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Link to relevant study record(s)

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Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed to GLP
Qualifier:
according to guideline
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
- Name of test material (as cited in study report): Fyrol PCF
- Substance type: flame retardant
- Physical state: clear colourless liquid
- Analytical purity: 99.75%
- Impurities (identity and concentrations):
- Composition of test material, percentage of components:
- Isomers composition:
- Purity test date: not given
- Lot/batch No.: 06 130A-03-xx
- Expiration date of the lot/batch: 02 Jan 2008
- Radiochemical purity (if radiolabelling): 99.3%
- Specific activity (if radiolabelling): 58 mCi/mmol
- Locations of the label (if radiolabelling): [1,2-14C]
- Expiration date of radiochemical substance (if radiolabelling): 14 Sept 2010
- Stability under test conditions:
- Storage condition of test material: ambient for non-radiolabelled TCPP; -18°C for radiolabelled TCPP
- Other:
Radiolabelling:
yes
Remarks:
14C
Species:
human
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
Human skin membranes were prepared from frozen skin samples, present at TNO Quality of Life. Human skin was obtained from three donors directly after abdominal surgery.
Donor 1: TNA 10/06, born in 1974, arrival at TNO on 10 April 2006
Donor 2: TNA 21/06, born in 1969, arrival at TNO on 28 August 2006
Donor 3: TNA23/06, born in 1964, arrival at TNO on 7 September 2006

The transportation of the skin to the laboratory was carried out as soon as possible after dissection (ca 2 hours after receipt), while the skin was placed in a plastic container that was kept on ice. The skin of all three donors was stored overnight at 2-10C before sub-cutaneous fat was removed. After removal of subcutaneous fat, the skin was stored in aluminium foil at <-18C until use. Informed consent was provied by all skin donors.

After thawing, human skin was dermatomed using a Dermatome 25mm to a recorded thickness of 400µm. The exact thickness of all skin memebranes was measured with a digimatic micrometer. and recorded.
Type of coverage:
not specified
Vehicle:
acetone
Duration of exposure:
8 hrs
Doses:
0.002 mg/cm2
0.1 mg/cm2
1mg/cm2
No. of animals per group:
six membranes/diffusion cells per concentration consisting of 2 membranes from each of three donors
Control animals:
no
Details on study design:
An in vitro percutaneous absorption study (TNO Quality of Life, 2006) conducted to GLP guidelines and to OECD Guideline No. 428, was carried out to determine the rate and extent of absorption following topical application of [14C]-TCPP to human skin for 8 hours. Three dose levels were tested, 0.002, 0.1 and 1.0 mg/cm2, which corresponded approximately to the typical exposure during manufacture of 1K foams, a mid dose to enable a dose response extrapolation and the reasonable worst case exposure during manufacture of TCPP, respectively.
Details on in vitro test system (if applicable):
Human skin membranes, six membranes per dose level, were placed in 9 mm flow-through automated diffusion cells. Receptor fluid was pumped at a speed of ca. 1.6 ml/h. Prior to commencement of the study, the solubility of TCPP in the receptor fluid was determined to be ca. 270 µg/ml, which was considered sufficient. The integrity of the skin membranes was evaluated by measuring the permeability coefficient (Kp) for tritiated water and 18 skin membranes with a Kp value below the cut-off value of 2.5 x 10-3 cm/h were selected for the study.
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Total recovery:
The mean recovery of TCPP in human skin was 99.7 ± 6.2%, 99.2 ± 5.7% and 93.5 ± 6.9%, for the high, mid and low doses, respectively.
Dose:
0.002mg/cm2
Parameter:
percentage
Absorption:
ca. 22.7 %
Remarks on result:
other: 8hr
Dose:
0.1mg/cm2
Parameter:
percentage
Absorption:
ca. 13.6 %
Remarks on result:
other: 8hr
Dose:
1mg/cm2
Parameter:
percentage
Absorption:
ca. 3.7 %
Remarks on result:
other: 8hr
Conversion factor human vs. animal skin:
-

