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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

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Endpoint:
basic toxicokinetics in vivo
Type of information:
other: occupational exposure
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Limited documentation, no further information on half-life estimation
Objective of study:
excretion
Principles of method if other than guideline:
The excretion of phthalic anhydride in humans has been investigated in a study where urine samples were collected from nine subjects occupationally exposed to phthalic anhydride.
GLP compliance:
no
Specific details on test material used for the study:
Occupational exposure, purity not specified.
Radiolabelling:
no
Species:
human
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
Occupational exposure
Remarks:
Doses / Concentrations:
range: 0.03-10.5 mg/m³
No. of animals per sex per dose / concentration:
Nine subjects
Preliminary studies:
No data
Details on absorption:
Workers occupationally exposed to atmospheric phthalic anhydride absorbed the substance with some being excreted in the urine as unconjugated phthalic acid.
Details on distribution in tissues:
No data
Details on excretion:
At low atmospheric phthalic anhydride concentrations (mean +/- SD; 0.15 +/- 0.15 mg/m3, range 0.03 - 0.33 mg/m3, n=5) the excretion of phthalic acid increased from the pre-shift (7:00 hours) concentration to the post-shift (15:00 hours) concentration and decreased then until the pre-shift concentration was again reached. The pre-shift phthalic acid concentration in the urine (0.49 +/- 0.15 µmol/mmol creatinine) were not significantly different from those of occupationally unexposed people (0.34 +/- 0.25 µmol/mmol creatinine, range 0.02-0.089 µmol/mmol creatinine, n=22). Exposure to higher concentrations of phthalic anhydride in air (1.63 +/- 0.13 mg/m3, n=2) resulted in a body load of phthalic acid which was not totally cleared overnight, and with pre-shift phthalic acid concentrations in the urine with a mean value three times the mean control value (1.02 +/- 0.25 µmol/mmol creatinine). One worker exposed to high concentration of phthalic anhydride (10.2 mg/m³) had a pre-shift urinary concentration of 4.8 µmol of phthalic acid /mmol creatinine; approximately 14 times that of the control group. The concentration of phthalic acid in the urine was found to increase from the pre-shift level to a maximum in the immediate post-shift or evening urine sample. The concentration then decreased, with a half-life of approx. 14 hours (no further information on half-life estimation).
Key result
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: ca. 14 hours
Metabolites identified:
yes
Details on metabolites:
Unconjugated phthalic acid

No evidence was seen of conjugate formation.

Executive summary:

The excretion of phthalic anhydride in humans has been investigated in a study where urine samples were collected from nine subjects occupationally exposed to phthalic anhydride, primarily by the inhalation route.

At low atmospheric phthalic anhydride concentrations (mean +/- SD; 0.15 +/- 0.15 mg/m³, range 0.03 - 0.33 mg/m³, n=5) the excretion of phthalic acid increased from the pre-shift (7:00 hours) concentration to the post-shift (15:00 hours) concentration and decreased then until the pre-shift concentration was again reached. The pre-shift phthalic acid concentration in the urine (0.49 +/- 0.15 µmol/mmol creatinine) were not significantly different from those of occupationally unexposed people (0.34 +/- 0.25 µmol/mmol creatinine, range 0.02-0.089 µmol/mmol creatinine, n=22). Exposure to higher concentrations of phthalic anhydride in air (1.63 +/- 0.13 mg/m³, n=2) resulted in a body load of phthalic acid which was not totally cleared overnight, and with pre-shift phthalic acid concentrations in the urine with a mean value three times the mean control value (1.02 +/- 0.25 µmol/mmol creatinine). The concentration of phthalic acid in the urine was found to increase from the pre-shift level to a maximum in the immediate post-shift or evening urine sample.

The concentration then decreased, with a half-life of approx. 14 hours.
No evidence was seen of conjugate formation.


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: scientifically acceptable and well documented
Objective of study:
other: hydrolysis test
Principles of method if other than guideline:
The rate of hydrolysis of phthalic anhydride was determined at different pHs at 25°C in water/buffer containing a small amount of acetonitrile.
GLP compliance:
no
Radiolabelling:
no
Species:
other: not applicable - in vitro test
Strain:
other: not applicable - in vitro test
Sex:
not specified
Route of administration:
other: not applicable - in vitro test
Vehicle:
other: aqueous solution with HCl or buffer + acetonitrile
Duration and frequency of treatment / exposure:
Not applicable - in vitro test
Remarks:
Doses / Concentrations:
not applicable - in vitro test
No. of animals per sex per dose / concentration:
Not applicable - in vitro test
Control animals:
other: not applicable - in vitro test
Preliminary studies:
no data
Details on absorption:
Not applicable- in vitro test
Details on distribution in tissues:
Not applicable - in vitro test
Details on excretion:
Not applicable - in vitro test
Toxicokinetic parameters:
half-life 2nd: not applicable - in vitro test
Toxicokinetic parameters:
half-life 1st: not applicable - in vitro test
Toxicokinetic parameters:
half-life 3rd: not applicable - in vitro test
Metabolites identified:
yes
Details on metabolites:
Phthalic anhydride hydrolyzes rapidly in the presence of water forming phthalic acid.

No remarks

Executive summary:

The rate of hydrolysis of phthalic anhydride was determined at different pHs at 25°C in water/buffer containing a small amount of acetonitrile.

Phthalic anhydride hydrolyzes rapidly in the presence of water forming phthalic acid. Half-life for phthalic anhydride was 30.5 seconds at pH 7.24. At pH 6.8 the half-life of phthtalic anhydride in water was prolonged to 61 seconds.

Description of key information

The excretion has been examined in subjects occupational exposed to phthalic anhydride. The substance was eliminated as phthalic acid. In in vitro experiments in aqueous solution the substance was also rapidly hydrolyzed to phthalic acid. No evidence was found for conjugate formation. Thus, workers occupationally exposed to atmospheric phthalic anhydride absorbed the substance with subsequent excretion in the urine as unconjugated phthalic acid (Pfaeffli, 1986).

In summary, on contact with water, phthalic anhydride is rapidly hydrolyzed to phthalic acid. Unconjugated phthalic acid was found in the urine of humans exposed to phthalic anhydride by the inhalation route, demonstrating systemic absorption and elimination via the urine and the existence of phthalic acid as the only hydrolysis product in vivo.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Phthalic anhydride is metabolized in humans to phthalic acid. No conjugate formation was observed. Partly phthalic anhydride was bound to tissue as found with radiolabelled phthalic anhydride in animal experiments, but the degree and tissues were not specified.