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EC number: 251-646-7 | CAS number: 33703-08-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Deviations:
- yes
- Remarks:
- urine and fecal excretion was not measured
- Principles of method if other than guideline:
- Yes, see description of method below.
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Midwest Research institute
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): DEHA
- Analytical purity: >99.7%
- Impurities (identity and concentrations): no data - Radiolabelling:
- yes
- Remarks:
- Radiolabeled material was prepared by NEN (Boston), and supplied through the CMA. Lot No. 1679-109, specific activity 32.2 mCi/mmol. Radiochemical purity 98.9% (TLC). HPLC analysis by MRI showed >97%.
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Lab. (Wilmington, Massachusetts).
- Age at study initiation: 50-57 days
- Weight at study initiation: 14-24 gram
- Fasting period before study: 18 hours prior to dosing
- Individual metabolism cages: yes
- Diet: ad libitum
- Water :ad libitum
- Acclimatisaton period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°F): 68-72:
- Humidity (%): 40-60
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- The mice were dosed orally with 14C-DEHA at the low, mid, or high dose (50, 500 and 5000 mg/kg).
- Duration and frequency of treatment / exposure:
- once
- Dose / conc.:
- 50 mg/kg bw/day
- Dose / conc.:
- 500 mg/kg bw/day
- Dose / conc.:
- 5 000 mg/kg bw/day
- No. of animals per sex per dose / concentration:
- hydrolysis and absorption: 6 animals per sex and dose group
hydrolysis and absorption repeat: 3 animals per sex and dose group
preliminary disposition (only males): 2 males per dose group
disposition: 4 animals per sex for the low and high dose group, 8 animals per sex for the high dose group - Control animals:
- no
- Positive control reference chemical:
- no data
- Details on study design:
- Three groups of four male and four female mice each were treated orally with the low, mid, or high dose levels of 14C-DEHA
(50, 500 and 5000 mg/kg) and were placed in individual glass metabolism cages (Delmar-Rath type).
Expired air, urine, and feces were collected during 0-6, 6-12, and 12-24 hr intervals following dosing.
The expired 14 C02 was trapped with 5-Methol-amine in 2-methoxyethanol. Other volatile products were collected in
methanol:water (50:50).
Urine was collected in containers kept on dry ice. After each collection, the cages were rinsed and the cage washings were measured
and analyzed.
At 24 hr, the mice were anesthesized with ether, blood was withdrawn by cardiac puncture, and the following tissues and organs were
removed, weighed, and assayed for 14-C content: Liver, Spleen, Urinary bladder, Kidneys, Adrenals, Skeletal muscle, Lungs, Testes ,
Retroperitoneal tissue, Brain, Epididymides, GI tract plus contents, Heart, Skin, pancreas, ovaries and uterus.
Portions of blood were centrifuged to separate plasma and red blood cells (RBC's). Bladder contents were removed and the bladder was
washed thoroughly with 0.9% saline. The contents and washings were combined with the final urine samples and analyzed.
Blood and tissues were kept on ice during the necropsy procedures. Sample preparatian and analyses were performed immediately after collection, or the samples were frozen until analyzed. The remaining tissue and excreta were stored frozen. - Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : Expired air, urine, and feces, cage washes, and:
blood, Liver, Spleen, Urinary bladder, Kidneys, Adrenals, Skeletal muscle, Lungs, Testes ,
Retroperitoneal tissue, Brain, Epididymides, GI tract plus contents, Heart, Skin, pancreas, and ovaries and uterus.
- Time and frequency of sampling: Expired air, urine, and feces and cage washings during 0-6, 6-12, and 12-24 hr intervals following dosing.
Other tissues at sacrifice after 24 hrs.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled : urine, GI-content
- Time and frequency of sampling: 24 hrs
- From how many animals: samples pooled
- Method type(s) for identification: HPLC-MS-MS
- Statistics:
- The means ± standard errors were calculated for each test group with a programmable calculator. Data were subjected to analysis of variance.