 Summary of percutaneous penetration of TCPP through human skin in vitro

A

B

C

Concentration measured [mg/ml]

0.066

3.199

31.914

Dose [µg/cm2]

2.049

99.96

997.33

n

6

6

6

Penetration into the receptor fluid after 24 h

% of dose

µg/cm2

% of dose

µg/cm2

% of dose

µg/cm2

18.81

0.39

9.65

9.64

1.78

17.75

Maximal flux [µg/cm2/h]

0.027

0.602

0.836

Lag time [h]

2.7

4.1

2.8

Mean total absorption [%]* (SD)

22.7 (5.8)

13.6 (3.6)

3.7 (1.3)

* Total absorption is defined as the amount in the receptor fluid, the receptor compartment wash and skin membrane, excluding tape strips.

The mean penetration of TCPP into the receptor fluid after 24 hours was 0.39, 9.64 and 17.75 µg/cm2, for the low, mid and high dose, respectively. The mean maximal flux was 0.027, 0.602 and 0.836 µg/cm2/h, for the three doses respectively. The mean total absorption is defined as the compound related radioactivity present in the receptor fluid, the receptor compartment wash and the skin membranes (excluding tape strips). At 0.002 mg/cm2, the total absorption ranged from 17 % to 32.8%, with a mean total absorption of 22.7 %. At the mid dose of 0.1 mg/cm2, the total absorption ranged from 9.8% to 18.2%, with the mean total absorption of 13.6%. At 1 mg/cm2, the total absorption ranged from 2.3% to 5.2%, with a mean total absorption of 3.7%.

Conclusions:
In in vitro dermal absorption studies, the amount of penetrated substances found in the receptor fluid are considered to be systemically available. The epidermis (except for the stratum corneum) and the dermis are considered as a sink, and therefore amounts found in these tissues should also be considered absorbed (SCCNFP/0750/03 Final, October 2003). Therefore, a worst case mean total absorption value of 23 % is derived from this study for exposure to "neat" TCPP. This is considered to be a reasonable worst case value since 16 of 18 individual membrane measurements taken were found to be 23% or lower.
Executive summary:

In in vitro dermal absorption studies, the amount of penetrated substances found in the receptor fluid are considered to be systemically available. The epidermis (except for the stratum corneum) and the dermis are considered as a sink, and therefore amounts found in these tissues should also be considered absorbed (SCCNFP/0750/03 Final, October 2003). Therefore, a worst case mean total absorption value of 23 % is derived from this study for exposure to "neat" TCPP. This is considered to be a reasonable worst case value since 16 of 18 individual membrane measurements taken were found to be 23% or lower.

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: peer-reviewed publication: well reported study not conducted to GLP or Guideline
Objective of study:
other: Comparative study on the adsorption, distribution and excretion of flame retardants tris(2,3-dibromopropyl) phosphate, bis(2,3-dibromopropyl)phosphate, tris(1,3-dichloro-2-propyl) phosphate, tris(1-chloro-2-propyl)phosphate and tris (2-chloroethyl)phosph
Principles of method if other than guideline:
Absorption, distribution and excretion of fixed doses (50µmol/kg) of radiolabelled halogenated flame retardants in rats were studied up to 168hrs after dosing by liquid scintillation counting. Urine and faeces were collected every 24 hours for 7 days. Expired 14CO2 was determined after 72 and 96 hours. Bile was collected via cannulation every 2 hours for the first 30 hours following administration, from 30-46 hours and from 46-48 hours. Tissue samples were taken at 3, 6, 12, 24, 72 and 168 hours. Tissue radioactivity was analysed by oxidation followed by LSC and also by GC.
GLP compliance:
no
Radiolabelling:
yes
Remarks:
14C
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Nippon BioSupp Centre Tokyo Japan
- Age at study initiation: 5 weeks
- Weight at study initiation: 150+/- 5 g (300-330g for biliary excretion study)
- Fasting period before study: none
- Housing: group housed during acclimatisation then singly post dosing
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): standard diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period:1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25C
- Humidity (%): 60-70% relative humidity
- Air changes (per hr): no stated
- Photoperiod (hrs dark / hrs light): 12hrs/day


IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): not given
- Concentration in vehicle: not given- total dose 50 umol/kg bw
- Amount of vehicle (if gavage): not given
- Lot/batch no. (if required): not known
- Purity: 99% w/w


HOMOGENEITY AND STABILITY OF TEST MATERIAL: not determined
Duration and frequency of treatment / exposure:
single dose administration
Remarks:
Doses / Concentrations:
5 rats were orally administered a single dose of 50 µmol/kg (16.38 mg/kg) 14C-TCPP (purity 99%; specific activity 0.213 mCi/mmol) in olive oil
No. of animals per sex per dose / concentration:
5 males per group.
Control animals:
not specified
Details on study design:
- Dose selection rationale: not recorded
- Rationale for animal assignment (if not random): not recorded
Details on dosing and sampling:
Urine and faeces were collected every 24 hours for 7 days. Expired 14CO2 was determined after 72 and 96 hours. Bile was collected via cannulation every 2 hours for the first 30 hours following administration, from 30 ¿ 46 hours and from 46 ¿ 48 hours. Tissue samples were taken at 3, 6, 12, 24, 72 and 168 hours.The following tissues were sampled: blood, heart, lung, liver, kidney, spleen, brain, testis, adipose and muscle. Tissue radioactivity was analysed by oxidation followed by LSC and also by GC.
Statistics:
Analysis of distributions and recoveries were evaluated by Bartlett's test for homogeneity of varience, ANOVA (or Kruskal-Wallis nonparametric ANOVA when variance was non-homogeneous) and Scheffe's multiple comparison test (Scheffe's type mean rank test for Kruskal-Wallis ANOVA). Paired comparisons were made using Sheffe's multiple comp[arison test.
Preliminary studies:
The recovery of radioactivity after 7 days was urine (67.2%), faeces (22.2%), expired air (7.7%) and carcass (0.7%) (total recovery was 97.8%).
Details on distribution in tissues:
Seven days after oral administration of TCPP, the tissue distribution of radioactivity was, in order of decreasing concentration, liver, kidney, lung, fat, muscle, gonads, spleen, blood, heart and brain.
Transfer type:
other: Tissue/blood ratios calculated at various intervals over 7 days were > 1 for liver, kidney and lung and from 12 hours in adipose tissue indicating incorporation of radioactivity into these tissues.
Observation:
distinct transfer
Transfer type:
other: The decreases in radioactivity in all tissues were biphasic. The longest t1/2 was recorded in adipose tissue in both phases of elimination (16.5 hours and 103.4 hours). However, the concentration of radioactivity in those tissues was low.
Details on excretion:
Approximately 45% of administered radioactivity was excreted via the bile in 48 hours. This excretion was quite rapid, with approximately 30% being excreted after 3 hours.The biliary/faecal excretion ratio was 2.23 at 48 hours indicating enterohepatic re-circulation from the GI tract.
Test no.:
#1
Toxicokinetic parameters:
Tmax: The average Tmax value for TCPP radioactivity in tissues was 5.7 hours.
Toxicokinetic parameters:
other: Approx. 45% of admin. radioactivity was excreted via the bile in 48 h. This excretion was quite rapid, with approximately 30% being excreted after 3h.The biliary/faecal excretion ratio was 2.23 at 48 hrs indicating enterohepatic re-circulation from the G
Metabolites identified:
not specified

The decrease in radioactivity in all tissues was biphasic. The longest t½ was recorded in adipose tissue in both phases of elimination (16.5 hours and 103.4 hours, respectively). However, the concentration of radioactivity was low implying no bioaccumulation. The biliary/faecal excretion ratio was 2.23 at 48 hours indicating enterohepatic re-circulation from the GI tract.

