Santicizer 278®

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Not a guideline study, and no details on whether study performed to GLP. However, data seem scientifically acceptable and well reported. Not on the test substance defined in Section 1.

Justification for type of information:

No toxicokinetic studies have been conducted on Santicizer 278, however read-across information available for the structurally related, high molecular weight phthalates DIDP (European Chemicals Bureau, 2003a), DINP (European Chemicals Bureau, 2003b), and butyl benzyl phthalate (BBP) provides useful supporting information.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Not a guideline study, and no details on whether study performed to GLP. However, data seem scientifically acceptable and well reported. Not on the test substance defined in Section 1.

Justification for type of information:

No toxicokinetic studies have been conducted on Santicizer 278, however read-across information available for the structurally related, high molecular weight phthalates DIDP (European Chemicals Bureau, 2003a), DINP (European Chemicals Bureau, 2003b), and butyl benzyl phthalate (BBP) provides useful supporting information.

Reason / purpose for cross-reference:

read-across source

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

ADME evaluated in rats given DINP orally or by dermal application.

GLP compliance:

not specified

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, Stoneridge, NY.
- Age at study initiation: 60-70 days
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: Animals placed in stainless steel metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 40-60
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

other: oral (gavage) and dermal

Vehicle:

other: corn oil for gavage

Details on exposure:

ORAL:
PREPARATION OF DOSING SOLUTIONS: Test material dissolved in corn oil and administered in constant volumes of 2 ml/kg bw/day. Each dosing solution contained 100-200 uCi of 14C, and the specific activity ranged from 500 to 9000 dpm (disintegrations per minute)/ug, depending on the DINP concentration.



DERMAL:
TEST SITE
- Area of exposure: no data
- % coverage: no data
- Type of wrap if used: Test sites were covered with styrofoam cups lined with aluminium foil and secured in place with adhesive tape
- Time intervals for shavings or clippings: In the first dermal study, test material was applied to "freshly shaved skin". In the second dermal study, the test material was applied to skin that had previously been conditioned by the application of unlabelled DINP, which remained covered for 3 days, therefore presumably the skin was shaved prior to this conditioning. In the third dermal study, the test material was applied to presumably freshly shaven skin.



TEST MATERIAL
- Amount(s) applied (volume or weight with unit): In the first, second and third dermal studies, each rat recieved an applicaiton of 0.2, 0.2, or 0.1 ml of neat DINP, respectively. In the second dermal study, the skin had previously been conditioned by the application of 0.2 ml/rat of unlabelled DINP and covered for 3 days.
- concentration (if solution): undiluted


USE OF RESTRAINERS FOR PREVENTING INGESTION: Cover prevented animals from licking applied material, but allowed them free movement

Duration and frequency of treatment / exposure:

The oral studies were either acute or repeated (5 consecutive days). For the dermal studies the test material was applied and covered for 1, 3 or 7 days.

Remarks:

Doses / Concentrations:
In the oral studies, test doses were 50 and 500 mg/kg bw (acute) and 50, 150 and 500 mg/kg bw/day (repeated).

In the first two dermal studies, DINP was applied at 1.2 ml/kg bw, and in the third dermal study at 0.6 ml/kg bw.

No. of animals per sex per dose / concentration:

Groups of 20 males and 4 females were used in the acute oral studies and gropus of 15 males in the repeated oral studies.

Six males were used in each of the first two dermal studies, and 3 males in the third dermal study.

Control animals:

no

Positive control reference chemical:

no

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): Assorted randomly by weight and sex.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, plasma, cage washes, liver, kidneys, lungs, brain, spleen, testes/ovaries, skin , skeletal muscle, fat and gastrointestinal tract (plus contents)
- Time and frequency of sampling: For the oral studies, blood samples were taken at various times ranging from 1 to 24 hours after test administration. Urine and faeces were collected at intervals over a 96-hour post-dosing period. For the tissue sampling, animals were sacrificed at 1, 4, 8, 24 and 72 hours post-dosing. For the dermal studies, animals were sacrificed 1, 3 or 7 days after treatment.


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, gastrointestinal contents and liver
- Time and frequency of sampling: For urine and faeces the collection period ranged from 0-24 hours, while the gastrointestinal contents and liver were sampled at 8 hours.
- From how many animals: results only presented for 4 rats, 1 rat, 1 rat and 3 rats, for the urine, faeces, gastrointestinal contents and liver samples, respectively.
- Method type(s) for identification: HPLC and Liquid scintillation counting
- Limits of detection and quantification: no data

Statistics:

The means and standard errors were calculated for each test group, and statistical significance was evaluated by a two-tailed Student's t-test. Data from the multiple dosing study were subjected to analysis of variance. Significant F ratios were then analysed by Dunnett's test. Significant differences were indicated by p<0.05.

