Dimethyltin dichloride

Endpoint summary

Description of key information

Short description of key information on absorption rate: 
Absorption of tin through human epidermis after 24h exposure under occlusion was 1.39% of the applied tin dose, but was only 0.25% when left unoccluded.Based on results of this study and considering the percentage recovered from the epidermis as potentially absorbable, a dermal absorption value of 20% for human skin is derived. Through rat epidermis, 10% of the applied tin was absorbed by 24h from both the occluded and unoccluded applications.

Additional information

1.0             Introduction

The physico-chemical properties, and results from in vitro and in vivo toxicokinetic and absorption studies have been used to determine a toxicokinetic profile for DMTC.   The studies used material of at least 89% purity.

 

 

2.0             Physicochemical properties

DMTC is a colourless/white solid and has the molecular formulaC₂H₆Cl₂Snwith a molecular weight of219.685g/mol. It is very water soluble (823 g/L at 20 °C)with a log Pow value of-2.18 at 22 °C. DMTC contains two chloride ions and is therefore weakly acidic in nature, with an estimate pKa of 3.54. It is stated to be hydrolytically stable at pH 4, 7 and 9 at 50 °C. 

 

 

3.0             Absorption

 

3.1               Oral absorption

A fully compliant GLP toxicokinetic study is available (Sved, D.W. 2001). Groups of 3 male and 3 female Sprague-Dawley rats received a single dose of DMTC (containing approximately 10% of monomethyltin trichloride) at 10 mg/kg bw either by intravenous injection (i.v.) or by oral gavage, at a dosing volume of 2 mL/kg bw (in water for injections). One group from each route of administration was used for blood collections and the other one for urine collections. Blood samples were collected 5, 10, 15 and 30 minutes, and 1, 2, 4, 6, 12, 24, 48 and 72 hours post-dosing. Plasma and the blood cellular fraction were then separated by centrifugation. Urine samples were collected over the following intervals: 0-8, 8-16, 16-24, 24-48, 48-72 and 72-96 hours post-dosing. Plasma and urine samples were analysed for total tin by graphite furnace atomic absorption spectrometry.

Data for tin concentration in plasma and urine were subjected to toxicokinetic analysis to establish the following parameters:

C_max (the maximum mean concentration in plasma – empirically determined),

t_max (the sampling time at which C_max was reached – empirically determined),

AUC_{0 -x} (the area under the mean plasma concentration vs. time curve from 0-x hr – calculated by linear trapezoidal summation using the equation AUC_0-x = Σ (0.5 x (y1 + y2) x Δt where y1 and y2 are successive plasma concentrations and Δt is the sampling interval, in hours, between y1 and y2),

AUC_0-∞ [the estimate of the area under the plasma concentration vs. time curve from 0 hr to infinity – calculated using the formula AUC_0-∞ = AUC_0-x+ (plasma concentration at x hr/K_el); Comparative bioavailability was expressed as the ratio of the mean AUC_0-∞ for the oral treatments to the mean AUC_0-∞ for the intravenous treatments],

K_el (the elimination rate constant for the compound in plasma or urine – calculated using the formula K_el = -ln[10] x b where b is the slope of the linear least-squares regression line of the log plasma concentrations [or log ARE] vs. time during the terminal elimination phase),

Half-life (the half-life in plasma or urine – calculated using the formula Half-life = -ln[0.5]/K_el),

Cl (the systemic clearance in plasma – calculated using the formula Cl = Dose/AUC_0-∞),

V_d (the apparent volume of distribution in plasma – calculated using the formula V_d = Cl/K_el), ARE[the amount remaining to be eliminated – calculated using the formula ARE = Total amount eliminated – Amount eliminated in previous interval(s); Log ARE values were used in the calculation of K_el and subsequent values for urinary elimination]

Cl_r (the renal clearance for the compound – calculated using mean values for each group using the formula Cl_r = Total urinary Recovery/ AUC_0-∞ /bw where AUC_{0 -∞} is expressed in µg-hr/mL and bw is the mean body weight (in kg) at the time of dosing).

 

Except for differences in plasma concentrations, the toxicokinetics of tin in plasma of rats were generally similar for the 2 routes of administration. There were sex-related differences with males showing higher concentrations of tin in plasma and higher AUC_0-∞values (although the coefficient of variation was extremely high in the i.v. group compared to the oral group). Following i.v. administration, plasma concentrations of tin fluctuated during the first 8 hours and t_maxranged from 10 minutes to 4 hours. Less fluctuation of tin concentrations occurred following oral administration although the range of t_maxwas wide, extending from 10 minutes to 8 hours. Based on the mean AUC_0-∞values, comparative oral bioavailability was 52% for males and 71% for females.