Significant F-ratios were then analyzed by Dunnett's procedure. Significant differences were indicated when p < 0.05. - Preliminary studies:
- A preliminary study in males only:
Absorption
dose mg/kg: 50, 500, 5000
Urine +expired air : 81% 86% 67%
excretion (24 hr)
dose mg/kg: 50, 500, 5000
Urine +expired air+ feces : 94% 101% 75% - Details on absorption:
- At 24 hr
dose mg/kg: 50, 500, 5000
Urine +expired air: 92-94% 98-100% 67- 76%
- Details on distribution in tissues:
- Levels in organs were low (< 0.3%) . From all tissues examined the liver and kidneys showed the highest level ( 0.1-0.2% and 0.03-0.086% resp.).
Also in the GI-tract the levels were relatively high, and highest in 5000 mg/kg group (12%). - Details on excretion:
- At 24 hr
dose mg/kg: 50, 500, 5000
Urine +expired air+ feces : 97-98% 98-100% 69-81% - Metabolites identified:
- yes
- Details on metabolites:
- The GI tract contained the diester, monoester, and the alcohol, and traces of the polar material.
The liver contained primarily the oxidation products.
The urine contained major amounts of the oxidation products and their conjugated derivatives. Although the liver
profiles did not contain appreciable amounts of the less polar metabolites, these products may have been excreted shortly following formation.
Metabolites identified:
MEHA : monoethylhexyladipate
EH: ethylhexanol and EH glucuronide
EHA: ethylhexanoic acid, and EHA glucuronide
DiEHA: ethylhexanedioic acid - Endpoint:
- basic toxicokinetics
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Objective of study:
- distribution
- excretion
- metabolism
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Principles of method if other than guideline:
- Yes, see decription of method below.
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Midwest Research institute
- Specific details on test material used for the study:
- The non-labeled DEHA was suppled by Badische Corporation:
- Name of test material (as cited in study report): DEHA
- Analytical purity: >99.7%
- Impurities (identity and concentrations): no data - Radiolabelling:
- yes
- Remarks:
- Radiolabeled material was prepared by NEN (Boston), and supplied through the CMA. Lot No. 1679-109, specific activity 32.2 mCi/mmol. Radiochemical purity 98.9% (TLC). HPLC analysis by MRI showed >97%.
- Species:
- monkey
- Strain:
- other: Cynomolgus
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River research primates corp. (Port Washington, New York).
- Age at study initiation: not exactly known, age estimated based on body weight and teeth examination
- Weight at study initiation: 2.0-2.8 kg
- Fasting period before study: 18 hrs prior to dosing
- Individual metabolism cages: yes
- Diet: ad libitum
- Water :ad libitum
- Acclimatisaton period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°F): 68-72
- Humidity (%): 40-60
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- The monkeys were dosed orally with 14C-DEHA at 500 mg/kg.
- Duration and frequency of treatment / exposure:
- once
- Dose / conc.:
- 500 mg/kg bw/day
- No. of animals per sex per dose / concentration:
- 2
- Control animals:
- no
- Positive control reference chemical:
- no data
- Details on study design:
- Two male and two female monkeys were treated orally with 500 mg/kg 14C-DEHA, and were placed in individual glass metabolism cages (Ketaset, Bristol veterinary products, Syracuse, New York).
Blood samples were collected at 2, 4, 8, 24 and 48 hrs.
Urine, and feces were collected during 0-6, 6-12, and 12-24 and 24-48 hr intervals following dosing.
The expired 14 C02 was trapped with 5-Methol-amine in 2-methoxyethanol. Other volatile products were collected in
methanol:water (50:50).
Urine was collected in containers kept on dry ice. After each collection, the cages were rinsed and the cage washings were measured
and analyzed.
