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EC number: 700-342-7 | CAS number: 1163775-81-2
- 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
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- Nanomaterial crystallite and grain size
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- Endpoint summary
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- 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 in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 19-May-2016 to 09-Sept-2016
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Objective of study:
- bioaccessibility (or bioavailability)
- toxicokinetics
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Version / remarks:
- Version adopted 22-July-2010
- Deviations:
- yes
- Remarks:
- For toxicokinetic arm of study, only two animals of each gender were studied rather than the four stipulated in the test guidelines.
- Principles of method if other than guideline:
- N/A
- GLP compliance:
- yes (incl. QA statement)
- Specific details on test material used for the study:
- N/A
- Radiolabelling:
- no
- Remarks:
- An analytical method was developed to measure the unlabelled test material.
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- SPF Grade.
- Details on species / strain selection:
- The rat was selected for this study because it is recognized as a species commonly used in toxicology studies. The rat is recommended by the Ministry of Environmental Protection of P. R. China "The Guidelines for the Testing of Chemicals - Health Effects (2nd edition)".
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Beijing WeiTongLiHua Test Animal Technology Co. Ltd
- Age: 6-8 weeks.
- Weight at end of quarantine period: Males 301.9 to 378.9 g. Females 232.3 to 275.6 g.
- Housing: Animals were housed in groups in transparent polycarbonate boxes and each cage rack contained 3-5 animals. Study number, test substance number, animal code, group, sex, and dose were labelled on the cage cards. Cages and bedding were replaced twice a week.
- Diet: Ad libitum. Standard extruded food for test animals (source: Beijing KeaoXieli Food Co. Ltd).
- Water: Ad libitum. Municipal water. Drinking water quality was monitored.
- Quarantine: All animals were quarantined for seven (7) days. During this period, no abnormalities of animals were observed. Clinical Verterinarian checked the animals and issued quarantine inspection report before the animals were used on-study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 25
- Humidity (%): 40 - 70
- Photoperiod: 12 hrs dark /12 hrs light - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- The appropriate amount of the test sample plus corn oil volume, mix, dubbed with 1000 mg/mL suspension for animal exposure. The volume of administration was 10 mL/kg. Animals were fasted for at least 12 h prior to administration.
- Duration and frequency of treatment / exposure:
- A single dose of test substance was administered.
- Dose / conc.:
- 1 mg/kg bw/day
- Remarks:
- iv adminstration
- Dose / conc.:
- 5 mg/kg bw/day
- Remarks:
- iv administration
- Dose / conc.:
- 10 mg/kg bw/day
- Remarks:
- iv administration
- Dose / conc.:
- 1 000 mg/kg bw (total dose)
- Remarks:
- Toxicokinetics arm of study.
- Dose / conc.:
- 50 mg/kg bw (total dose)
- Remarks:
- Digestive residue arm of study.
- No. of animals per sex per dose / concentration:
- 3 males for iv administration
2 males and 2 females for toxicokinetics arm of study.
8 males and 8 females for digestive residue arm of study. - Control animals:
- no
- Positive control reference chemical:
- N/A
- Details on study design:
- DOSE SELECTION
The dose selection was based on three preliminary experiments, details of which are provided in the pertinent RESULTS AND DISCUSSION section below.
ANALYTICAL METHOD
A LC-MS/MS method for LINPLAST 812 TM (m/z 547.4→305) was established as part of the study.
The method was validated for use in rat plasma anticoagulated by heparin in the range 50-500 ng/mL LINPLAST 812 TM.
The method was validated for use with digestive tract homogenate in the range 50-500 ng/mL LINPLAST 812 TM. - Details on dosing and sampling:
- TOXICOKINETIC ARM OF STUDY
Dosing details have already been provided.
Following dosing, approximately 0.2 mL of blood was collected via the orbital vein and was added with anticoagulant heparin solution. Blood samples were collected at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h following the dose administration and before dose administration.
Blood samples should be pretreatment and analysed as soon as possible.
DIGESTIVE RESIDUE ARM OF STUDY
Dosing details have already been provided.