 

Following the distribution phase, which lasted at least 8 hours regardless the route of administration, plasma concentrations of tin at 12 hours post-dosing had decreased by approximately an order of magnitude. After this rapid clearance phase, tin was cleared from plasma more slowly, with terminal half-life ranging from 60 to 268 hours. The rapid decrease after the distribution phase and the long terminal half-life suggests that some fraction of tin is retained within the animal, possibly in the red blood cells that is capable of maintaining equilibrium with the plasma, at least over the duration examined in this study. This is supported by the study from Noland. E.A., McCauley, P.T. & Bull, R.J. (1983), which showed constant tin levels in blood of dams continuously exposed to DMTC via drinking water from 2 weeks before mating, through gestation and lactation.

 

Clearance and apparent volume of distribution were lower in males than in females, consistent with the differences in AUC_0-∞ values, but were similar for the 2 routes of administration.

 

Urinary kinetics of tin were similar between the sexes, however, there were differences related to the route of administration. On average, only approximately 40% of the oral dose of tin was eliminated in the urine whereas the total dose was eliminated in urine following the i.v. injection. This was lower than would be expected based on the comparative bioavailability of approximately 50-70%. Urinary elimination of tin appeared biphasic after i.v. injection, with the initial phase occurring within 24 hours of dosing and a slower terminal phase correspondent to the low and relatively constant terminal plasma concentrations. Urinary elimination of tin following oral dosing appeared to be triphasic, with the first phase coinciding with the distribution phase, the second one being similar to the initial phase following i.v. administration, and the third phase similar to the terminal phase following i.v. administration. Terminal urinary half-lives ranged from 6.4 to 14 hours.

 

Main plasma toxicokinetic parameters are summarised in Table 1.

 

Table 1: Plasma toxicokinetics of DMTC after i.v. and oral administration

Parameter	Males		Females
	i.v.	oral	i.v.	oral
Cmax(ng/mL)	3834	1255	1088	481
Tmax(range of 3 animals)	10 min – 4 hrs	10 min – 8 hrs	30 min – 2 hrs	10 min – 4 hrs
Vd(L/kg)	44.3	52.7	109	138
Half-life (hr)	184	173	157	146
Cl (L/hr/kg)	0.203	0.204	0.486	0.685
AUC0-∞ (ng-hr/mL)	51327	26675	11032	7868

 

Based on the mean AUC_0-∞ values following i.v. and oral administration, oral absorption is considered to be 50%.

 

3.2               Dermal absorption

The registered substance is corrosive to the skin and therefore it would be expected that absorption through the skin would be enhanced by this property. An in vitro dermal absorption GLP compliant study is available (Ward, R.J. 1999), and is broadly compliant with OECD 428. The study used human and rat skin, and a mixture of DMTC (89%) and monomethyl tin trichloride (11%) as the test substance. Water was used as the receptor fluid. Samples generated in the study were analysed for tin using an inductively coupled plasma mass spectrometer (ICP-MS).

 

In the first part of the study, experiments were performed using human skin only to determine an appropriate way of applying the test substance, which did not damage the skin. The mixture could not be applied directly to the epidermis, because the electrical resistance showed a mean damage ratio (i.e. ratio of pre-treatment electrical resistance/post-treatment electrical resistance) of 24 compared to a control value of 1.4. A dose of 100 µg/cm² , applied as a 10000 µg/mL solution in ethanol, was determined not to damage the epidermis. This non-damaging dose was used thereafter to determine the absorption of tin from both occluded and non-occluded conditions in rat and human skin.

 

The absorption of tin over 24 hours was very slow in human skin. Under occlusion conditions tin absorption was 0.015 µg/cm²/h during the first 6 hours of exposure, increasing to 0.233 µg/cm²/h during the 6-24 hours period. For the non-occluded application, relevant values were 0.003 µg/cm²/h and 0.006 µg/cm²/h, respectively. Tin absorbed into the receptor fluid within 24 hours accounted for 1.4% of the applied dose under occlusion conditions, and 0.25% under the non-occluded conditions.

