Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2015

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): Di-n-octyl phthalate

Test animals

Species:
rat

Administration / exposure

Route of administration:
oral: gavage
Duration and frequency of treatment / exposure:
single
Doses / concentrations
Remarks:
Doses / Concentrations:
300 mg/kg

Results and discussion

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Phthalic acid (PA), mono-n-octyl phthalate (MnOP) and monocarboxy propyl phthalate (MCPP) being excreted in the urine
at least five other oxidative metabolites at concentrations much higher than MnOP were also detected: monocarboxy methyl phthalate
(MCMP), mono-(5-carboxy-n-pentyl) phthalate (MCPeP), mono-(7-carboxy-n-heptyl) phthalate (MCHpP), mono-hyrdoxy-n-octyl phthalate
(MHOP) and mono-(7-oxo-octyl) phthalate (MOOP).
MCPP was the major metabolite excreted (mean urinary level of 163.3 µg/mL) followed by MCHpP (mean urinary level of 71.6 µg/mL) after 24 hours.

Applicant's summary and conclusion

Conclusions:
Interpretation of results: low bioaccumulation potential based on study results
Overall, elimination of DnOP and their respective metabolites is rapid, as for other assessed phthalates.
Executive summary:

In the oral study conducted by Silva et al. (2005), the metabolism of Di-n-octyl phthalate (DnOP) in rats (administered one day at 300 mg/kg bw/day via gavage) resulted in Phtalic acid (PA), mono-n-octyl phthalate (MnOP) and monocarboxy propyl phthalate (MCPP) being excreted in the urine. At least five other oxidative metabolites at concentrations much higher than MnOP were also detected: monocarboxy methyl phthalate (MCMP), mono-(5-carboxy-n-pentyl) phthalate (MCPeP), mono-(7-carboxy-n-heptyl) phthalate (MCHpP), mono-hyrdoxy-n-octyl phthalate (MHOP) and mono-(7 -oxo-octyl) phthalate (MOOP). MCPP was the major metabolite excreted (mean urinary level of 163.3 µg/mL) followed by MCHpP (mean urinary level of 71.6 µg/mL) after 24 hours. Furthermore, the toxicokinetics of DnOP metabolites supports the postulated biphasic elimination pattern of DnOP with initial rapid clearance of all in vivo DnOP metabolites followed by a slow elimination phase. It was also suggested that, in rats, the major pathway for DnOP metabolism involves ω-oxidation followed by β oxidation in vivo. The metabolite levels decreased significantly over the following 24 hours, although MCPP, MCHpP, MHOP and MOOP were still detectable four days after dosing. The average levels of oxidative urine metabolites when collected 48-hours (day 2) after dosing were approximately 95% lower than in the first 24-hour urine collection.

Silva MJ, Kato K, Gray EL, Wolf C, Heedham LL & Calafat AM 2005. Urinary metabolites of di-n-octyl phthalate in rats. Toxicology, 210:123–133 cited in NICNAS, 2015