After the exposure of animals placed in metabolic cages for 30 min, 2 h, 6 h, and 24 h, each time two male and two female animals were euthanized, whichever digestive tract and faeces collected after administration, the digestive tract and feces combined weighed, then immediately added 0.01 M PBS at a weight ratio of 1:5 homogenate, homogenate vortex mix, 50 μL was added to 500 μL acetonitrile and then measured. - Statistics:
- TOXICOKINETIC ARM OF STUDY
DAS2.0 pharmacokinetic program was used to analyse data and calculate the main pharmacokinetic parameters: AUC, Cmax, F, Tmax, MRT, t1/2 and so on.
DIGESTIVE RESIDUE ARM OF STUDY
Microsoft Excel was used for data processing, computing the gastrointestinal remaining amount. - Preliminary studies:
- PRELIMINARY EXPERIMENT 1
Two SD male rats were administered LINPLAST 812 TM at 20 or 1000 mg/kg by oral gavage, one male rat was administered LINPLAST 812 TM at 5 mg/kg by intravenous (iv) injection, obtained plasma to determine (plasma sample treatment: samples treated at 13000rpm, at 4 °C Centrifugal for 10min). Preliminary test results are shown in Table 1. The results indicate that LINPLAST 812 TM eliminates slowly in iv injection treatment group and can’t absorb in oral gavage group.
PRELIMINARY EXPERIMENT 2
Two SD male rats were administered LINPLAST 812 TM at 20 or 1000 mg/kg by oral gavage, one male rat was administered LINPLAST 812 TM at 5 mg/kg by intravenous (iv) injection, obtained blood to determine (sample treatment: 50 μL of rat whole blood was added into 500 μL acetonitrile). Preliminary test results are shown in Table 2. The result indicates that LINPLAST 812 TM eliminates slowly in iv injection treat group; and can’t absorb in oral gavage, without different plasma result.
PRELIMINARY EXPERIMENT 3
Two SD male rats were administered LINPLAST 812 TM at 1 or 10 mg/kg by intravenous (iv) injection, obtained plasma to determine (sample treatment: samples treated at 13000rpm, at 4 °C Centrifugal for 10min). Preliminary test results are shown in Table 3. The result indicates that LINPLAST 812 TM eliminates slowly in all iv injection treat group, and exposure level did not increase with the increase of dose. - Type:
- other: Bioavailability
- Results:
- After oral gavage, LINPLAST 812 TM prototype was undetectable in the plasma of SD rats.
- Type:
- other: Digestive residue
- Results:
- Less than 1% of the administered LINPLAST 812 TM was recovered in digestive tract and feces.
- Details on absorption:
- N/A
- Details on distribution in tissues:
- N/A
- Details on excretion:
- N/A
- Metabolites identified:
- not measured
- Details on metabolites:
- N/A
- Enzymatic activity measured:
- N/A
- Bioaccessibility (or Bioavailability) testing results:
- TOXICOKINETIC ARM OF STUDY
Four SD rats were administered LINPLAST 812 TM at 1000 mg/kg by oral gavage. The concentration time-course data for LINPLAST 812 TM in plasma is shown in Table 4. LINPLAST 812 TM prototype was undetectable in plasma.
DIGESTIVE RESIDUE ARM OF STUDY
Sixteen (16) rats were administered LINPLAST 812 TM at 50 mg/kg by oral gavage. The concentration time course data for LINPLAST 812 TM in plasma, digestive track, feces are shown in Table 5 to Table 7. The recovery rate time course data for LINPLAST 812 TM in plasma, digestive tract, feces are shown in Table 8 and Table 9.
At different times after oral gavage, the recovery rate of LINPLAST 812 TM in digestive tract and feces is very low, less than 1%, and LINPLAST 812 TM prototype was undetectable in plasma. - Conclusions:
- The absorption kinetics characteristics of LINPLAST 812 TM in rats by oral gavage is:
LINPLAST 812 TM prototype wasn’t found in plasma following gavage administration, it may be metabolized and decomposed in digestive tract and/or there has first pass effect in liver. - Executive summary:
An LC-MS/MS analytical method for LINPLAST 812 TM in rat biological samples was established. The method was based on quantifying the mass transition m/z 547.4→305. The identity of the precursor and fragment ions are not provided in the report and it is not clear whether the method measures one, more, or all of the constituents in the test material.