Details on absorption:

For the acute and repeated oral studies, absorption from the gastrointestinal tract was rapid. Radioactivity was detected in the blood (about 1.5% of the administered dose) within 1 hour of dosing (the earliest sampling time), peaked 2-4 hours after dosing, and declined thereafter. By 24 hours the blood radioactivity had declined to 10-20% of peak values. The majority of the blood radioactivity was recovered in the plasma. It appeared that the blood levels went up more rapidly in the rats exposed repeatedly, than in those exposed only once.

The results from the three dermal studies showed that 2-3.8% of the applied DINP was absorbed within 7 days, with the highest absorption seen in the rats conditioned with DINP. Data from animals sacrificed at 1 and 3 days after dermal DINP application evidently suggested that the absorption rate was about 0.3-0.6% per day.

Details on distribution in tissues:

For the acute and repeated oral studies, the highest levels of radioactivity (after the gastrointestinal tract) were found in the liver, and to a lesser extent in the kidneys. These levels were highest 1 hour after dosing and, as with the blood, radioactivity declined to 10-20% of the peak values within 24 hours. One hour after dosing, about 5% and 2% of the last administered was recovered in the liver of rats receiving 50 and 500 mg/kg bw/day, respectively, The equivalent figures for the kidney were 0.35 and 0.33%, respectively. Levels of radioactivity in other tissues (lungs, brain, spleen, testes, fat, skin, muscle) were much lower and also declined rapidly over time. There was no sex differences in the tissue distribution, and no evidence of persistence or accumulation in any organ. When animals were sacrificed 24 hours after dosing, the majority of the recovered material (16-23% of the administered dose) was found in the gastrointestinal tract.

Details on excretion:

For the acute oral studies, most of the test material was recovered in the excreta. Urinary excretion was essentially complete within the first 24 hours and faecal excretion within about 48 hours. At the low dose (50 mg/kg bw/day) about 50% of the radioactivity was recovered in the urine and the remainder in the faeces. At the high-dose (500 mg/kg bw/day), between 35 and 40% was excreted in the urine and the remainder in the faeces. There did not appear to be any significant sex differences.

For the repeated oral studies, between 50 and 60% of the administered test material was excreted in the urine and the remainder in the faeces, with no great differences in either the rate or pattern of excretion between the three doses (50, 150 and 500 mg/kg bw/day). Urinary excretion was essentially complete within the first 24 hours and faecal excretion within about 48 hours.

In the dermal studies, around 1-2% of the applied dose was excreted in the urine, and 0.5-1% in the faeces. Accorrding to the investigators, the presence of radioactivity in the faeces implied its excretion in the bile.

Toxicokinetic parameters:

half-life 1st: Based on the urinary excretion data from the oral studies, the half-life for elimination of absorbed DINP was about 7 hours.

Metabolites identified:

yes

Details on metabolites:

When orally administered to rats, DINP was rapidly metabolised in the gastrointestinal tract to the corresponding monoester (MINP). Both DINP and MINP were absorbed from the gastrointestinal tract, and excreted, primarily in the urine, as phthalic acid and oxidation products. Only very low levels of unchanged DINP and MINP were found in the urine. In urine collected within 24 hours of administration, phthalic acid comprised about 20 and 10% of the urinary metabolites in rats treated at 50 and 500 mg/kg bw/day, respectively, the remaining 80-90% being oxidation products. In contrast, most of the radioactivity recovered in the faeces was unmetabolised DINP at an oral dose of 500 mg/kg bw/day; about 67% (acute) and 46% (repeated) of the administered dose was recovered as DINP in the faeces (collected within 24 hours), about 20% as MINP, less than 1% as phthalic acid, and the remainder as oxidation products. The gastrointestinal contents, collected 8 hours after an acute oral dose of 50 mg/kg bw, contained 38% unmetabolised DINP, 35% MINP, 24% oxidation products, and 1% phthalic acid. The liver (also collected 8 hours after an acute oral dose of 50 mg/kg bw) contained about 76% oxidation products, 22% MINP, and about 1% phthalic acid, with no detectable DINP.