At 48 hr, the monkeys were sedated with a 0.2 niL intramuscular injection of ketamine (Ketaset@, Bristol Veterinary Products, Syracuse, New York) and
were euthanized by intravenous dose of saturated pentobarbital solution. The following tissues and organs were
removed, weighed, and assayed for 14-C content:
Liver, Spleen, Urinary bladder, Kidneys, Adrenals, Skeletal muscle, Lungs, Testes ,
Retroperitoneal tissue, Brain, Epididymides, GI tract plus contents, Heart, Skin, pancreas, ovaries and uterus.
Portions of blood were centrifuged to separate plasma and red blood cells (RBC's). Bladder contents were removed and the bladder was
washed thoroughly with 0.9% saline. The contents and washings were combined with the final urine samples and analyzed.
Blood and tissues were kept on ice during the necropsy procedures. Sample preparation and analyses were performed immediately after collection, or the samples were frozen until analyzed. The remaining tissue and excreta were stored frozen. - Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Distribution, excretion)
- Tissues and body fluids sampled : Urine, and feces, cage washes, and:
Blood, Liver, Spleen, Urinary bladder, Kidneys, Adrenals, Skeletal muscle, Lungs, Testes ,
Retroperitoneal tissue, Brain, Epididymides, GI tract plus contents, Heart, Skin, pancreas, and ovaries and uterus.
- Time and frequency of sampling: Expired air, urine, and feces and cage washings during 0-6, 6-12, and 12-24 hr intervals following dosing.
Other tissues at sacrifice after 24 hrs.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled : urine, GI-content
- Time and frequency of sampling: 24 hrs
- From how many animals: samples pooled
- Method type(s) for identification: HPLC-MS-MS
- Statistics:
- The means ± standard errors were calculated for each test group with a programmable calculator. Data were subjected to analysis of variance.
Significant F-ratios were then analyzed by Dunnett's procedure. Significant differences were indicated when p < 0.05. - Details on distribution in tissues:
- Levels in organs were low (< 0.3-0.6%) . From all tissues examined the liver and kidneys showed the highest level ( 0.1-0.2% and 0.03-0.086% resp.).
Also in the GI-tract the levels were relatively high. - Details on excretion:
- Dose mg/kg: 500
Urine + feces (after 48 hr) : 89-90% (m/f) - Metabolites identified:
- yes
- Details on metabolites:
- The GI tract contained the diester, monoester, and the alcohol, and traces of the polar material.
The liver contained primarily the oxidation products.
Urine of monkeys contained less of the polar metabolites and more MEHA, EH and its glucoronides.
Although the liver profiles did not contain appreciable amounts of the less polar metabolites,
these products may have been excreted shortly following formation.
Metabolites identified:
MEHA : monoethylhexyladipate, and MEHA glucuronide
EH: ethylhexanol , and EH glucuronide
EHA: ethylhexanoic acid , and EHA glucuronide
DiEHA: ethylhexanedioic acid
5-OH EHA: 5- hydroxyethylhexanoic acid - Endpoint:
- basic toxicokinetics
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Objective of study:
- distribution
- excretion
- metabolism
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Principles of method if other than guideline:
- Yes, see description of method below.
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Midwest Research institute
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): DEHA
- Analytical purity: >99.7%
- Impurities (identity and concentrations): no data - Radiolabelling:
- yes
- Remarks:
- Radiolabeled material was prepared by NEN (Boston), and supplied through the CMA. Lot No. 1679-109, specific activity 32.2 mCi/mmol. Radiochemical purity 98.9% (TLC). HPLC analysis by MRI showed >97%.
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Lab. (Wilmington, Massachusetts).
- Age at study initiation: 54 days
- Weight at study initiation: 90-117 gram
- Fasting period before study: 18 hr prior to dosing
- Individual metabolism cages: yes
- Diet: ad libitum
- Water :ad libitum
- Acclimatisaton period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°F): 68-72:
- Humidity (%): 40-60
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- The rats were dosed orally with 14C-DEHA at 500 mg/kg.