The method was validated for use with rat plasma. Specificity was confirmed and linearity was established over a range of 50-500 ng/mL, with the lower bound representing the LLOQ for the method. Inter- and intra-assay precision and accuracy were satisfactory. Recovery was approximately 75%. Sample and extracted sample stability was determined.
Linear range, precision, accuracy, recovery rate and matrix effects were also confirmed partially for the alimentary canal of rats.
Preliminary test results showed that LINPLAST 812 TM has slow elimination in rats administered the substance by intravenous injection. Moreover, plasma exposure did not proportionally increase with increasing dose.
After oral administration of LINPLAST 812 TM by oral gavage (1000 mg/kg), LINPLAST 812 TM prototype was undetectable in plasma. Moreover, after oral gavage administration of 50 mg/kg LINPLAST 812 TM, the recovery rate in the digestive tract and feces was less than 1%. LINPLAST 812 TM may be metabolized and decomposed in the digestive tract and/or subject to significant first-pass hepatic metabolism.
Reference
Table 1 Plasma concentration of LINPLAST 812 TM following administration in SD rats
J01 means intravenous administration, R01 and R02 means oral gavage administration, NA means not detected, BLLOQ below the low limit of quantization.
Time (h) |
Concentration of LINPLAST 812 TM in plasma (ng/mL) |
||
J01 (5 mg/kg, iv) |
R01 (20 mg/kg, ig) |
R02 (1000 mg/kg, ig) |
|
0.0166667 |
199.73 |
N/A |
N/A |
0.0833333 |
189.88 |
BLLOQ |
BLLOQ |
0.25 |
165.83 |
BLLOQ |
BLLOQ |
0.5 |
165.00 |
BLLOQ |
BLLOQ |
1 |
151.14 |
BLLOQ |
BLLOQ |
2 |
138.23 |
BLLOQ |
BLLOQ |
4 |
119.85 |
BLLOQ |
BLLOQ |
6 |
111.89 |
BLLOQ |
BLLOQ |
8 |
BLLOQ |
BLLOQ |
BLLOQ |
12 |
BLLOQ |
BLLOQ |
BLLOQ |
24 |
BLLOQ |
BLLOQ |
BLLOQ |
Table 2 The whole blood concentration of LINPLAST 812 TM following administration in SD rats
J01 means intravenous administration, R01 and R02 means oral gavage administration, NA means not detected, BLLOQ below the low limit of quantization.
Time (h) |
Concentration of LINPLAST 812 TM in whole blood (ng/mL) |
||
J01 (5 mg/kg, iv) |
R01 (20 mg/kg, ig) |
R02 (1000 mg/kg, ig) |
|
0.0166667 |
126.31 |
N/A |
N/A |
0.0833333 |
108.99 |
BLLOQ |
BLLOQ |
0.25 |
106.89 |
BLLOQ |
BLLOQ |
0.5 |
BLLOQ |
BLLOQ |
BLLOQ |
1 |
101.81 |
BLLOQ |
BLLOQ |
2 |
100.01 |
BLLOQ |
BLLOQ |
4 |
101.60 |
BLLOQ |
BLLOQ |
6 |
BLLOQ |
BLLOQ |
BLLOQ |
8 |
BLLOQ |
BLLOQ |
BLLOQ |
12 |
BLLOQ |
BLLOQ |
BLLOQ |
24 |
BLLOQ |
BLLOQ |
BLLOQ |
Table 3 Plasma concentration of LINPLAST 812 TM following administration in SD rats
J03, J04 means intravenous administration, BLLOQ below low limit of quantization.
Time (h) |
Concentration of LINPLAST 812 TM in plasma (ng/mL) |
|
J03 (1 mg/kg, iv) |
J04 (10 mg/kg, iv) |
|
0.0166667 |
79.25 |
394.48 |
0.0833333 |
84.43 |
376.48 |
0.25 |
80.44 |
351.89 |
0.5 |
78.57 |
348.58 |
1 |
72.30 |
299.75 |
2 |
74.07 |
243.01 |
4 |
59.91 |
255.68 |
6 |
57.16 |
178.23 |
8 |
52.22 |
168.81 |
12 |
BLLOQ |
130.88 |
24 |
BLLOQ |
89.17 |
Table 4 Concentration time-course data for 1000 mg/kg LINPLAST 812 TM in plasma
BLLOQ means below the low limit of quantitation (50 ng/mL).
