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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is rated a "2" because appropriate testing methods were used; however, the study does not follow and accepted guideline or indicate compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981

Materials and methods

Objective of study:
metabolism
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Unspecified DIDP; CAS No not provided
Radiolabelling:
yes
Remarks:
14C-DIDP

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: adult
- Weight at study initiation: 200g
- Housing: individually
- Individual metabolism cages: yes
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 days

Administration / exposure

Route of administration:
inhalation: aerosol
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: head only


GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
As described in Pegg (1979). Toxicity and biologic fate of di-2-ethylhexyl phthalate following inhalation exposure in rats. GM Research Report. RI-135
Duration and frequency of treatment / exposure:
The day of the experiment the rats were exposed to 14C DIDP aerosol atmosphere (nominal concentration 100 mg/m3) for 6 hours.
Doses / concentrations
Remarks:
Doses / Concentrations:
100 mg/m3
No. of animals per sex per dose:
6 rats/dose
Control animals:
yes, concurrent no treatment
Details on study design:
Immdiately following the exposure, three animals were sacrificed and tissues frozen for analysis. The other three animals were transferred directly to th eRoth-type cages and collections begun. Airflow in the cages was maintained at 500 ml/min. Feces was collected for 24 hour intervals at room temperature. Urine receptacles were maintained in dry ice and changed at 12 hour intervals. All samples were stored at -10 deg C for analysis.

Seventy-two hours after the exposure, at termination of the collection period, the animals were sacrificed. Carcasses were skinned and lungs, liver, heart, spleen, kidneys, brain, testes, thymus, and samples of retroperitoneal fat were weighed and frozen. The frozen organ tissues were pulverized and samples taken for analysis. Carcas and feces were homogenized in distilled water. Radioactivity in organ tissues, skin, and feces and carcass homogenates was assayed at 14CO2 evolved from combustion in an RJ Harvey biological materials oxidizer and quanified by liquid scintillation spectromtery. Radioactivity in urine was determined by direct addition of 0.1 ml to 20 ml Aquasol liquid scintillation cocktail. Data were expressed as umole equivalents. DIDP.
Statistics:
Data were analyzed using the Student's t test and random complete block analysis of variance. Regression and linearity of interval excretion data were tested by analysis of variance. The 0.05 level of probability was used as the criterion of significance.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Total body burden following the exposure was 6.75 umole equivalents or ~3.0 mg. The excretion of radioactivity was distributed equally between urinary and fecal routes through the 72 hour sampling period, comprising 45.3 and 41.3% respectively of the total body burden. The remaining radioactivity was recovered in carcas (9.4%), skin (2.4%) and in acetone:water (50:50) rinses of the metabolism cage surfaces (1.6%).
Details on distribution in tissues:
The distribution of radioactivity in rat tissues immediately following the 6 hour 14C-DIDP inhalation exposure and after 72 hours was measured. The highest concentration of radioactivity was detected in lung immediately after exposure, followed by gastrointestinal tract, liver and kidney. The remaining tissues, brain, thymus, heart, spleen, fat and testes contained far lesser amounts.

After 72 hours the concentration was decreased in all tissues. The highest levels of radioactivity were still found in lung, which contained 27% of the content of 14C present immediately following exposure. The pulmonary content of radioactivity decreased to a lesser extent than all other tissues except fat, which did not appear to change. Radioactivity was below detection limits in brain, spleen, and testes. Heart tissue in only 1 of 3 animals contained detectable quantities of radioactivity.
Details on excretion:
The excretion of radioactivity in urine during the 72 hour collection period following inhalation exposure was best described using first order kinetics. Based on 12 hour interval excretion data the hal-life of elimination was 16 hours with an elimination rate constant, Ke, or 0.042 hr-1. Though the analysis was limited with only 3 data points, when tested for regression it was found the points did not represent a straight line.

Using total recovered radioactivity to represent body content or body burden of 14C immediately following exposure, and given urinary and fecal interval excretion data, an estimate of the disappearance of radioactivity from the whole body with time can be obtained. The decline in body burden is linear and apparent first order with a half life of 26 hours and an elimination rate constant, Ke, of 0.027 hr-1.

Applicant's summary and conclusion

Conclusions:
The data indicate that inhaled DIDP is metabolized and excreted rapidly exhibiting a low order of toxicity.
Executive summary:

The fate of DIDP was evaluated in 6 male Sprague Dawley rats (mean body weight 200 g) receiving head only exposure to 14C-DIDP aerosol atmosphere nominal concentration: 100 mg/m3 for 6 hours (General Motors Research Laboratories, 1981). The mass median aerodynamic diameter of DIDP aerosol was 0.98 μm. Three animals were sacrificed immediately following exposure, the remaining animals at the end of the 72-hour collection period. Feces were collected at 24-hour intervals and urine was collected at 12-hour intervals for 72 hours. The radioactivity was determined by liquid scintillation spectrometry.

Absorption: Total body burden following the exposure was 6.75 μmole equivalents or approximately 3 mg.  Radioactivity derived from 14C -DIDP was excreted in urine and feces during the 72-hour post-exposure collection period: 45.3% and 41%, respectively, of the total body burden. At the end of the collection period following exposure, 9.4% of the absorbed dose of radioactivity was recovered from carcass and tissues, 2.4% from skin and 1.6% from cage wash.

Distribution: The distribution of radioactivity in rat tissues immediately following exposure, indicated the highest concentration of radioactivity was in lung followed by GIT, liver and kidney. The remaining tissues contained far lesser amounts. Radioactivity was below detection limit in brain, spleen and testes.

Elimination: After 72 hours the concentration was decreased in all tissues. The highest level of radioactivity was still found in lung which contained 27% of the content of radioactivity present immediately following exposure. The pulmonary load decreased to a lesser extent than all the tissues except fat which did not appear to change. Radioactivity derived from 14C -DIDP was excreted in urine and feces during the 72-hour post-exposure collection period: 45.3% and 41%, respectively, of the total body burden. The excretion of radioactivity in urine during the 72-hour collection period following inhalation exposure was best described using first order kinetics. Based on 12-hour interval excretion data, the half-life (T½) of elimination was 16 hours with an elimination rate constant Ke of 0.042/hour. Radioactivity derived from 14C -DIDP was excreted in urine (45.3%) and feces (41.3%) during the 72-hour post-exposure collection period. An additional 1.6% was recovered in washings of the metabolic cage collection surfaces and was derived from urine and fecal contamination. From these data 88% of the total absorbed dose of the radioactivity was excreted from the body, and the carcass retention data imply that a small fraction of DIDP or metabolites was retained in the body for a longer period of time. Using total recovered radioactivity to represent body content or body burden of 14C immediately following exposure, and given urinary and fecal interval excretion data, an estimate of the disappearance of radioactivity from the whole body with time can be obtained. The decline in body burden was linear with an apparent first order with T½ of 26 hours and an elimination rate constant Ke of 0.027/h.