- Duration and frequency of treatment / exposure:
- once
- Dose / conc.:
- 500 mg/kg bw/day
- No. of animals per sex per dose / concentration:
- 3
- Control animals:
- no
- Details on study design:
- Three male and three female rats were treated orally with 14C-DEHA at the mid (500 mg/kg) dose level, and were placed in individual glass metabolic cages (Delmar-Rath type).
Expired air, urine, and feces were collected during 0-6, 6-12, and 12-24 hr intervals following dosing.
The expired 14 C02 was trapped with 5-Methol- amine in 2-methoxyethanol. Other volatile products were collected in
methanol:water (50:50).
Urine was collected in containers kept on dry ice. After each collection, the cages were rinsed and the cage washings were measured
and analyzed.
At 24 hr, the rats were anesthesized with ether, blood was withdrawn by cardiac puncture, and the following tissues and organs were
removed, weighed, and assayed for 14-C content: Liver, Spleen, Urinary bladder, Kidneys, Adrenals, Skeletal muscle, Lungs, Testes,
Retroperitoneal tissue, Brain, Epididymides, GI tract plus contents, Heart, Skin, pancreas, ovaries and uterus.
Portions of blood were centrifuged to separate plasma and red blood cells (RBC's). Bladder contents were removed and the bladder was
washed thoroughly with 0.9% saline. The contents and washings were combined with the final urine samples and analyzed.
Blood and tissues were kept on ice during the necropsy procedures. Sample preparation and analyses were performed immediately after collection, or the samples were frozen until analyzed. The remaining tissues and excreta were stored frozen. - Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Distribution, excretion)
- Tissues and body fluids sampled : Expired air, urine, and feces, cage washes, and:
blood, Liver, Spleen, Urinary bladder, Kidneys, Adrenals, Skeletal muscle, Lungs, Testes ,
Retroperitoneal tissue, Brain, Epididymides, GI tract plus contents, Heart, Skin, pancreas, and ovaries and uterus.
- Time and frequency of sampling: Expired air, urine, and feces and cage washings during 0-6, 6-12, and 12-24 hr intervals following dosing.
Other tissues at sacrifice after 24 hrs.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled : urine, GI-content
- Time and frequency of sampling: 24 hrs
- From how many animals: samples pooled
- Method type(s) for identification: HPLC-MS-MS
- Statistics:
- The means ± standard errors were calculated for each test group with a programmable calculator. Data were subjected to analysis of variance.
Significant F-ratios were then analyzed by Dunnett's procedure. Significant differences were indicated when p < 0.05. - Details on distribution in tissues:
- Approx. 0.2/1.4% (m/f) was recovered in blood, about 4% was remaining in the GI tract (m/f) and tissue contained only 2.2% . Levels in liver and adrenals were higher than in other tissues, with males showing significantly higher tissue contents than females.
- Details on excretion:
- Dose mg/kg: 500
Urine +expired air+ feces (24h following dosing): 95% (males and females) - Metabolites identified:
- yes
- Details on metabolites:
- The GI tract contained the diester, monoester ,and the alcohol, and traces of the polar material.
The liver contained primarily the oxidation products.
The urine contained 2-ethylhexanoic acid (EHA), its glucuronic acid conjugate, a hydroxy acid (5-hydroxy-2-ethylhexanoic acid, 5-OH EHA), and the diacid (2-ethyl-1,6-hexanedioic acid, DiEHA).
Although the liver profiles did not contain appreciable amounts of the less polar metabolites, these products may have been excreted shortly following formation.
