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EC number: 284-461-5 | CAS number: 84896-44-6
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- Endpoint summary
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- Ecotoxicological Summary
- Aquatic toxicity
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- Short-term toxicity to fish
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Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics, other
- Remarks:
- In-vitro metabolism as part of a OECD 111 type study
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 27.10-27.11.2015
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- not under GLP
- Objective of study:
- metabolism
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD 111 (Hydrolysis as function of pH)
- Deviations:
- yes
- Remarks:
- The poorly soluable neat material was added without co-solvent to the buffer solutions
- GLP compliance:
- no
- Radiolabelling:
- no
- Details on study design:
- yes
Details on sampling
the respective reaction mixtures were extracted with hexan after pre defined times. The solvent was
removed and analysed by 119Sn NMR
aqueous phase were analysed for tin content by AAS
Details on analytical methods
119-Sn-NMR for hexan solubla fraction
AAS fot tin content in aqueous phase
Buffers
pH 1.2 HCl 0.1 M
pH 4.0 HCl/NaCl/Citric acid
pH 7.0 Na2HPO4/NaH2PO4
pH 9.0 H3BO3/KCl/NaOH
Details on test conditions
Test item was incubated at pH 4 / 7 / 9 for 150 h at 50 °C resp at pH 1.2 for 150 h at 37 °C
At pH 1.2 / 37 °C the test item was incubated for 30 seconds, 30 minutes, 1, 2, 4, 8 hours
Number of replicates
The tests at low pH were run in duplicate - Preliminary studies:
- DBT-MPTD Hydrolysis at pH 1.2
A sample of the test item was added to an excess 0.1 M Hydrochloric Acid at 37 °C for 5 days (120
h). The 119Sn-NMR spectrum of the recovered reaction product showed that DBT-MPTD is hydrolyz
ed to DBTC-MPTD. Both substances were present in an equilibrium in a 15/85 DBT-MPTD / DBTCMPTD
mol. % ratio.
DBTC-MPTD, the product of hydrolysis, has been identified based on the 119 Sn-NMR signal. Pure
DBTC-MPTD substance was synthesized separately.
No signal corresponding to DBTC (typically present at 130 ppm) was detected. - Metabolites identified:
- yes
- Details on metabolites:
- Dibutyltin monochloro isotridecylmercaptopropionate / Dibutyltin tridecyl 3-mercaptopropionate
chloride was found as the only metabolite of the exposure to 0.1 M HCl in an equiibrium with the unreacted test item - Conclusions:
- The study showed that DBT-MPTD at pH 9, 7 and 4 can be considered hydrolytically stable. After 5
days at 50 °C less than 10% DBT-MPTD was hydrolyzed (t 0.5 25°C > 1 year).
Under the simulated gastric conditions (0.1 M HCl / pH 1.2 / 37 °C) DBT-MPTD was hydrolyzed to
DBTC-MPTD, its monochloro ester.
It can be concluded that DBTC-MPTD is the only metabolite of DBT-MPTD that was formed in the si
mulated mammalian gastric environment.
No DBTC was formed under the conditions of this study. - Executive summary:
The study showed that DBT-MPTD is hydrolytically stable at pH 9, 7 and 4. After 5 days of hydrolysis
at 50 °C less than 10% DBT-MPTD was hydrolyzed (t 0.525°C> 1 year).
At the simulated gastric conditions (0.1 M HCl/pH 1.2 /37°C) 75% DBT-MPTD was hydrolyzed to it’s
monochloride DBTC-MPTD
No formation of DBTC was detected under the conditions of the study.
Hydrolysis of DBT-MPTD can be monitored by the decrease in the relative intensity of the respective
119Sn-NMR signal at ~ 120 ppm and the increase of the DBTC-MPTD signal at ~ 71 ppm. The sum of
both intensities agrees well with DBT-MPTD signal intensity of the untreated test item.
DBTC could not be identified in any of the hydrolyzed DBT-MPTD samples atdDBTC= 130 ppm using
the 119Sn-NMR spectroscopy.
