Dibutyl phthalate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well documented and scientifically acceptable, but lacking testing guidelines

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Dibutyl phthalate

EC Number:

201-557-4

EC Name:

Dibutyl phthalate

Cas Number:

84-74-2

Molecular formula:

C16H22O4

IUPAC Name:

dibutyl phthalate

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Administration / exposure

Route of administration:

oral: feed

Duration and frequency of treatment / exposure:

34-36 d

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.5, 5.0 % in powder diet

No. of animals per sex per dose / concentration:

5 males

Control animals:

yes

Results and discussion

Any other information on results incl. tables

Body weight, expressed as a percent of each control, decreased gradually (Fig. 1). Organ weights are shown in Table 1. The relative weights of liver, kidney and spleen showed significant increases in the 5% diet group for DBP, whereas the respective substance in the 0.5% diet group elicited almost no change. The testicle weight was markedly decreased in the 5% diet group, but not in the 0.5% diet group. The succinate and pyruvate dehydrogenase activities in liver mitochondria were significantly inhibited with a 5% diet of DBP (Table 2). Such inhibitions were also observed at a 0.5% level of the compound. Glutamate dehydrogenate activity, however, was not affected in any of these groups. These results in mitochondria of DBP-treated rats corresponded well with our previous results).

The inhibitory effects of the compounds on succinate dehydrogenase activity were examined in vitro. DBP significantly inhibited activity in correspondence with its concentration in good accord with our previous results (Table 3). Serum biochemical results are shown in Table 5. The activities of ALP, GOT and GPT increased in rats that received high doses of DBP. Decreased globulin and increased A/G were observed in all groups. Increased CPK activity was found in the DBP group.

Histopathological changes and numbers of rats with such changes are shown in Table 6. The rats treated with DBP revealed abnormal changes in the liver and testicles. In the liver, cytotoxic injury including single cell necrosis, zonal necrosis and degeneration with balloning were observed in many of the rats that received high does of the compounds. Marked spermatogenic damage was seen in the testicles of the 5%-dose group.

Ultrastructural examination of hepatocells was carried out only on the high dose DBP and MBP groups. As shown in Table 7, the effects of DBP treatment were more extensive in increasing peroxisome, lysosome and mitochondria.

Applicant's summary and conclusion

Conclusions:

The rats treated with a 5% diet of DBP revealed growth depression, liver enlargement, testicular atrophy, decreased activities of succinate and pyruvate dehydrogenases in liver mitochondria, and abnormal changes in biochemical tests of serum and in histological examinations of the liver and testicle. These adverse effects were also observed in rats fed a 0.5% diet of the compound, although they were less severe.
The changes in hepatocellular ultrastructure were more prominent in rats treated with DBP than in those given MBP. The most striking difference between DBP and MBP was that DBP showed a potent inhibitory effect on succinate dehydrogenase activity in liver mitochondria in vitro, wherease MBP
showed no such effect. This difference was also observed in liver mitochondrial respiration in vitro.
It was suggested that the adverse effects of orally administered DBP at least on the liver may be caused partly by the direct action of intact DBP entering the liver.

Executive summary:

Rats were given a powder diet containing dibutyl phthalate (DBP), monobutyl phthalate (MBP), di-2-ethylhexyl phthalate (DEHP) or phthalic acid (PA) at a level of 0.5 or 5% for 34 to 36 days, respectively. Only the examinations of DBP are documented here, but cf. "overall remarks" for a comparison of the effects of the different substances.