Sampling time |
Concentration of LINPLAST 812 TM in plasma (ng/mL) |
|||
FEMALE |
MALE |
|||
R01 |
R02 |
R03 |
R04 |
|
Predose |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
15 min |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
30 min |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
1 h |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
2 h |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
4 h |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
8 h |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
24 h |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
Table 5 Testing result for 50 mg/kg LINPLAST 812 TM in plasma
BLLOQ means below the low limit of quantitation (50 ng/mL).
Time (h) |
Animal No. |
Gender |
LINPLAST 812 TM (ng/mL) |
0.5 |
D01 |
F |
BLLOQ |
0.5 |
D02 |
F |
BLLOQ |
0.5 |
D03 |
M |
BLLOQ |
0.5 |
D04 |
M |
BLLOQ |
2 |
D05 |
F |
BLLOQ |
2 |
D06 |
F |
BLLOQ |
2 |
D07 |
M |
BLLOQ |
2 |
D08 |
M |
BLLOQ |
6 |
D09 |
F |
BLLOQ |
6 |
D10 |
F |
BLLOQ |
6 |
D11 |
M |
BLLOQ |
6 |
D12 |
M |
BLLOQ |
24 |
D13 |
F |
BLLOQ |
24 |
D14 |
F |
BLLOQ |
24 |
D15 |
M |
BLLOQ |
24 |
D16 |
M |
BLLOQ |
Table 6 Testing result for 50 mg/kg LINPLAST 812 TM in digestive tract homogenate
BLLOQ means below the low limit of quantitation (50 ng/mL).
Time (h) |
Animal No. |
Gender |
LINPLAST 812 TM (ng/mL) |
LINPLAST 812 TM (ng/g) |
0.5 |
D01 |
F |
111.48 |
668.88 |
0.5 |
D02 |
F |
110.24 |
661.44 |
0.5 |
D03 |
M |
91.57 |
549.42 |
0.5 |
D04 |
M |
146.65 |
879.9 |
2 |
D05 |
F |
92.03 |
552.18 |
2 |
D06 |
F |
112.92 |
677.52 |
2 |
D07 |
M |
118.26 |
709.56 |
2 |
D08 |
M |
123.20 |
739.20 |
6 |
D09 |
F |
79.08 |
474.48 |
6 |
D10 |
F |
77.81 |
466.86 |
6 |
D11 |
M |
134.61 |
807.66 |
6 |
D12 |
M |
109.67 |
658.02 |
24 |
D13 |
F |
BLLOQ |
BLLOQ |
24 |
D14 |
F |
BLLOQ |
BLLOQ |
24 |
D15 |
M |
BLLOQ |
BLLOQ |
24 |
D16 |
M |
BLLOQ |
BLLOQ |
Table 7 Testing result for 50 mg/kg LINPLAST 812 TM in feces
BLLOQ means below the low limit of quantitation (50 ng/mL).
Time (h) |
Animal No. |
Gender |
LINPLAST 812 TM (ng/mL) |
LINPLAST 812 TM (ng/g) |
0~6 |
D10 |
F |
BLLOQ |
BLLOQ |
0~6 |
D12 |
M |
BLLOQ |
BLLOQ |
6~24 |
D13 |
F |
118.86 |
713.16 |
6~24 |
D14 |
F |
212.64 |
1275.84 |
6~24 |
D15 |
M |
189.42 |
1136.52 |
6~24 |
D16 |
M |
303.93 |
1823.58 |
Table 8 Residue and recovery for 50 mg/kg LINPLAST 812 TM in digestive tract
BLLOQ means below the low limit of quantitation (50 ng/mL).