Conclusions:

Interpretation of results: other: no bioaccumulation potential for DINP based on study results
No data are available on the toxicokinetics of S278. Following administration to rats via stomach tube, the structurally related compound, di(isononyl) phthalate (DINP; CAS 68515-48-0), was rapidly metabolised in the gastrointestinal tract to the corresponding monoester (MINP). Both DINP and MINP were absorbed from the gastrointestinal tract, and excreted, primarily in the urine, as phthalic acid and oxidation products. Shortly after administration, DINP was distributed to the tissues of the liver, and to a lesser extent the kidneys, but it did not appear to persist or accumulate in any organ or tissue. On dermal application to rats, DINP was very poorly absorbed, with only about 2-4% of the applied material recovered from the urine, faeces or body tissues after 7 days.

Executive summary:

No data are available on the toxicokinetics of S278. The absorption, distribution, metabolism and excretion (ADME) of the structurally related material, di(isononyl) phthalate (DINP; CAS 68515-48-0), were evaluated in young rats exposed orally or by dermal application.

 

For the acute oral studies, groups of 20 males and 4 females received radiolabelled DINP (in corn oil) by stomach tube on a single occasion at 50 or 500 mg/kg bw. For the repeated dose oral studies, groups of 15 males received radiolabelled DINP (in corn oil) by stomach tube at 50, 150 or 500 mg/kg bw/day for five consecutive days. For the dermal studies, radiolabelled DINP was applied (occluded) to the skin of male rats at 1.2 ml/kg bw for the first two studies (involving six rats each) and at 0.6 ml/kg bw for the third study (involving only 3 rats). In the second dermal study, the skin had previously been conditioned by the application of 1.2 ml/kg bw of unlabelled DINP and covered for 3 days. Body fluids and certain tissues (including the urine, faeces, blood, liver, kidneys, lungs, brain, spleen, testes/ovaries, skin, skeletal muscle, fat and gastrointestinal tract) were sampled and collected at various time points after oral or dermal treatment to assess the distribution of radiolabel (14C) and to identify the metabolites.

 

For the acute and repeated oral studies, absorption from the gastrointestinal tract was rapid. Radioactivity was detected in the blood (about 1.5% of the administered dose) within 1 hour of dosing, peaked 2-4 hours after dosing, declining thereafter. The highest levels of radioactivity (after the gastrointestinal tract) were found in the liver (about 4% of the administered dose) and to a lesser extent the kidneys (about 0.35%). These levels were highest 1 hour after dosing, and (as with the blood) radioactivity declined to 10-20% of the peak values within 24 hours. Levels of radioactivity in other tissues were much lower and declined rapidly over time. No evidence of persistence or accumulation in any organ was reported. When animals were sacrificed 24 hours after dosing, the majority of the recovered material (16-23% of the administered dose) was found in the gastrointestinal tract. Excretion occurred primarily in the urine and was essentially complete within the first 24 hours, the remainder recovered in the faeces within about 48 hours following oral dosing. DINP was rapidly metabolised in the gastrointestinal tract to the corresponding monoester (MINP). Both DINP and MINP were absorbed from the gastrointestinal tract, and excreted, primarily in the urine, as phthalic acid and oxidation products.

 

The results from the three dermal studies showed that 2-4% of the applied DINP was absorbed within 7 days, with the highest absorption seen in the rats conditioned with DINP. Data from animals sacrificed at 1 and 3 days after dermal DINP application evidently suggested that the absorption rate was about 0.3-0.6% per day.Around 1-2% of the dermally applied dose was excreted in the urine, and 0.5-1% in the faeces.

 

In conclusion, when orally administered to rats, DINP was rapidly metabolised in the gastrointestinal tract to the corresponding monoester (MINP). Both DINP and MINP were absorbed from the gastrointestinal tract, and excreted, primarily in the urine, as phthalic acid and oxidation products. Shortly after administration, DINP was distributed to the tissues of the liver, and to a lesser extent the kidneys, but it did not appear to persist or accumulate in any organ or tissue. DINP was very poorly absorbed from the skin, with only about 2-4% of the applied material recovered after seven days. The investigators conclude that “the results of these rodent studies are in contrast to data from studies involving humans or other primates, which indicate low absorption at low oral doses and much more limited total absorption at high doses. Because many of the effects in rodent studies are associated with internal doses that would be difficult, if not impossible, for humans to achieve under any circumstances, the results of rodent studies may not be very useful in assessing the potential risks to humans from high-molecular-weight phthalates.”