Conclusions:
No bioaccumulation potential based on study results
Executive summary:

In an in vivo toxicokinetic study adsorption, distribution and excretion of fixed doses (50µmol/kg) of radiolabelled halogenated flame retardants in rats were studied up to 168 hrs after dosing by liquid scintillation counting.


The decrease in radioactivity in all tissues was biphasic. The longest t½was recorded in adipose tissue in both phases of elimination(16.5 hours and 103.4 hours, respectively). However, the concentration of radioactivity was low implying no bioaccumulation. The biliary/faecal excretion ratio was 2.23 at 48 hours indicating enterohepatic re-circulation from the GI tract.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Non-Guideline investigative study performed to GLP. Endpoint study record transfered from Draft EU Risk Assessment, 2008
Objective of study:
metabolism
Principles of method if other than guideline:
An in vitro comparative metabolism study. In the present study, the in vitro-metabolism of TCPP was investigated in liver S9 fraction and liver slices from rats.
Liver S9 fraction and liver slices were prepared from livers of male Wistar_Han rats. The liver S9 fraction was characterized by analyzing glutathion-S-trasferase (GST) activities as well as by the determination of cytochrome P450 activities in microsomes, derived from these S9 fraction. In addition, the model substrate testosterone was metabolized in parallel to the test substances. These incubations served as positive controls to prove the validity of the test system, the applied incubation conditions and the methology. The metabolic turn over of Testosterone was >90% under the current incubation conditions.
GLP compliance:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): TCPP
- Substance type: flame retardant
- Physical state: liquid
- Analytical purity: 99.75%
- Impurities (identity and concentrations):
- Composition of test material, percentage of components:
- Isomers composition:
- Purity test date: not given
- Lot/batch No.: 06 130A-03-xx
- Expiration date of the lot/batch: 02 jan 2008
- Radiochemical purity (if radiolabelling): 99.3%
- Specific activity (if radiolabelling): 58mCi/mmol
- Locations of the label (if radiolabelling): 1,2 14C
- Expiration date of radiochemical substance (if radiolabelling): not given
- Stability under test conditions: confirmed by radio-HPLC
- Storage condition of test material: ambient temperature
- Chemical name: Tris(2-chloro-1-methylethyl)-phosphate
- Molecular formula: C9H18Cl3O4P
Radiolabelling:
yes
Remarks:
14C
Species:
rat
Strain:
other: Wistar Han
Sex:
male
Route of administration:
other: in vitro incubation
Vehicle:
DMSO
Details on exposure:
14C-TCPP was prepared in DMSO at a concentration of 4000µM.
S9 fraction was incubated with a nominal concentration of 100µM 14C-TCPP for 4 hrs at 37C. Liver slices were incubated with a concentration of 100µM 14C-TCPP for 24hrs at 37C and 5% Carbogen atmosphere
Duration and frequency of treatment / exposure:
In the first assay, 14C-TCPP, TCEP and TDCP were incubated in rat liver S9 fraction for four hours. In the second assay, the radiolabelled substances were incubated with rat liver slices for 24 hours and following the incubation, the liver slices were removed and the mediums used directly for Radio HPLC and LC/MS analysis.
Remarks:
Doses / Concentrations:
14C-TCPP was incubated with rat liver S9 fraction at a nominal concentration of 100 µM. Incubations with S9 fraction were carried out with 250µl S9 fraction/mL incubate.
No. of animals per sex per dose / concentration:
no data
Control animals:
other: Negative controls were performed in heat-deactivated S9 fraction or liver slices as appropriate
Positive control reference chemical:
Testosterone
lot 055K1785
CAS no 58-22-0
Purity >99%
Details on dosing and sampling:
.
Metabolites identified:
yes
Details on metabolites:
TCPP was extensively metabolized to a chlorine substitutend hydroxyl-metabolite (S9 fraction and liver slices) and to a subsequent glucuronic acid conjugate (liver slices). 11% and 39% of un-metabolized TCPP were detected in incubates of liver S9 fraction and liver slices, respectively.