Metabolites identified:
MEHA : monoethylhexyladipate
EH: ethylhexanol, and EH glucuronide trace amounts
EHA: ethylhexanoic acid , and EHA glucuronide
DiEHA: ethylhexanedioic acid , and DiEHA glucuronide
5-OH EHA: 5-hydroxyethylhexanoic acid , and 5-OH EHA glucuronide - Endpoint:
- dermal absorption in vitro / ex 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:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 428 (Skin Absorption: In Vitro Method)
- GLP compliance:
- no
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): DEHA
- Physical state: liquid
- Composition of test material, percentage of components: 1.56% of DEHA as part of a roll-on deodorant - Radiolabelling:
- no
- Species:
- human
- Duration of exposure:
- 24h
- Doses:
- 5mg total (7.8mg/cm²)
100mg total (156mg/cm²) - No. of animals per group:
- 4 skin samples per dose from four different individuals, tested in triplicate
- Details on in vitro test system (if applicable):
- SKIN PREPARATION
- Source of skin: General Hospital, Ottawa, Ontario, Canada
- Type of skin: Breast surgical waste skin samples
- Preparative technique: the skin was dermatomed and circular-punched (area 0.64cm²)
- Thickness of skin (in mm): 0.4-0.5mm
- Storage conditions: first skin was used fresh while the subsequent 3 samples were stored at -20°C
- Justification of species, anatomical site and preparative technique: storage at -20°C for up to 2 months does not change barrier function of human skin (Moody et al (2009))
PRINCIPLES OF ASSAY
- Diffusion cell: Bronaugh cell
- Receptor fluid: Hanks HEPES buffered balanced salt solution containing 4% bovine serum albumin
- Flow-through system: 1.5mL/h
- Test temperature: 32°C
- Occlusion: occlusive conditions
- Solubility od test substance in receptor fluid: not tested, but supposedly similar to water solubility of 3.2ng/mL
- Collection intervals: fractions were collected at 6h intervals
- Final sampling procedure: After 24 h the skin surface was wiped with a cotton swab that had been treated with 200 μl of 10% Radiacwash soap; this procedure was repeated with another two swabs that each had been soaked with 200 μl distilled water. All three swabs were placed in a glass vial
labeled as “Soap Skin Wash.” The skin disc was then removed from the cell and placed in another vial labeled as “Skin Depot.” Both the top and bottom chambers of the diffusion cell were then rinsed with 5 ml ethanol at a time, and collected and labeled as “Top-wash” and “Bottom-wash,” respectively. All samples were stored at −20◦C prior to chemical analysis. - Absorption in different matrices:
- Values given as average mass recovery (4 skin samples, triplicate measurements)
Skin Depot: 28% (low dose), 34% (high dose)
Soap skin wash: 52% (low dose), 21% (high dose)
Top wash: 0.5% (low dose), 0.4% (high dose)
Bottom wash: 0.08% (low dose), 0.01% (high dose)
Receiver Solution (sum over 24h): 0.04% (low dose), 0.002% (high dose)
DEHA amounts in the receiver solutions remained essentially constant among samples collected at any of the 6-h intervals. - Total recovery:
- 81% (low dose)
56% (high dose)
Low recovery might have been due to metabolism by esterases still active in the skin, but was not further investigated. - Time point:
- 24 h
- Dose:
- 5 and 100mg
- Parameter:
- amount
- Absorption:
- 2.2 other: ng/cm²/h
- Executive summary:
Our results showed that the majority of applied DEHA mass remained in the Skin Depot and Soap Skin Wash. Together they accounted for the majority of mass recovered. A small percentage of the total mass approximately 0.5% was also found in the Top-wash and Bottom-wash solutions. The average percent mass recovery in the in vitro dermal absorption experiments was 81 and 56% for the low dose and high dose, respectively. Rather low solubility in receptor solution (app. 4 fold above the measured concentrations) might have influenced dermal penetration.
Referenceopen allclose all
Hydrolysis and Absorption: 14C-DEHA and/or its metabolites was rapidly absorbed from the GI tract. The highest 14C levels were found in blood and liver 1 or 3 hr after dosing. In the GI tracts large amounts of the diester (DEHA) , monoester(MEHA)and alcohol (EH) were found. The quantities of DEHA decreased with time while other products increased. The major metabolites in the livers were more polar than EH. In general, only small amounts of DEHA, MEHA and EH were found. The livers of male mice also contained large amounts of an early eluting metabolite which was found in female livers in only small quantities. The extent of the two major metabolites recovered in livers of female mice differed significantly.