Time (h) |
Animal No. |
Exposure Amount (mg) |
Digestive Tract Weight (g) |
Digestive Tract Residues (mg) |
Recovery rate (%) |
Average Recovery (%) |
0.5 |
D01 |
13.0 |
25.580 |
0.0171 |
0.132 |
0.128 |
0.5 |
D02 |
13.0 |
28.263 |
0.0187 |
0.144 |
|
0.5 |
D03 |
18.5 |
33.301 |
0.0183 |
0.099 |
|
0.5 |
D04 |
18.0 |
28.244 |
0.0249 |
0.138 |
|
2 |
D05 |
14.5 |
36.977 |
0.0204 |
0.141 |
0.141 |
2 |
D06 |
12.5 |
25.145 |
0.0170 |
0.136 |
|
2 |
D07 |
19.5 |
39.462 |
0.0280 |
0.144 |
|
2 |
D08 |
17.5 |
33.953 |
0.0251 |
0.143 |
|
6 |
D09 |
13.0 |
28.265 |
0.0134 |
0.103 |
0.103 |
6 |
D10 |
12.5 |
19.742 |
0.0092 |
0.074 |
|
6 |
D11 |
18.0 |
29.170 |
0.0236 |
0.131 |
|
6 |
D12 |
16.5 |
26.404 |
0.0174 |
0.105 |
|
24 |
D13 |
13.5 |
17.835 |
BLLOQ |
0 |
0 |
24 |
D14 |
14.0 |
19.586 |
BLLOQ |
0 |
|
24 |
D15 |
17.0 |
18.739 |
BLLOQ |
0 |
|
24 |
D16 |
20.0 |
23.098 |
BLLOQ |
0 |
Table 9 Residue and recovery for 50 mg/kg LINPLAST 812 TM in feces
BLLOQ means below the low limit of quantitation (50 ng/mL).
Time (h) |
Animal No. |
Exposure Amount (mg) |
Feces Weight (g) |
Feces Excretion (mg) |
Recovery rate (%) |
Average Recovery (%) |
0~6 |
D10 |
12.5 |
0.932 |
BLLOQ |
0 |
0 |
0~6 |
D12 |
16.5 |
1.808 |
BLLOQ |
0 |
|
6~24 |
D13 |
13.5 |
3.001 |
0.0021 |
0.016 |
0.019 |
6~24 |
D14 |
14 |
2.927 |
0.0037 |
0.027 |
|
6~24 |
D15 |
17 |
0.998 |
0.0011 |
0.007 |
|
6~24 |
D16 |
20 |
2.721 |
0.0050 |
0.025 |
Description of key information
A key OECD 417 study has been conducted on 1,2,4-Benzenetricarboxylic acid, mixed dodecyl and octyl triesters
Accumulation in man of 1,2,4-Benzenetricarboxylic acid, mixed dodecyl and octyl triesters is unlikely. Reasons (including data on structurally related phthalates and the trimellitate tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate):
-low bioaccumulation factor of the substance
-likely that mainly the hydrolysis products will be absorbed, likely that hydrolysis is slow, therefore also oral absorption is low
-dermal and inhalative absorption are lower than oral absorption (dermal < < inhalative < oral)
- rats are far more efficient at hydrolysing the esters and, subsequently, absorbing the monoester than primates (and presumably humans)
- rapidly metabolised and excreted in the urine and faeces
- accumulation is negligible (based on an oral rat study)
- minimal or no evidence of accumulation in rodent tissues.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
The substance is a trimellitate ester with linear C8 and C12 alkyl chains. In a key OECD 417 study (Yongbiao Guan, 2016), two male and 2 female Sprague Dawley rats were administered 1000 mg/kg TM 812 in corn oil via oral gavage. Blood was sampled pre-dose, 15 and 30 mins, 1, 2, 4, 8 and 24 hours post administration. No TM 812 was detected in the plasma at any of the sample timepoints, all below LLOQ (50 ng/mL).
An additional group of eight male and 8 female Sprague Dawley rats were dosed with 50 mg/kg TM 812 to determine the digestive residue. Animals were placed in metabolism cages for either 30 min, 2, 6 or 24 hours. On each timepoint two male and 2 female rats were euthanized and digestive tract and faeces collected for evaluation. Plasma samples were also analysed which resulted in all samples below LLOQ (50 ng/mL). Low level residues of TM 812 were detected in digestive tract homogenate up to 6 hours post dose and in faeces (6-24 hours post dose).
It is concluded that after oral administration with 1000 mg/kg TM 812 in Sprague Dawley rats, no TM 812 was detected in the plasma samples and is therefore considered to be metabolized and decomposed in the digestive tract and/or has first pass effect in the liver.