Data source

Reference

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 22: 293-302

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

ADME evaluated in rats given DINP orally or by dermal application.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Di(isonyl) phthalate

IUPAC Name:

Di(isonyl) phthalate

Constituent 2

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

Constituent 3

Reference substance name:

DINP 1

IUPAC Name:

DINP 1

Details on test material:

- Name of test material (as cited in study report): Di-isonoonyl phthalate (DINP)
Molecular formula (if other than submission substance): C26H42O4
- Molecular weight (if other than submission substance): 420 [g/mol]
- Analytical purity: >99.5%
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: "The stock and dosing solutions were analyzed over the course of the study to monitor purity".
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Radiochemical purity (if radiolabelling): 97-98%
- Specific activity (if radiolabelling): 53 mCi/mmol
- Locations of the label (if radiolabelling): 14C
- Expiration date of radiochemical substance (if radiolabelling): no data
- Stability under test conditions: no data
- Storage condition of test material: A stock solution of the labelled compound in ether was stored at -20 degrees celcius

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, Stoneridge, NY.
- Age at study initiation: 60-70 days
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: Animals placed in stainless steel metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 40-60
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

other: oral (gavage) and dermal

Vehicle:

other: corn oil for gavage

Details on exposure:

ORAL:
PREPARATION OF DOSING SOLUTIONS: Test material dissolved in corn oil and administered in constant volumes of 2 ml/kg bw/day. Each dosing solution contained 100-200 uCi of 14C, and the specific activity ranged from 500 to 9000 dpm (disintegrations per minute)/ug, depending on the DINP concentration.



DERMAL:
TEST SITE
- Area of exposure: no data
- % coverage: no data
- Type of wrap if used: Test sites were covered with styrofoam cups lined with aluminium foil and secured in place with adhesive tape
- Time intervals for shavings or clippings: In the first dermal study, test material was applied to "freshly shaved skin". In the second dermal study, the test material was applied to skin that had previously been conditioned by the application of unlabelled DINP, which remained covered for 3 days, therefore presumably the skin was shaved prior to this conditioning. In the third dermal study, the test material was applied to presumably freshly shaven skin.



TEST MATERIAL
- Amount(s) applied (volume or weight with unit): In the first, second and third dermal studies, each rat recieved an applicaiton of 0.2, 0.2, or 0.1 ml of neat DINP, respectively. In the second dermal study, the skin had previously been conditioned by the application of 0.2 ml/rat of unlabelled DINP and covered for 3 days.
- concentration (if solution): undiluted


USE OF RESTRAINERS FOR PREVENTING INGESTION: Cover prevented animals from licking applied material, but allowed them free movement

Duration and frequency of treatment / exposure:

The oral studies were either acute or repeated (5 consecutive days). For the dermal studies the test material was applied and covered for 1, 3 or 7 days.

Doses / concentrations

Remarks:

Doses / Concentrations:
In the oral studies, test doses were 50 and 500 mg/kg bw (acute) and 50, 150 and 500 mg/kg bw/day (repeated).

In the first two dermal studies, DINP was applied at 1.2 ml/kg bw, and in the third dermal study at 0.6 ml/kg bw.

No. of animals per sex per dose / concentration:

Groups of 20 males and 4 females were used in the acute oral studies and gropus of 15 males in the repeated oral studies.

Six males were used in each of the first two dermal studies, and 3 males in the third dermal study.

Control animals:

no

Positive control reference chemical:

no

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): Assorted randomly by weight and sex.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, plasma, cage washes, liver, kidneys, lungs, brain, spleen, testes/ovaries, skin , skeletal muscle, fat and gastrointestinal tract (plus contents)
- Time and frequency of sampling: For the oral studies, blood samples were taken at various times ranging from 1 to 24 hours after test administration. Urine and faeces were collected at intervals over a 96-hour post-dosing period. For the tissue sampling, animals were sacrificed at 1, 4, 8, 24 and 72 hours post-dosing. For the dermal studies, animals were sacrificed 1, 3 or 7 days after treatment.