Disposition:
Preliminary studies with males: after treatment with 50 and 500mg/kg 14C-DEHA, 95-102% was eliminated in urine, feces and expired air within 24 hr. After 5,000 mg/kg, most of the 14C was excreted in 24 hr but ~12% were also recovered in the GI tracts.
Definitive studies with male and female mice (50, 500 and 5,000 mg/kg 14C-DEHA): urinary elimination of 14C was rapid and extensive. About 91% of the low and mid doses were eliminated in urine in 24 hr; only 75% after 5,000 mg/kg. Elimination in feces was 7-8% at the low and mid doses and 4% at the high dose. The latter group showed high recovery in the GI tract. Only 0.8 to 1.2% in males and 1.5 to 3.8% in females were eliminated in the expired air. Respiratory elimination was highest in the female low dose group. Only small amounts were found in blood and tissue 24 and 48 hr after dosing. Adrenals and livers showed the highest levels at low and mid dose, especially in males. After 5,000 mg/kg, blood also contained high 14C levels; blood and liver content of the females were significantly higher than of males. At 48 hr, the skin (both sexes) and the fat (females) showed higher retention of 14C than other tissues.
The high recovery in the GI tract following the high dose (12%) may account for the lower elimination in feces.
Urinary and fecal elimination: In males the initial rate of elimination of 14C in urine and feces was very rapid; the majority of 14C recovered from both routes was excreted during the first 6 hr after dosing (~ 34% of the dose in urine and ~ 39% in feces). After this time an additional 14% of the dose was eliminated in urine and only 2% in feces. The two female showed a large variation in urinary and fecal elimination of radioactivity. One female displayed a steady rate (~ 2% of the dose per hour) of urinary excretion of 14C during the first 24 hr; after this time, the rate dropped considerably. Fecal elimination of 14C was quite similar to that of the males. The other female eliminated the majority of the dose in urine (~ 88%) at a rate of ~ 3% of the dose per hour during the first 24 hr. Approx. 18% of the administered dose was eliminated in urine between 24 and 48 hr. Fecal exeretion of 14C in this animal was minimal in comparison to the other monkeys; only ~ 3% of the dose being eliminated by this route.
Blood levels: Radioactivity appeared in blood rapidly; peak levels occurred at the earliest sampling time (2 hr) after dosing. Males showed rapid disappearance of 14C from blood. The rate of disappearance in females was slower than that observed in the males. Throughout the 48-hr period, the majority of blood radioactivity was recovered in plasma.
Tissue levels: Males showed the highest levels of 14C in the skin, followed by fat and liver, on average. Levels in pancreas, kidneys and adrenals also exceeded those of blood. One male showed higher levels of 14C in all tissues, especially skin, fat, and liver than did the other. Females showed average concentrations of radioactivity to be highest in liver, followed by fat, kidneys, adrenals, pancreas, and skin. One female showed higher tissue levels except in fat and skin. It also displayed a unique pattern of elimination of 14C in urine and feces, and in the disappearance of 14C from blood compared to the other monkeys. Despite the variable levels of 14C in tissues shown between animals of the same sex, females showed greater retention of radioactivity in most tissues, especially in liver, adrenals, bladder, and pancreas.
Tissue-to-blood ratios: Males showed the highest ratios in skin, fat, and liver. Ratios greater than 1 were also shown in pancreas, kidneys, and adrenals. Female ratios were highest in liver, fat, skin, and adrenals. Other tissues showing ratios greater than 1 included kidneys and pancreas. These ratios demonstrate a high uptake of 14C-DEHA or its metabolites by liver, fat and skin.
Recoveries in excreta and tissue: Males showed that the majority of administered doses were recovered almost equally in urine and feces. Trace amounts of radioactivity were present in the GI tract and blood, and minor levels were detected in tissue. Females also showed major recovery of the dose in urine and feces. Large variations in excretion patterns were displayed by the females. Total recoveries in the four animals ranged from 89.4 to 92.6% of the dose.