A comparable result for Dioctyltin bis-2-ethylhexyl mercaptoacetate (DOTE) is described in literature for
the fate of DOTE in PVC [6]
AAS analysis has been conducted to ensure completeness of the analysis and recover all tin compounds
in aqueous phases including all possible water-soluble organotin substances and their breakdown
components.
The analyses detected tin in amounts of 25-40 ppm, which demonstrates that only traces of the water
soluble tin compounds remain in the aqueous phase.
This is consistent with the high, nearly quantitative, recovery rates found in all experiments.
6
Reference
Tier 1 Testing:
Hydrolysis at pH 4.0, 7.0, and 9.0:
Samples of the test item were added to the respective buffer solutions at 50 °C for 5 days (120 h). Th
e 119Sn-NMR spectra of the reaction products (Annex 2) show only slight signs of hydrolysis. The NM
R peak characteristic to the DBT-MPDT molecule at about 120 ppm decreased from 99 Mol% in the
untreated staring material to a minimal value of 90.7 Mol% in the pH 4 buffer solution. In all cases the
degree of hydrolysis was lower than 10 %. Thus, the higher tier testing was not considered for these
pH-value buffers.
DBT-MPTD Hydrolysis at pH 1.2
A sample of the test item was added to an excess 0.1 M Hydrochloric Acid at 37 °C for 5 days (120
h). The 119Sn-NMR spectrum of the recovered reaction product showed that DBT-MPTD is hydrolyz
ed to DBTC-MPTD. Both substances were present in an equilibrium in a 15/85 DBT-MPTD / DBTCMPTD
mol. % ratio.
DBTC-MPTD, the product of hydrolysis, has been identified based on the 119 Sn-NMR signal. Pure
DBTC-MPTD substance was synthesized separately.
No signal corresponding to DBTC (typically present at 130 ppm) was detected.
Tier 2 testing at pH 1.2
Additional 1 g (1.2 mmol) samples of the test item were hydrolyzed over 6 different time periods (from
30 seconds to 8 hours) in an excess of 0.1 M Hydrochloric Acid at 37 °C. The recorded 119Sn-NMR
spectra detected DBTC-MPTD (# ~ 71 ppm) as the only product of DBT-MPTD hydrolysis.
Kinetics of the hydrolysis was studied measuring intensities of the NMR-signals for DBT-MPTD and
DBTC-MPTD. The sum of both signal intensities remains constant The kinetics of the first and the
second test series were nearly identical so following the average of both test series are used.
After 30 seconds of contact with the preheated buffer (an aqueous solution of hydrochloric acid), the
test item was worked up immediately. The 119Sn-NMR showed that the DBT-MPTD signal was r
educed by about 60 % of its initial signal intensity. Conversion of DBT-MPTD continued during 30
minutes of hydrolysis to about 20 % of the initial signal intensity, whereas the DBTC-MPTD signal in
creased proportionally at the same rate.
The rate of hydrolysis remained constant – with slight variation – at ~ 20 % of DBT-MPTD between 1
and 8 hours of incubation. The long term incubation from Tier 1 resulted in a 15 % DBT-MPTD / 85
% DBTC-MPTD equlibribrium..
Description of key information
Dibutyltin monochloro isotridecylmercaptopropionate / Dibutyltin tridecyl 3-mercaptopropionatechloride was found as the only metabolite of the exposure to 0.1 M HCl in an equilibrium with the unreacted test item
The formation of the Dichloride, DBTC, could not have been detected.
