Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Short description of key information on bioaccumulation potential result: 
The following studies have been submitted to address the basic toxicokinetics endpoint:
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 except the two Kimmel studies (both dated 1977) 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 read-across 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.

In a simulated gastric hydrolysis study (Schilt, 2004) of dibutlytin maleate (DBTM) the half-life time was estimated as < 0.5 hours, because at 0.5 hours the percentage of simulated gastric hydrolysis had already reached a plateau level.

It was expected that DBTM would hydrolyze to dibutyltin chloride (DBTC) and maleic acid. During HPLC analysis it was observed that no maleic acid could be detected in the study samples, however, another peak was seen in the chromatogram. One of the possible explanations was that maleic acid was converted into its anhydride. Using the maleic anhydride standard substance it was confirmed that the maleic acid formed in the test samples was dehydrated to the anhydride form. Therefore, maleic anhydride instead of maleic acid was determined.

It was observed that the simulated gastric hydrolysis of DBTM to DBTC and maleic anhydride was rapid, to a percentage of hydrolysis of 100.1% after 0.5 hours for DBTC. The percentage of hydrolysis based on the maleic anhydride data reached 102.3% after 2 hours. Overall, a very good correlation between the DBTC and maleic anhydride data were noticed, with only a small decline in time for the DBTC levels of 5%.

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 European Food Safety Authority (EFSA) in the Option of the Scientific Panel on Contaminants in the Food Chain on a request from the Commission to assess the health risks to consumers associated with exposure to organotins in foodstuffs (2004), 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 Option 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, & Zondervan-van den Beuken (2004) an experiments was performed on dibutyltin maleate (DBTM, CAS # 78 -04 -6). The substance was 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.

It was expected that DBTM would hydrolyze to dibutyltin chloride (DBTC) and maleic acid. During HPLC analysis it was observed that no maleic acid could be detected in the study samples, however, another peak was seen in the chromatogram. One of the possible explanations was that maleic acid was converted into its anhydride. Using the maleic anhydride standard substance it was confirmed that the maleic acid formed in the test samples was dehydrated to the anhydride form. Therefore, maleic anhydride instead of maleic acid was determined.

It was observed that the simulated gastric hydrolysis of DBTM to DBTC and maleic anhydride was rapid, to a percentage of hydrolysis of 100.1% after 0.5 hours for DBTC. The percentage of hydrolysis based on the maleic anhydride data reached 102.3% after 2 hours. Overall, a very good correlation between the DBTC and maleic anhydride data were noticed, with only a small decline in time for the DBTC levels of 5%.

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)2 to 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.