Urinary, fecal, and respiratory elimination: Urinary exeretion of 14C was rapid and the dominant route of elimination. In males, ~ 19% of the dose appeared in urine at 6 hr after dosing. The largest amount of 14C was eliminated in urine between 12 and 24 hr, a total of ~ 74% being exereted by this time. A total of ~ 20% of the administered radioactivity was exereted in feces during 24 hr, mostly between 6 and 12 hr. Female rats showed similar rates and amounts of 14C in urine and feces. Smaller amounts of radioactivity were recovered in the expired air throughout the 24-hr period; both sexes eliminated a total of ~ 1.4% and 2.1% of the dose. As volatile material, ~ 0.7% of the dose was collected from both sexes. Expired 14CO2 amounted to ~ 0.6 and 1.4% of the dose from both sexes.
Blood and tissue levels: In males, the highest concentrations of radioactivity were found in the GI tract 24 hr after dosing, followed by liver, adrenals, kidneys, fat, and skin. Most of the blood radioactivity was recovered in plasma. Females also demonstrated the highest levels of 14C in GI tract, followed by liver, adrenals, and kidneys. Male rats showed higher 14C levels than females in all tissues. Some of these differences were significant. Particularly apparent were the higher levels shown in pancreas, spleen, muscle, and fat of males.
Tissue-to-blood ratios: In males, the highest ratios were detected in GI tract, followed by liver and adrenals. Ratios higher than 1 were also found for plasma, kidneys, fat, skin and spleen. Females showed the highest ratios for the GI tract, liver, and adrenals. Although the actual concentration of radioactivity was higher in tissues of males, these ratios show no differences in preferential uptake, retention, or storage of 14C-DEHA or its metabolites in both sexes.
Recoveries in excreta and tissue: In males, the majority of the dose was recovered in urine (~ 74%) and feces (~20%). Approx. 1.4% of the dose was collected in the expired air, while ~ 3.7% was remaining in the GI tract at 24 hr after dosing. Tissue contained ~ 2.2% of the dose and only ~ 0.2% was found in blood. Females showed similar results except for slightly lower amounts of 14C in tissue.
Description of key information
There is only very little data for diisononyl adipate available. However, for the structural analogue diethylhexyl adipate (DEHA) plenty of data is available.
Summary
The data show that DEHA, administered orally to mice, rats, and monkeys, is readily absorbed, distributed to various tissues, metabolized and excreted in urine and to a lesser extent in feces and expired air. Dose-dependent changes in absorption, tissue uptake, metabolism, and elimination could be found. Sex differences were apparent in the hepatic uptake and metabolism. The data indicate little, if any, prolonged retention of DEHA or its metabolites in blood and tissue after oral administration in all three species. As could be expected based on the high logPoW, dermal penetration is fairly limited.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
Hydrolysis and Absorption in Mice
14C-DEHA and/or its metabolites was rapidly absorbed from the GI tract. The highest 14C levels were found in blood and liver 1 or 3 hr after dosing. In the GI tracts large amounts of the diester (DEHA) , monoester (MEHA) and alcohol (EH) were found. The quantities of DEHA decreased with time while other products increased. The major metabolites in the livers were more polar than EH. In general, only small amounts of DEHA, MEHA and EH were found. The livers of male mice also contained large amounts of an early eluting metabolite which was found in female livers in only small quantities. The extent of the two major metabolites recovered in livers of female mice differed significantly.
Dermal absoption
After occlusive application of 5 or 100mg DEHA as a component of a roll-on deodorant onto human breast skin in vitro, 50 to 20% did not penetrate the skin, while 20 - 30% stayed within the skin. No differentiation was made in the study between stratum corneum and further layers of the skin. Only a small fraction (< 0.1%) were absorped through the skin at a constant rate of 2.2ng/cm²/h within 24h. Because DEHA is highly lipophilic, low penetration and high retention within and on top of the skin meet the expectations. But limited solubility of DEHA in the receiver solution (app. factor 4 above the actual concentration reached during the experiment) might lead to an underestimation of the maximum penetration, despite the use of a non-static system. Additionally, only 56 - 81% of the initial amount of DEHA was recovered. One explantion might be hydrolysis by esterases in the skin, which could lead to an additional uptake of DEHA metabolites.
