Nipple retention andreduced AGD in male offspring at250 mg/kg/day or above.Hypospadias, undescended testis,hypoplasia of the prostate,epididymis and vas deferens,epithelial degeneration inseminiferous tubules andhyperplasia of interstitial cells intestis in male offspring at 500mg/kg/day.Lowest-observed adverse-effect-level (LOAEL) for F1 generation =100 mg/kg/day.
Mylchreestet al., 1999
Di-n-butyl phthalate
271
Animal species Administrationmethod
Administrationperiod Dose Results References
Rat (SD,female)
Oral gavage Mated at the age of8 weeksGestation days 12-21
0, 0.5, 5, 50, 100,500 mg/kg/day
No maternal toxicity.Effects on F1 animals:Retained nipple in male offspring at100 mg/kg/day or above.Hypospadias, absent ventralprostate, hypoplastic epididymis,hypoplastic vas deferens,hyperplasia of testicular interstitialcells, hypoplastic seminal vesicle,atrophy of vas deferens, reducedAGD and decreased weights of thetestis, seminal vesicle, epididymis,prostate and levator ani-balbocarvenosus in male offspringat 500 mg/kg/day.No-observed adverse-effect-level(NOAEL) for F1 generation = 50mg/kg/day, LOAEL = 100mg/kg/day.
Mylchreestet al., 2000
Rat (F344,female)
By feeding Age, unspecifiedGestation day 0 -lactation day 28(48 days)
0, 20,000 ppm(Corresponding to1,000 mg/kg/day)
Complete resorptions of all embryosat 1,000 mg/kg/day.
Oral gavage From weaningthrough growth,mating andlactation periodsMating betweenDBP-treatedanimals anduntreated animals
0, 250, 500 and1,000 (only inmales) mg/kg/day
F0: Delayed sexual maturation inboth sexes at 250 mg/kg/day orabove. Reduced fertility at 500mg/kg/day or above (1,000mg/kg/day: Infertile).Testicular atrophy and decreasedspermatogenic capacity in males at500 mg/kg/day or above.F1: Malformations, decreasedconception rate and decreasedepididymal sperm count at 250mg/kg/day or above.LOAEL for F1 generation = 250mg/kg/day.
Gray et al.,1999
Rat (LE,female)
Oral gavage Age, unspecifiedGestation days 16-19
0, 500 mg/kg/day Increased resorptions, reducedAGD, decreased weights of seminalvesicle, prostate andbulbospongiosus muscle+levatorani-balbocarvenosus and retainednipple at 500 mg/kg/day.
Rat (SD,female)
Oral gavage Age, unspecifiedGestation day 14 -day 3 after birth
0, 500 mg/kg/day Decreased number of pupsdelivered, reduced AGD,hypospadias, testicular andepididymal atrophy or hypoplasia,decreased weights of the seminalvesicle, prostate, epididymis, testis,bulbospongiosus muscle+levatorani-balbocarvenosus and penis andretained nipple at 500 mg/kg/day.
Di-n-butyl phthalate
272
Animal species Administrationmethod
Administrationperiod
Dose Results References
Rat (F344,female)
By feeding Age, unspecifiedGestation day 0 –lactation day 28(48 days)
0, 2,500 ppm(Corresponding to 0and 125 mg/kg/day)
Suppressed offspring body weightgain at 125 mg/kg/day.
ATSDR,1990,
Killinger etal., 1988b
Rat (SD, maleand female)
NTP protocol10 weeks of ageContinuous breeding protocol study
0, 0.1, 0.5 and 1.0%in diet(equivalent to 0, 52,256 and 509mg/kg/day in malesand to 0, 80, 385and 794 mg/kg/dayin females)
F0: Suppressed body weight gainand increased liver and kidneyweights in dams at 1%.Decreased number of live F1 pups at0.1% or above. Decreased bodyweight of live F1 pups at 0.5% orabove.
F1: Increased kidney weight inmales at 0.5%. Decreasedcopulation and pregnancy indexes,decreased body weight in bothsexes, and increased liver andkidney weights, decreased prostate,seminal vesicle and testis weights,decreases in epididymal spermcount and testicular spermatid headcount, degeneration of seminiferoustubules, hyperplasia of testicularinterstitial cells and poorlydeveloped epididymis in males at1.0%.Decreased body weight of live F2
pups at 0.1% or above.
In the cross-over mating, bodyweight decreased in offspring fromthe pairs between females in high-dose group and control males.
Wine et al.,1997
Di-n-butyl phthalate
273
<The results of mono-butyl phthalate as a metabolite.>
Animal species Administrationmethod
Administrationperiod
Dose Results References
Rat (SD, male) Oral gavage 4-6 weeks of age,9 days
0, 2,000 mg/kg/day Decreased testis weight and diffuseatrophy of seminiferous tubules.
Gray et al.,1982
Rat (Wistar,female)
Oral gavage Age, unspecifiedGestation days 7-15
0, 250, 500, 625mg/kg/day
Increased fetal mortality, decreasedfetal body weight, skeletalmalformations, cleft palate anddilatation of renal pelvis at 500mg/kg/day or above.
CERHR,2000, Ema
et al., 1995b
Mated at the age of12 weeks,Gestation days 7-9
0, 500, 625, 750mg/kg/day
Suppressed maternal body weightgain at 625 mg/kg/day or above.Skeletal malformations anddecreased fetal body weight at 500mg/kg/day or above. Increasedpost-implantation losses andexternal malformations at 625mg/kg/day or above. Decreasednumber of live fetuses at 750mg/kg/day.
Mated at the age of12 weeks,Gestation days 10-12
0, 500, 625, 750mg/kg/day
Suppressed maternal body weightgain at 625 mg/kg/day or above.Increased post-implantation lossesand decreased number of livefetuses at 625 mg/kg/day or above.Decreased fetal body weight at 750mg/kg/day.No malformed fetuses.