The recovery of radioactivity following incubation with liver S9 fraction was generally greater than 95% for 14C-TCPP, TCEP and TDCP. For the incubations in liver slices, the recovery of radioactivity was greater than 80% for 14C-TCPP and TCEP, and greater than 62% for14C-TDCP.

The metabolic turnover for 14C-TCPP was 89% and 61% when incubated with liver S9 fraction and liver slices, respectively. The results indicate that TCPP was metabolised to a hydroxylated metabolite by chlorine substitution in liver S9 fraction and liver slices, followed by glucuronic acid conjugation in liver slices. 11% and 39% of unmetabolised TCPP were detected in S9 fraction and liver slices, respectively.

Executive summary:

In the present study, the in vitro-metabolism of the flame retardant TCPP was investigated in liver S9 fraction and liver slices from rats. Liver S9 fraction and liver slices were prepared from livers of male Wistar-Han rats. The liver S9 fraction was characterized by analyzing glutathion-S-trasferase (GST) activities as well as by the determination of cytochrome P450 activities in microsomes, derived from these S9 fraction. In addition, the model substrate testosterone was metabolized in parallel to the test substances. These incubations served as positive controls to prove the validity of the test system, the applied incubation conditions and the methology. The metabolic turn over of Testosterone was >90% under the current incubation conditions.

For the metabolism investigations of the flame retardants, the radiolabeled test substance 14C-TCPP was incubated in liver S9 fraction in phosphate buffer (pH 7.4) containing NADPH and HSH as cofactors at 37°C for 4 hours. The incubation was stopped by the addition of acetone (1/1:v/v), the received suspension was centrifuged to precipitate the proteins and the supernatant was used for Radio-HPLC and LC/MS-analysis. For the in-vitro metabolisation in liver slices, 14C-TCPP was incubated with liver slices in Williams Medium E at 37°C for 24 hours. After the incubation, the liver slices were removed and medium was used directly for Radio-HPLC and LC/MS-analysis. The nominal test substance concentration in both in vitro-systems was 100 µM. To distinguish between biotic and non-biotic test substance transformations, control incubations proved the stability of 14C-TCPP during the incubation and demonstrated that no abiotic degradation occured under the chosen incubation conditions.

In liver S9 -fraction, the mean metabolit turn over of 14C-TCPP was about 89%, whereas in liver slices values of 61% were obtained.

Interestingly, the structure elucidation of the formed metabolites (not performed under GLP conditions) demonstrated that the metabolites investigated flame retardants was compound specific:

14C-TCPP was metabolized to a chlorine substituted hydroxylated metabolite in S9 fraction and liver slices. The subsequent glucuronic acid conjugate of the hydroxylated-metabolite was formed in liver slices.

Description of key information

In vitro Metabolism (BASF, 2007): In liver S9 -fraction, the mean metabolic turnover of 14C-TCPP was about 89%, whereas in liver slices values of 61% were obtained.  The structure elucidation of the formed metabolites demonstrated that the metabolites investigated flame retardants was compound specific.  14C-TCPP was metabolized to a chlorine substituted hydroxylated metabolite in S9 fraction and liver slices. The subsequent glucuronic acid conjugate of the hydroxylated-metabolite was formed in liver slices.


In vivo metabolism (Minegishi, 1988): Adsorption, distribution and excretion of fixed doses (50µmol/kg) of radiolabelled test item in rats were studied up to 168 hrs after dosing.  The decrease in radioactivity in all tissues was biphasic. The longest t½ was recorded in adipose tissue in both phases of elimination (16.5 hours and 103.4 hours, respectively). However, the concentration of radioactivity was low implying no bioaccumulation. The biliary/faecal excretion ratio was 2.23 at 48 hours indicating enterohepatic re-circulation from the GI tract.