As a consequence the following studies have been disregarded
Schilt, R & Zondervan-van den Beuken EK (2004) Dibutyltin dilaurate (DBTL, CAS# 77-58-7), Dibutyltin maleate (DBTM, CAS# 78-04-6), Dibutyltin oxide (DBTO, CAS# 818-08-6) and Dioctyltin oxide (DOTO, CAS# 870-08-6): Simulated gastric hydrolysis. 2004-07-12 Kimmel et al (1977) Bioorganotin Chemistry. Metabolism of Organotin Compounds in Microsomal Monooxygenase Systems and in Mammals. J. Agric. Food Chem. 25(1): 1-9. (Presented as two separate summaries) Yoder, RE (2000) Development of a Method to Directly Determine Monobutyltin Trichloride and Dibutyltin Dichloride Under Simulated Gastric Conditions 2000-05-11 Bautista & Herzig (2000) Simulated Gastric Hydrolysis of Butyltin and Octyltin Mercaptides 2000-05-26 Gillard-Factor & Yoder (2000) MS Study of the Hydrolysis of Various Organotins Under Simulated Gastric Conditions Elf Atochem 2000-05-23 All studies were assigned a reliability score of 2. All studies were performed on read-across subtances. Short description of key information on absorption rate:
The following study was included to address dermal absorption: Ward, R.J. (2003) Dibutyltin bis(2-ethylhexyl mercaptoacetate): in vitro absorption through human and rat epidermis. Testing Laboratory: Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, UK. Owner Company: Tin Stabilizer Association, 1900 Arch Street, Philadelphia, PA 19103-1498, USA. Project No.: JV1699. Company study number: CO1374. Report date: 2003-01-08 The study was assigned a reliability score of 2 as the study was read-across from dibutyltin bis(2-ethylhexylmercaptoacetate).
Key value for chemical safety assessment
- Absorption rate - dermal (%):
- 1
Additional information
The results obtained from an in vitro gastric hydrolysis study (Yoder 2000) support the use of Dibutyltin Dichloride (DBTC) as an appropriate surrogate for mammalian toxicology studies of the corresponding DBT moiety. A study conducted via the oral route on the thioester DBT (2-EHMA) demonstrated this substance readily hydrolized to DBTC under physiological conditions (100% hydrolysis within 1 hour). Thus, it is considered that DBTC is an appropriate anchor compound and surrogate for the repeat dose toxicity, genotoxicity, reproduction and developmental toxicity and other long term toxicology endpoints, for all dibutyltin compounds when they are assessed following oral administration of the test material. Acute toxicity and irritation endpoints are not covered under the category approach and were evaluated individually for each dibutyltin compound. Sensitization, although not related to the hydrolysis discussion above, is considered acceptable to read across for Dibutyltin substances and as a group they are considered to be sensitisers.
A further study, Schilt, R et al (2004), investigating the simulated hydrolysis of dibutyltin compounds under gastric conditions was also available for assessment. Three separate experiments, were performed on each of dibutyltin dilaurate (DBTL), dibutyltin maleate (DBTM) and dibutyltin oxide (DBTO). The degree of hydrolysis was studied by determination of the amount of dibutyltin chloride (DBTC) formed after 0.5, 1.0, 2.0 and 4.0 hours, using GC-FPD. Where possible the ligand was also analyzed using an appropriate method. The hydrolysis of DBTM and DBTL to DBTC plus the ligands was rapid. The calculated percentages of hydrolysis were 100.1 % after 0.5 hours for DBTM and 87.8% after 2 hours for DBTL. The half-life of DBTM and DBTL under simulated gastric hydrolysis conditions was < 0.5 hours. DBTO hydrolyzed to 87.3% after 4 hours, with a half-life at 3.5 hours. The results concur with the conclusions of the Yoder (2000) study, in support of the use of dibutyltin dichloride as an appropriate surrogate test material.
Available ADME data for DBTC, using intraperitoneal injection, indicate a half-life of approximately 3-5 days in liver, kidney and blood. Further data reviewed by the EU’s Scientific Panel on Contaminants in the Food Chain (EFSA/SPCFC) indicated that tributyl tin may be debutylated to dibutyl- and monobutyl tin, dibutyl tin acetate is further metabolised to monobutyltin. These data would suggest that the toxicity of all of the butylated tins can qualitatively be read across. The extent of metabolism would appear limited (for instance, only 3.5% of dibutyltin acetate being recovered as monobutyltin). The validity of any read-across from tributyltin to dibutyltin NOAELs is therefore limited. DNELs proposed in this CSR on the basis of robust toxicity data specifically for dibutyltin are entirely appropriate.