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, gastrointestinal contents and liver
- Time and frequency of sampling: For urine and faeces the collection period ranged from 0-24 hours, while the gastrointestinal contents and liver were sampled at 8 hours.
- From how many animals: results only presented for 4 rats, 1 rat, 1 rat and 3 rats, for the urine, faeces, gastrointestinal contents and liver samples, respectively.
- Method type(s) for identification: HPLC and Liquid scintillation counting
- Limits of detection and quantification: no data

Statistics:

The means and standard errors were calculated for each test group, and statistical significance was evaluated by a two-tailed Student's t-test. Data from the multiple dosing study were subjected to analysis of variance. Significant F ratios were then analysed by Dunnett's test. Significant differences were indicated by p<0.05.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

For the acute and repeated oral studies, absorption from the gastrointestinal tract was rapid. Radioactivity was detected in the blood (about 1.5% of the administered dose) within 1 hour of dosing (the earliest sampling time), peaked 2-4 hours after dosing, and declined thereafter. By 24 hours the blood radioactivity had declined to 10-20% of peak values. The majority of the blood radioactivity was recovered in the plasma. It appeared that the blood levels went up more rapidly in the rats exposed repeatedly, than in those exposed only once.

The results from the three dermal studies showed that 2-3.8% of the applied DINP was absorbed within 7 days, with the highest absorption seen in the rats conditioned with DINP. Data from animals sacrificed at 1 and 3 days after dermal DINP application evidently suggested that the absorption rate was about 0.3-0.6% per day.

Details on distribution in tissues:

For the acute and repeated oral studies, the highest levels of radioactivity (after the gastrointestinal tract) were found in the liver, and to a lesser extent in the kidneys. These levels were highest 1 hour after dosing and, as with the blood, radioactivity declined to 10-20% of the peak values within 24 hours. One hour after dosing, about 5% and 2% of the last administered was recovered in the liver of rats receiving 50 and 500 mg/kg bw/day, respectively, The equivalent figures for the kidney were 0.35 and 0.33%, respectively. Levels of radioactivity in other tissues (lungs, brain, spleen, testes, fat, skin, muscle) were much lower and also declined rapidly over time. There was no sex differences in the tissue distribution, and no evidence of persistence or accumulation in any organ. When animals were sacrificed 24 hours after dosing, the majority of the recovered material (16-23% of the administered dose) was found in the gastrointestinal tract.

Details on excretion:

For the acute oral studies, most of the test material was recovered in the excreta. Urinary excretion was essentially complete within the first 24 hours and faecal excretion within about 48 hours. At the low dose (50 mg/kg bw/day) about 50% of the radioactivity was recovered in the urine and the remainder in the faeces. At the high-dose (500 mg/kg bw/day), between 35 and 40% was excreted in the urine and the remainder in the faeces. There did not appear to be any significant sex differences.

For the repeated oral studies, between 50 and 60% of the administered test material was excreted in the urine and the remainder in the faeces, with no great differences in either the rate or pattern of excretion between the three doses (50, 150 and 500 mg/kg bw/day). Urinary excretion was essentially complete within the first 24 hours and faecal excretion within about 48 hours.

In the dermal studies, around 1-2% of the applied dose was excreted in the urine, and 0.5-1% in the faeces. Accorrding to the investigators, the presence of radioactivity in the faeces implied its excretion in the bile.

Toxicokinetic parameters

Toxicokinetic parameters:

half-life 1st: Based on the urinary excretion data from the oral studies, the half-life for elimination of absorbed DINP was about 7 hours.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

When orally administered to rats, DINP was rapidly metabolised in the gastrointestinal tract to the corresponding monoester (MINP). Both DINP and MINP were absorbed from the gastrointestinal tract, and excreted, primarily in the urine, as phthalic acid and oxidation products. Only very low levels of unchanged DINP and MINP were found in the urine. In urine collected within 24 hours of administration, phthalic acid comprised about 20 and 10% of the urinary metabolites in rats treated at 50 and 500 mg/kg bw/day, respectively, the remaining 80-90% being oxidation products. In contrast, most of the radioactivity recovered in the faeces was unmetabolised DINP at an oral dose of 500 mg/kg bw/day; about 67% (acute) and 46% (repeated) of the administered dose was recovered as DINP in the faeces (collected within 24 hours), about 20% as MINP, less than 1% as phthalic acid, and the remainder as oxidation products. The gastrointestinal contents, collected 8 hours after an acute oral dose of 50 mg/kg bw, contained 38% unmetabolised DINP, 35% MINP, 24% oxidation products, and 1% phthalic acid. The liver (also collected 8 hours after an acute oral dose of 50 mg/kg bw) contained about 76% oxidation products, 22% MINP, and about 1% phthalic acid, with no detectable DINP.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: other: no bioaccumulation potential for DINP based on study results
No data are available on the toxicokinetics of S278. Following administration to rats via stomach tube, the structurally related compound, di(isononyl) phthalate (DINP; CAS 68515-48-0), was rapidly metabolised in the gastrointestinal tract to the corresponding monoester (MINP). Both DINP and MINP were absorbed from the gastrointestinal tract, and excreted, primarily in the urine, as phthalic acid and oxidation products. Shortly after administration, DINP was distributed to the tissues of the liver, and to a lesser extent the kidneys, but it did not appear to persist or accumulate in any organ or tissue. On dermal application to rats, DINP was very poorly absorbed, with only about 2-4% of the applied material recovered from the urine, faeces or body tissues after 7 days.