Rat (Wistar,female)
Oral gavage
Mated at the age of12 weeks,Gestation days 13-15
0, 500, 625, 750mg/kg/day
Suppressed maternal body weightgain at 500 mg/kg/day or above.Increased post-implantation lossesat 500 mg/kg/day or above.Decreased number of live fetuses,cleft palate and abnormal sternalfusion at 625 mg/kg/day or above.
Ema et al.,1996b
Rat (WistarKing A, female)
p.o. Age, unspecifiedGestation days 15-18
0, 300mg/animal/day
Undescended testis in male pups(30-40 days of age) at 300mg/animal/day.
Imajima etal., 1997
Di-n-butyl phthalate
274
Attachment-3 Results of repeated-dose toxicity studies
Animal species Administrationmethod
Administrationperiod
Dose Results References
Mouse (ICR,male)
By feeding Age, unspecified7 days
0, 20,000 ppm(Corresponding to 0and 2,600mg/kg/day)
Decreased body weight, increasedliver weight, decreased kidneyweight and decreased zincconcentration in testis and liver at2,600 mg/kg/day.
ATSDR,1990, Oishi& Hiraga,
1980b
MouseStrain,unspecified
By feeding Age, unspecified21 days
Corresponding to 0,628 and 1,248mg/kg/day
Decreased body weight at 1,248mg/kg/day.
ASDR,1990
Mouse(B6C3F1, maleand female)
By feeding 6 weeks of age13 weeks
0, 1,250, 2,500,5,000, 10,000,20,000 ppm (Male:Corresponding to 0,163, 353, 812,1,601 and 3,689Female:Corresponding to 0,238, 486, 971,2,137 and 4,278mg/kg/day)
Suppressed body weight gain andincreased liver weight in males at812 mg/kg/day or above.Increased kidney weight in femalesat 238 mg/kg/day or above.Eosinophilic granules, increasedstaining intensity of cytoplasm andincreased lipofuscin granules inhepatocytes in females at 4,278mg/kg/day.NOAEL = 353 mg/kg/day formales, - for females.
Decreased body weight andincreased liver weight at 1,750mg/kg/day.
CERHR,2000;
Reel etal., 1984
RatStrain,unspecified
By feeding Age, unspecified21 days
Corresponding to 0and 348 mg/kg/day
Decreased blood cholesterol leveland increased liver weight at 348mg/kg/day.
ATSDR,1990;
Bell, 1982RatStrain,unspecified
By feeding Age, unspecified21 days
Corresponding to 0,628 and 1,248mg/kg/day
Increased liver weight at 628mg/kg/day.Increased kidney weight at 1,248mg/kg/day.
ATSDR,1990
Rat (Wistar,male andfemale)
By feeding Age, unspecified34-36 days
Corresponding to 0and 250 mg/kg/day
Decreased body weight,hepatocellular necrosis andinhibition of hepatic mitochondrialenergy metabolism at 250mg/kg/day.
ATSDR,1990,
Murakamiet al. 1986a
Rat (Wistar,male andfemale)
By feeding Age, unspecified35-45 days
Corresponding to 0and 2,500mg/kg/day
Decreased body weight, increasedspleen weight and decreasedmitochondrial oxidation in liver at2,500 mg/kg/day.
ATSDR,1990,
Murakamiet al.1986b
Di-n-butyl phthalate
275
Animal species Administrationmethod
Administrationperiod
Dose Results References
Rat (Wistar,male andfemale)
By feeding 6 weeks of age3 months
0, 400, 2,000,10,000 ppm(Male:Corresponding to 0,27, 141 and 688Female:Corresponding to 0,33, 162 and 816mg/kg/day)
Peroxisome proliferation andhistopathological changes in liver,decrease thyroid hormone (T3)levels in serum and anemia in malesat 688 mg/kg/day. Increased liverand kidney weights and decreasethyroid hormone (T3) levels inserum in females at 816 mg/kg/day.
NOAEL = 142 mg/kg/day formales, 162 mg/kg/day for females.
CERHR,2000,BASF,1992
Rat (F344, maleand female)
By feeding 5-6 weeks of age13 weeks
0, 2,500, 5,000,10,000, 20,000,40,000 ppm (Male:Corresponding to 0,176, 359, 720,1,540 and 2,964Female:Corresponding to 0,177, 356, 712,1,413 and 2,943mg/kg/day)
Males: Decreases in hemoglobinconcentration and erythrocytecount, increases in platelet countand serum albumin, increasedpalmitoyl CoA oxidase (PCAO)activity in liver and increased liverand kidney weights at 359mg/kg/day or above. Suppressedbody weight gain andhistopathological changes in liver at720 mg/kg/day or above.Peroxisome proliferation in liver at2,964 mg/kg/day.Females: Increased PCAO activityin liver at 356 mg/kg/day or above.Increased liver and kidney weightsat 712 mg/kg/day or above.Suppressed body weight gain at1,413 mg/kg/day or above.Peroxisome proliferation in liver at2,943 mg/kg/day.NOAEL = 176 mg/kg/day formales, 177 mg/kg/day for females.
CERHR,2000,
Marsman1995
RatStrain,unspecified
Inhalation Age, unspecified6 hr/day×5 days
0, 2.5 ppm Decreased cytochrome P-450content in lung at 2.5 ppm.
ATSDR,1990,
Walseth &Nilsen1984
Rat (Wistar,male)
Inhalation 4 weeks of age6 hr/day×5days/weeks×3-6months
0, 0.5, 50 mg/m3
(0, 0.044, 4.4 ppm)Decreased body weight andincreased relative lung weight at 4.4ppm.