Dermal Absorption OECD 428 (TNO, 2005 & 2006): Dermal absorption = 23 % (neat TCPP) - 40 % (foam containing TCPP)


  

Key value for chemical safety assessment

Additional information

Hazards identified by EU Risk Assessment in May 2008:

"After oral administration, there were indications of <100% absorption, when oral and i.v. dosing were compared. It is quite difficult to estimate the percent oral absorption. However, it appears from the available information that oral absorption is at least 75%, and may be slightly higher (based on the Minegishi data, and supported by the Stauffer data). Therefore, 80% oral absorption will be taken forward to risk characterisation.

After oral administration, Cmax in plasma was reached in 0.5 to 2 hours and 5.7 hours in tissues. Tissue radioactivity concentrations were dose and administration route-dependent (oral and intravenous). Although tissue/blood ratios over 7 days were > 1 for liver, kidney, lung and adipose tissue, absolute concentrations were low and the bioaccumulation potential was considered minimal. TCPP is extensively metabolised and accounted for 2% of urinary or faecal radioactivity after oral administration. Metabolites identified in urine and faeces, in order of abundance, were 0,0-[Bis(1-chloro-2-propyl)]-0-(2-propionic acid)phosphate, bis(1-chloro-2-propyl)monophosphoric acid and 1-chloro-2-propanol. Elimination of TCPP from plasma and tissues was biphasic. The average terminal plasma t½ was 48.7 hours. The longest tissue t½ was recorded in adipose tissue (up to 103.4 hours). Urinary and faecal excretion of radioactivity was dose and administration route-dependent (oral and intravenous), and occurred quite rapidly. The observed biliary/faecal excretion ratio is indicative of enterohepatic recirculation. In a separate in vitro comparative metabolism study with 14C-TCPP, TCEP and TDCP, TCPP was metabolised to 89 and 61% respectively in rat liver S9 mix and liver slices. An in vitro percutaneous absorption study using human skin membranes was conducted to determine the absorption following topical application of [14C]-TCPP. The skin membranes were exposed to TCPP for 8 hours, mimicking a normal working day. The mean total absorption was 22.7 %, 13.6 % and 3.7 %, for doses 0.002, 0.1 and 1 mg/cm2, respectively. The total absorption value of 23% is taken forward to risk characterisation for scenarios where there is exposure to "neat" TCPP. A second in vitro study was conducted to determine the percentage of TCPP absorbed across the skin resulting from manual handling of flexible PUR foam containing TCPP. The skin membranes were exposed to the target concentrations of TCPP in artificial sweat for a period of 8 hours, mimicking a normal working day. It was determined that the total mean absorptions were 33.3% and 38.1% for the low and high doses of TCPP respectively. Therefore, with respect to risk characterisation, 40% dermal absorption will be taken forward for those scenarios where there is exposure due to handling of foam containing TCPP, i.e. Scenario 3 "Cutting of flexible PUR foam", Scenario 4 "Production of rebounded PUR foam and Scenario 8 Use of rigid PUR foam".

No toxicokinetic data is available for the inhalation routes at present. For this route, and in line with the TGD, 100% absorption is assumed."

Updated relevant information (March 2018):

A hydroxylated human metabolite of TCPP was found in the urine of the Australian population, i.e. 1-hydroxy-2-propyl bis (1-chloro-2-propyl)phosphate (Van den Eede et al. (2015).

The updated risk assessment for TCPP follows the most recent and relevant ECHA Guidance Documents. As such, only one DNEL (or qualitative assessment) is derived for each type of hazard based on the lowest and most relevant NOAEL/LOAEL or qualitatively, on the most relevant critical effect for the route and exposure duration.

The experimentally derived value of 80% oral absorption and the worst-case dermal absorption rate of 40% will be taken forward to risk characterisation.