Executive summary:

No data are available on the toxicokinetics of S278. The absorption, distribution, metabolism and excretion (ADME) of the structurally related material, di(isononyl) phthalate (DINP; CAS 68515-48-0), were evaluated in young rats exposed orally or by dermal application.

 

For the acute oral studies, groups of 20 males and 4 females received radiolabelled DINP (in corn oil) by stomach tube on a single occasion at 50 or 500 mg/kg bw. For the repeated dose oral studies, groups of 15 males received radiolabelled DINP (in corn oil) by stomach tube at 50, 150 or 500 mg/kg bw/day for five consecutive days. For the dermal studies, radiolabelled DINP was applied (occluded) to the skin of male rats at 1.2 ml/kg bw for the first two studies (involving six rats each) and at 0.6 ml/kg bw for the third study (involving only 3 rats). In the second dermal study, the skin had previously been conditioned by the application of 1.2 ml/kg bw of unlabelled DINP and covered for 3 days. Body fluids and certain tissues (including the urine, faeces, blood, liver, kidneys, lungs, brain, spleen, testes/ovaries, skin, skeletal muscle, fat and gastrointestinal tract) were sampled and collected at various time points after oral or dermal treatment to assess the distribution of radiolabel (14C) and to identify the metabolites.

 

For the acute and repeated oral studies, absorption from the gastrointestinal tract was rapid. Radioactivity was detected in the blood (about 1.5% of the administered dose) within 1 hour of dosing, peaked 2-4 hours after dosing, declining thereafter. The highest levels of radioactivity (after the gastrointestinal tract) were found in the liver (about 4% of the administered dose) and to a lesser extent the kidneys (about 0.35%). These levels were highest 1 hour after dosing, and (as with the blood) radioactivity declined to 10-20% of the peak values within 24 hours. Levels of radioactivity in other tissues were much lower and declined rapidly over time. No evidence of persistence or accumulation in any organ was reported. When animals were sacrificed 24 hours after dosing, the majority of the recovered material (16-23% of the administered dose) was found in the gastrointestinal tract. Excretion occurred primarily in the urine and was essentially complete within the first 24 hours, the remainder recovered in the faeces within about 48 hours following oral dosing. DINP was rapidly metabolised in the gastrointestinal tract to the corresponding monoester (MINP). Both DINP and MINP were absorbed from the gastrointestinal tract, and excreted, primarily in the urine, as phthalic acid and oxidation products.

 

The results from the three dermal studies showed that 2-4% of the applied DINP was absorbed within 7 days, with the highest absorption seen in the rats conditioned with DINP. Data from animals sacrificed at 1 and 3 days after dermal DINP application evidently suggested that the absorption rate was about 0.3-0.6% per day.Around 1-2% of the dermally applied dose was excreted in the urine, and 0.5-1% in the faeces.

 

In conclusion, when orally administered to rats, DINP was rapidly metabolised in the gastrointestinal tract to the corresponding monoester (MINP). Both DINP and MINP were absorbed from the gastrointestinal tract, and excreted, primarily in the urine, as phthalic acid and oxidation products. Shortly after administration, DINP was distributed to the tissues of the liver, and to a lesser extent the kidneys, but it did not appear to persist or accumulate in any organ or tissue. DINP was very poorly absorbed from the skin, with only about 2-4% of the applied material recovered after seven days. The investigators conclude that “the results of these rodent studies are in contrast to data from studies involving humans or other primates, which indicate low absorption at low oral doses and much more limited total absorption at high doses. Because many of the effects in rodent studies are associated with internal doses that would be difficult, if not impossible, for humans to achieve under any circumstances, the results of rodent studies may not be very useful in assessing the potential risks to humans from high-molecular-weight phthalates.”