Diisotridecyl phthalate

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

06.12.1982 to 01.02.1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: A GLP compliant study undertaken to a standard considered equivalent to the OECD 427 test guidelines

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Reference 2

Reference Type:

publication

Title:

Absorption, disposition and metabolism of di-isononyl phthalate (DINP) in F-344 rats.

Author:

McKee RH, El-Hawari M, Stoltz M, Pallas F, Lington AW.

Year:

2002

Bibliographic source:

J Appl Toxicol. 2002 Sep-Oct;22(5):293-302.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 427 (Skin Absorption: In Vivo Method)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1,2-Benzenedicarboxylic acid, di-C8-10-branched alkyl esters, C9-rich

EC Number:

271-090-9

EC Name:

1,2-Benzenedicarboxylic acid, di-C8-10-branched alkyl esters, C9-rich

Cas Number:

68515-48-0

IUPAC Name:

bis(7-methyloctyl) phthalate

Details on test material:

- Name of test material (as cited in study report): Di-isononyl phthalate
- Physical state: No data
- Radiochemical purity (if radiolabelling): 97-98% (TLC)
- Specific activity (if radiolabelling): 53 mCi/mmole
- Locations of the label (if radiolabelling): 14C carboxyl
- Expiration date of radiochemical substance (if radiolabelling): No data
- Stability under test conditions: No data
- Storage condition of test material: No data

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 63 to 64 days
- Weight at study initiation: 140 to 182 g
- Fasting period before study: Not applicable
- Housing: polycarbonate cages
- Individual metabolism cages: Stainless steel metabolism cages
- Diet (e.g. ad libitum): Commercial rat chow ad libitum
- Water (e.g. ad libitum):Tap water ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70 +/- 2ºF
- Humidity (%): 50 +/- 10%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12-hrs light / 12 hrs dark


EXPERIMENTAL WORK PERFORMED: from: 6 December 1982 To: 1 February

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: Diethyl ether

Duration of exposure:

up to 7 days

Doses:

0.2 ml conditioned (Group1), 0.2 ml nonconditioned (Group2 ) or 0.1 ml nonconditioned (Group3). A single dose of 14C labelled DINP was applied dermally to the shaved skin on the back of each rat. Animals in Group 1 were pre-treated with nonlabelled DINP which was kept on the skin for three days and then blotted off prior to application of radio-labelled dose.

No. of animals per group:

Six Group 1, six Group 2, or three Group 3.

Control animals:

no

Details on study design:

DOSE PREPARATION
- Method for preparation of dose suspensions: A mixture of 14C-labelled and nonlabelled DINP was prepared as a stock solution in diethyl ether
- Method of storage: No data


APPLICATION OF DOSE:


VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Amount(s) applied (volume or weight with unit): 0.2 or 0.1 ml/rat



TEST SITE
- Preparation of test site: Freshly shaven dorsal skin
- Area of exposure: 3X4 cm
- % coverage: No data
- Type of cover / wrap if used: see below
-

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes:Styrofoam cup lined with aluminium foil and secured in place with adhesive tape




ANALYSIS
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC): Scintillation counting

Details on in vitro test system (if applicable):

Not applicable

Results and discussion

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Percutaneous absorption

Remarks on result:

other: Not applicable

Conversion factor human vs. animal skin:

Not applicable

Any other information on results incl. tables

A summary of the recovery of radioactivity following dermal application of 14C-DINP is appended in the 'Overall remarks, and attachments' window below.

Absorption of 14C-D1NP was slow as indicated by the recovery of only ~ 0.3% of applied doses in urine, feces, GI tract, and tissue at 24 hr following treatment. The rates of absorption increased slightly between 3 and 7 days following treatment, but the total absorption did not exceed 4% of the administered doses in rats receiving the high dose. Similar amounts (~3%) were absorbed during a 7-day period following treatment with the lower dose. Most of the applied radioactivity was recovered from the application areas (skin and cover). Blood and tissue contained low levels of radioactivity. Skin from non-application areas demonstrated the highest levels followed by variable amounts in livers, muscle, and fat . Tissue Levels were slightly higher at 3 and 7 days than at 1 day following treatment. No major differences were demonstrated in tissue levels or excretion rates of 14C-DINP in rats treated under the conditions used in this study.

Applicant's summary and conclusion

Conclusions:

Dermal absorption of 14C-DINP was slow but occurred at a steady rate as evidenced by the increased amounts of radioactivity recovered in urine, faeces, and tissues examined at the later time periods. However, the total amounts absorbed during the 7-day period ranged from 2 to 4% of the applied doses. Essentially all of the remaining doses were recovered from the skin application areas.

Executive summary:

In a 7-day dermal disposition study, 14C-DINP was applied to freshly shaven areas on the backs of three groups of 3 or 6 male rats (Fischer 344) at 0.1 or 0.2 ml/rat (~1.2 ml/kg) . Rats were sacrificed at 1, 3, or 7 days after treatment, and levels of radioactivity determined in excreta, GI tract, blood and selected tissues. Dermal absorption of 14C-DINP was slow but occurred at a steady rate as evidenced by the increased amounts of radioactivity recovered in urine, faeces, and tissues examined at the later time periods. However, the total amounts absorbed during the 7-day period ranged from 2 to 4% of the applied doses. Dermal absorption was therefore considered to be very low in rats, and most of the unabsorbed dose remained at the dermal application site. Assuming a treatment area of 12 cm2 (3 x 4 cm) and a total fraction absorbed of 3% in 7 days, the overall rate of dermal absorption = 0.03 /(7 days)(24 hr/day)(12 cm2) = 1.5x10^-5 /hr/cm2.

The dermal disposition study is considered acceptable and satisfies the guideline requirements for in vivo skin absorption studies.