The EFSA/SPCFC review suggests that oral absorption of tributyl and dibutyltins is incomplete; a figure of 50% oral absorption is considered appropriate (based on 41% unmetabolised dibutyltin di(acetate) recovered from the faeces of mice). Existing dermal penetration data for organotin compounds indicates dermal absorption to be low. By read-across from available data, a value of 1% for dermal absorption is considered appropriate.
In the 2003 Dermal Absorption study by Ward, 100 µL/cm2(= 21120 µg tin/cm2) was found to alter the barrier function of the rat epidermis. At 100 µL/cm2, approximately up to 18-45 % of the tin dose was unaccounted for, possibly due to adherence of the test material to the glass apparatus. The absorption of tin through human epiderims was very slow, when compared with the absorption rates of other penetrants. The proportions of dibutyltin bis(2-ethylhexylmercaptoacetate) absorbed through human epidermis were 0.0004% and 0.0010% (occluded and unoccluded respectively) after 24 hours exposure, compared to 0.261% and 0.189% through rat epidermis. The majority of the applied tin dose was washed from the surface of the epidermis during decontamination, only a relatively small proportion of the dose (human up to 1%; rat up to 10%) remained associated with the epidermis and therefore was not regarded as systemically available.
Discussion on bioaccumulation potential result:
All the studies presented were performed to a good standard and included a good level of detail in the reporting of the methods and the results.
The two Kimmel et al (1977) studies summarised were published within the same report. The first study presented investigated the metabolic fate of dibutyltin acetate was examined in a microsomal monooxygenase metabolism system (MO) derived from either rat or rabbit livers. Comparative data was also provided on other alkyltins in the MO system. Metabolism of Bu2Sn(OAc)2 yields BuSnX3, possibly by both nonenzymatic destannylation and by a- and β-carbon hydroxylation and decomposition of the hydroxy derivatives. The unidentified polar metabolites are probably formed by two or more sites of hydroxylation at different butyl groups. Bu3SnX and Bu2SnX2 bind extensively in some tissue fractions, making analysis difficult analysis and a plausible explanation for the relatively low metabolite yields. The second study investigated the metabolism of Bu2Sn(OAc)2 which yields BuSnX3, possibly by both nonenzymatic destannylation and by a- and β-carbon hydroxylation and decomposition of the hydroxy derivatives. The unidentified polar metabolites are probably formed by two or more sites of hydroxylation at different butyl groups. Bu3SnX and Bu2SnX2 bind extensively in some tissue fractions, making analysis difficult analysis and a plausible explanation for the relatively low metabolite yields.
In Schilt and Zondervan-van den Beuken (2004), three separate experiments were performed with each of the test substances, dibutyltin dilaurate (DBTL, CAS # 77-58-7), dibutyltin maleate (DBTM, CAS # 78-04-6) and dibutyltin oxide (DBTO, CAS # 818-08-6), which were individually tested under low pH (-1-2) conditions (0.07 N HC1) at 37 °C in order to simulate the hydrolytic action by mammalian gastric contents.
The hypothesis was that in the hydrochloric acid solution the tin-ligand bond breaks, leading to formation of the corresponding alkyltin chloride and simultaneous liberation of the ligand.
The degree of hydrolysis for the test substances DBTM, DBTL and DBTO was studied by determination of the amount of DBTC formed after 0.5, 1.0, 2.0 and 4.0 hours, using GC-FPD.
Where possible the ligand was also analyzed. The analytical approach to the individual ligands, maleate, laurate, and oxide, was different due to the unique chemical properties of each.