Disposition in Mice
Preliminary studies with males: after treatment with 50 and 500mg/kg 14C-DEHA, 95-102% was eliminated in urine, feces and expired air within 24 hr. After 5,000 mg/kg, most of the 14C was excreted in 24 hr but ~12% were also recovered in the GI tracts. Definitive studies with male and female mice (50, 500 and 5,000 mg/kg 14C-DEHA): urinary elimination of 14C was rapid and extensive. About 91% of the low and mid doses were eliminated in urine in 24 hr; only 75% after 5,000 mg/kg. Elimination in feces was 7-8% at the low and mid doses and 4% at the high dose. The latter group showed high recovery in the GI tract. Only 0.8 to 1.2% in males and 1.5 to 3.8% in females were eliminated in the expired air. Respiratory elimination was highest in the female low dose group. Only small amounts were found in blood and tissue 24 and 48 hr after dosing. Adrenals and livers showed the highest levels at low and mid dose, especially in males. After 5,000 mg/kg, blood also contained high 14C levels; blood and liver content of the females were significantly higher than of males. At 48 hr, the skin (both sexes) and the fat (females) showed higher retention of 14C than other tissues.
Disposition in Rats and Monkeys
Compared to mice, rats showed lower elimination in urine(~74%) and higher in feces(~20%). 14C elimination in the expired air was 1.4 to 2.1%. About 4% of the dose was recovered in the GI tract. 14C levels in livers and adrenals were higher than in other tissues. Males showed significantly higher tissue contents than the females. Tissue contents in rats were higher than in mice treated with 500 mg/kg (same conditions). The monkeys also showed rapid elimination of 14C in urine and to a lesser extent in feces. Absorption was rapid, as indicated by the fast rates of elimination and by the fast appearance of 14C in blood after 2 hr. Radioactivity disappeared faster from blood of male monkeys compared to females. At 48 hr following dosing, the skin, fat, and livers of males showed the highest levels. In females the 14C concentrations in livers were significantly higher than in other tissues.
Metabolism
The data show that DEHA is rapidly hydrolyzed to the monoester, then the alcohol and acid, without accumulation of MEHA. Supporting data from an in vitro study indicate that this reaction already takes place in the small intestine after oral exposure (in vitro half life of DEHA = 6min). The alcohol is oxidized by ß-oxidation, W-, and W-l oxidation generating acids, ketones, keto-acids, hydroxy acids, and diacids. Metabolism appeared to be less extensive in monkeys, which mostly excreted MEHA and EH (as their glucuronides). In contrast, mice and rats mostly excreted products of faster oxidation, mainly EHA, 5-0H EHA and diEHA. In a study with human volunteers similar metabolites were found in urine and MEHA was found in fecal samples (Loftus, 1993).
As supporting information, for DINA itself an excretion study with human volunteers is available. In this study three monoester metabolites with oxidative modifications (hydroxy, oxo, and carboxylic acid groups) in the isononyl (technical mixture, thus containing several isomers) side chain were identified (OHMINA, oxo-MINA, and cx-MIOA) as urinary metabolites of DINA.
After oral application, all three metabolites emerged quickly in urine, reaching peak concentrations at around 2 h post dose. Based on their urinary excretion, urinary excretion fractions (FUEs) were derived, which were low (sum of FUEs ≤0.034 %), but in a comparable range as those of the two adipates DEHA and DnBA. In analogy to these adipate plasticizers, adipic acid can be expected as a major metabolite of DINA (not investigated in this present study). OH-MINA was the major specific DINA metabolite with inter-individually highly consistent FUEs (0.020-0.023). In a pilot population of German adults, DINA monoester metabolite concentrations were below the LOQ.
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