A preliminary test conducted via intravenous administration to groups of Sprague Dawley rats at concentrations of 1, 5 and 10 mg/kg TM 812, demonstrated slow elimination in rats. The plasma exposure was not seen to increase proportionally with an increased dose and eliminate slowly.
The kinetic absorption study indicates that TM 812 cannot be absorbed into the bloodstream in its original form.
Accumulation in man of 1,2,4-Benzenetricarboxylic acid, mixed dodecyl and octyl triesters is unlikely. Reasons (including data on structurally related phthalates and the trimellitate tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate):
-low bioaccumulation factor of the substance
-likely that mainly the hydrolysis products will be absorbed, likely that hydrolysis is slow, therefore also oral absorption is low
-dermal and inhalative absorption are lower than oral absorption (dermal < inhalative < oral)
- rats are far more efficient at hydrolysing the esters and, subsequently, absorbing the monoester than primates (and presumably humans)
- rapidly metabolised and excreted in the urine and faeces
- accumulation is negligible (based on an oral rat study)
- minimal or no evidence of accumulation in rodent tissues.
A structural related trimellitate, the Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate (TOTM) was investigated in an oral rat study. Both substances contain the same acid function, but are esterified with different alcohols (linear C8 and C12 vs. branched C8). Additionally helpful information on phthalates is available. Based on structurally similarity to phthalate esters (with two instead of three carboxylic functions) a similar toxicokinetic behaviour can be expected for that substance class. Absorption and metabolism were studied for Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate (TOTM) (14C-labeled on the 2-carbon atom of 2-ethylhexyl group) mixed with corn oil and administered by gavage in a single dose of 100 mg/kg of body weight in four male Sprague Dawley rats. Rats were placed in glass metabolism cages and urine, feces and expired air were collected for 144 hrs. About 75% of the dose was excreted unchanged in the feces, 16% in the urine as metabolites and 1.9% was expired as 14CO2. Radioactivity was excreted in the feces as unchanged TOTM (85% of the fecal radioactivity), mono- and di(2-ethylhexyl) trimellitate (MOTM and DOTM, respectively,) and unidentified polar metabolites. Metabolites in the urine were identified as MOTM and metabolites of 2-ethylhexanol. Less than 0.6% of the dose remained in whole tissues. Elimination of 14CO2 was biphasic with half-lives of 4.3 and 31 hours, and excretion of radioactivity in the urine was biphasic with half-lives of 3.4 hours and 42 hours. Based on remaining labeled ratio (less than 0.6% of dose) in whole tissues at 144 hours, it is considered that the accumulation of this chemical is negligible (SIDS, Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate, 2002). The same is likely for 1,2,4-Benzenetricarboxylic acid, mixed dodecyl and octyl triesters. Hydrolysis of the phthalate diester to a monoester enhances absorption. Studies have shown that for high-MW esters, breakdown (metabolism; hydrolysis) of the ester bond to liberate one alcohol and a remaining monoester greatly increases the absorption, since the monoester and alcohol are absorbed more rapidly than the diester. The more hydrolysis occurs, the more monoester is available for absorption. Once absorbed, the monoester continues to be metabolised into subsatnces that are excreted in the urine. If exposure is through skin from contact with polyvinylchloride (PVC) articles containing phthalate esters, the absorption is very slow because the ester is not hydrolysed and must be absorbed intact. Experiments with laboratory animals and human skin have demonstrated that the absorption rate of high levels of exposure of the skin to neat chemical might not result in adverse health effects because the absorption is so slow and the metabolism of the ester is minimal. For inhalation exposure, absorption is likely to be slow but faster than absorption through the skin and slower than absorption from ingestion. The route of exposure that results in the most efficient absorption of phthalate esters is ingestion. Laboratory studies have demonstrated, however, that rats are far more efficient at hydrolysing the esters and, subsequently, absorbing the monoester than primates (and presumably humans). This means that when studies of phthalate esters are conducted in laboratory animals where health effects are observed following very high doses of an ester, it is very difficult to reproduce such effects in primates (and presumably humans) because primates do not absorb phthalate esters as efficiently as other laboratory animals. Primates and humans absorb about seven times less phthalate than do rats (especially for high MW-esters). At low doses, the absorption may be more comparable (Staples, 2003). It is likely that the hydrolysis of trimellitates to the corresponding monoesters is worse simply because of the existence of three instead of two ester groups and additionally because of possible steric hinderance of hydrolysis. Hence it is likely that the absorption is also worse compared to phthalates.