The hydrolysis of DBTM and DBTL to DBTC plus the ligands was rapid. The calculated percentages of hydrolysis were 100.1 % after 0.5 hours for DBTM and 87.8% after 2 hours for DBTL. The half-life of DBTM and DBTL under simulated gastric hydrolysis conditions was < 0.5 hours. DBTO hydrolyzed to 87.3% after 4 hours, with a half-life at 3.5 hours.
It was not possible to carry out the simulated gastric hydrolysis study for dioctyltin oxide (DOTO, CAS # 870-08-6). From the information available, it was concluded that DOTO only partially hydrolyzed in the test system and the estimated percentage of hydrolysis was 20 to 55%.
The further three studies presented were individual studies presented within a comprehensive unpublished report by the ORTEP stabilizer Task Force (The Simulated Gastric Hydrolysis of Tin Mercaptide Stabilizers (2000)).
Yoder, RE (2000): A direct injection gas chromatographic (GC) method has been developed to quantify monobutyltin trichloride (MBTC) and dibutyltin dichloride (DBTC) produced during the hydrolysis of Bu2Sn(EHMA)2 under simulated gastric conditions (37°C, pH = 1.2 or 4). DBTC can be quantified in the range of 0.1 to 5 µg/mL (as tin). MBTC can be quantified in the range of 0.2 to 5 µg/ml (as tin) at pH = 1.2, but can not be quantified at pH = 4. The repeatability of results is about ± 10%, relative. Results indicate that the hydrolysis of Bu2Sn(EHMA)2 is very rapid at pH = 1.2.
Bautista & Herzig (2000): Under acidic conditions, mono- or di- alkyltin mercaptides undergo a tin-EHMA bond break releasing EHMA. The free EHMA undergoes additional hydrolysis with ethyl hexanol and thioglycolic acid as products. EHMA and ethyl hexanol are easily quantified at low ppm level by GC-AED. The water soluble thioglycolic acid could be determined indirectly by total sulfur analysis-ICP emission spectroscopy.
Gillard-Factor & Yoder (2000): Direct infusion electrospray MS is used to study the hydrolysis of Bu2Sn(EHMA)2to its corresponding chloride derivative under simulated gastric conditions (pH = 1 and pH = 4). The results indicate that the hydrolysis occurs more completely at pH = 1 than at pH = 4. In addition, the same behaviour is observed for the four organotins investigated in this study.
Discussion on absorption rate:
Ward, R.J. (2003) was presented as the key study for this endpoint. The study was performed to the guideline OECD 428 and in compliance with GLP. The study was assigned a reliability score of 2 as the study was performed on dibutyltin 2-bis (2-ethylhexyl mercaptoacetate) and read-across to the substance in question, but is still considered reliable and adequate for assessment. From the study, the following points were noted:
1. Following 24 hours dermal contact, the amount of dibutyltin bis(2-ethylhexlymercaptoacetate) required to alter the barrier function of rat epidermis was approximately 100 µL/cm2 (= 21120 µg tin/cm2).
2. The results indicate that at a dose level of 100 µL/cm2, approximately up to 18-45 % of the tin dose was unaccounted for, possibly due to adherence of the test material to the glass apparatus used during the study, especially during the decontamination process.
3. At 100 µL/cm2, the absorption of tin through human epiderims was very slow, when compared with the absorption rates of other penetrants measured using the same in vitro technique. (Dugard et al 1984; Dugard and Scott, 1984).
4. The proportions of dibutyltin bis(2-ethylhexylmercaptoacetate) absorbed through human epidermis were 0.0004% and 0.0010% (occluded and unoccluded respectively) of dose after 24 hours exposure, compared to 0.261% and 0.189% through rat epidermis.
5. The absorption of tin from dibutyltin bis(2-ethylhexylmercaptoacetate) through rat epidermis significantly overestimated absorption through human epidermis.
6. The vast majority of the applied tin dose was washed from the surface of the epidermis during the decontamination process, with only relatively small proportions of the dose (human up to 1%; rat up to 10%) remaining associated with the epidermis and therefore not regarded as systemically available.
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