Various reviews of different phthalate esters by the Australian National Industrial Chemicals Notification and Assessment Scheme (NICNAS) are available. There are at least some toxicokinetic data available for many of the 24 phthalates, with the majority of testing conducted via the oral and dermal route. Limited data on absorption are available. Data, mostly from rats and with one human study on DEHP, suggest phthalates are readily absorbed via the oral route. A clear trend was noted in dermal absorption with data collected from five phthalates, DEP, BBP, DEHP, DINP and DIDP. Studies indicated a decrease in dermal absorption with increasing side chain length. The only information available on inhalation is on DIDP, which was readily absorbed from the lung. There is minimal or no evidence of accumulation in rodent tissues (NICNAS, Phthalates Hazard Compendium, 2008). Studies on several phthalates indicate that they are rapidly metabolised and excreted in the urine and faeces. They undergo phase I biotransformation, that is, primary metabolism into their hydrolytic monoesters by hydrolysis of one of their ester bonds. Further enzymatic oxidation of the alkyl chain occurs in some of the phthalates, resulting in more hydrophilic oxidative metabolites. Monoesters and the oxidative metabolites of phthalates may continue to undergo phase II biotransformation to produce glucuronide conjugates with increased water solubility. The data on the toxicokinetics indicate that phthalates in general are likely to be rapidly absorbed as the monoester from the gut and excreted via the urine ((NICNAS, Phthalates Hazard Compendium, 2008). For example following ingestion, di-n-octyl phthalate (DnOP) is rapidly metabolised and absorbed from the gastrointestinal tract as the monoester mono-n-octylphthalate (MnOP). Half-life of the monoester in the blood is approximately 3 hours. The liver is capable of metabolising DnOP. Elimination occurs via the urine with levels of MnOP exceeded after 24 hours by the other oxidative metabolite mono-(3-carboxypropyl) phthalate (MCPP) (NICNAS, 2008).
Literature
NICNAS, 2008; Existing Chemical Hazard Assessment Report, di-n-octyl phthalate, Australian Government of Health and Ageing NICNAS
NICNAS, 2008; Phthalate Hazard Compendium, A summary of physicochemical and human health hazard data for 24 ortho-phthalate chemicals, Australian Government of Health and Ageing NICNAS, June 2008
SIDS, 2002, SIDS Initial Assessment Report For SIAM 14, Paris, France, 26-28 March 2002, Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate Staples, C.A., 2003, Phthalate Esters, The Handbook of Environmental Chemistry, Springer Verlag Berlin, Heidelberg, New York
Staples, C.A., 2003, Phthalate Esters, The Handbook of Environmental Chemistry, Springer Verlag Berlin, Heidelberg, New York
Justification of use of 1,2,4-Benzenetricarboxylic acid, decyl octyl ester (CAS-number 67989 -23 -5) and 1,2,4-Benzenetricarboxylic acid, decyl octyl triesters (CAS-number 90218 -76 -1) as supporting substances for 1,2,4 -Benzenetricarboxylic acid, mixed dodecyl and octyl triester for read-across
All substances have the same basic structure (triester of 1,2,4 -Benzenetricarboxylic acid). There are differences in the chain length of one alcohol part of the esters (C-12 versus C-10). This variation is not considered to cause substantial changes in the biological effects of the esters. Metabolism can be expected to be basically the same, likely with only variations in the amount and distribution of individual metabolites. Due to its structural and chemical closeness, both substances can be expected to behave similar if administered to experimental organism and animals.
Justification of use of Phthalate esters as supporting substances for 1,2,4 -Benzenetricarboxylic acid, mixed dodecyl and octyl triester for read-across
The phthalate esters are structurally similar to the 1,2,4 -Benzenetricarboxylic acid, mixed dodecyl and octyl triester because the only difference is that they have two instead of three carboxylic functions and therefore 2 instead of 3 alcohols are bounded. Therefore they could be used for the toxicokinetic behaviour.
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