 

The absorption of tin over 24 hours was faster in rat skin. Under occlusion conditions tin absorption was essentially constant at 0.233 µg/cm²/h during the 24-h test period. From the non-occluded application the process was essentially complete in the first 3 hours, with a maximum mean absorption rate of 1.07 µg/cm²/h. For both regimens, 10% of the applied tin was absorbed into the receptor fluid after 24 hours of exposure.

 

Skin washes performed at the end of the 24-h exposure period removed a considerable amount of dose from the surface of the epidermis (3.45% and 8% for the human skin, under occluded and non-occluded conditions, and 4% and 12% for the rat skin, respectively). A high proportion of the applied dose was recovered from the epidermis, 20% and 43% for human under occluded and non-occluded conditions, and 24% and 51%, respectively, for rat.

 

Due to volatility of the test substance (25.1 Pa at 25 ºC) and the use of ethanol, the overall recovery of tin from the test system was low. Recoveries were 55% and 31% for the human skin, under occluded and non-occluded conditions, and 67% and 48% for the rat skin, respectively.

 

Results are summarised in Table 2.

 

Table 2: Dermal absorption of tin (mean %) in humans and rat skin

Test system compartment	Occluded application		Non-occluded application
	Human	Rat	Human	Rat
Donor chamber	6.71	2.41	2.43	2.19
Skin wash	3.45	4.01	8.02	11.89
Absorbed into the receptor fluid	1.39	10.04	0.25	9.95
Epidermis	43.26	51.08	20.15	24.18
TOTAL	54.80	67.54	30.85	48.21

 

Based on results of this study and considering the percentage recovered from the epidermis as potentially absorbable, a dermal absorption value of 20% for human skin is derived.

 

3.3               Inhalation

The registered substance is very toxic by inhalation (category 2 – lethal if inhaled).

Absorption via inhalation is considered complete (100%).

 

 

4.0             Distribution

The available studies indicate that once absorbed DMTC is widely distributed within the body. The fact that the main toxic effect of DMTC is neurotoxicity (refers to the CSR) also indicates that the substance (or its metabolites) can reach also the central nervous system. 

 

Studies in pregnant rats (Noland. E.A., McCauley, P.T. & Bull, R.J. 1983) showed that tin from DMTC can easily pass the brain barrier in pups exposed in utero. Results of the cross-fostering experiment in the same study also revealed that transfer via the milk is minimal, if any. Blood concentrations of tin in pups exposed via the milk only, did not reached those of pups exposed pre-natally, even if levels in the lactating dams remained constant.

 

 

5.0             Metabolism

Metabolites of DMTC were not identified in the available studies. Biotransformation should be limited. DMTC is considered to be hydrolytically stable however, this stability is only apparent as in water the chloride ligand on DMTC readily hydrolyses to tin hydroxide and generates HCl. As the concentration of HCl increases, the chloride reacts back to form DMTC until equilibrium is reached.

 

 

6.0             Elimination

The available toxicokinetic study (Sved, D.W. 2001) showed complete urinary excretion of tin following an i.v. injection of DMTC at 10 mg/kg, whereas only 40% of the same dose administered by oral gavage was excreted in urine. The supportive study in pregnant rats (Noland. E.A., McCauley, P.T. & Bull, R.J. 1983) showed that transfer via the milk should not occur, and therefore breast milk is not considered to be a relevant route of elimination.

It is likely that elimination of tin from DMTC would be via the faeces.

 

 

7.0             Conclusion

For the purposes of human risk assessment there is sufficient information to consider that DMTC would be moderately absorbed (50%) after oral administration. Absorbed DMTC is widely distributed within the body and excreted via the urine within 24 hours. 

 

Human dermal absorption may be considered to be 20%.

 

Inhalation absorption is assumed to be complete.

 

 

8.0             References

Author (year)	Title Source (where different from company) Company, Report No. GLP or GEP status (where relevant) Published or Unpublished
Sved, D.W. (2001)	A Toxicokinetic Study with Dimethyltin Dichloride in Rats Report No. WIL-160107 GLP Unpublished
Noland. E.A., McCauley, P.T. & Bull, R.J. (1983)	Dimethyltin dichloride: investigations into its gastrointestinal absorption and transplacental transfer. J. Toxicol. Environ. Health 12: 89-93 Published
Ward, R.J. (1999)	In vitro absorption of a methyltin chloride mixture through human and rat epidermis Report No. JV1555 GLP Unpublished
Anonymous	SIDS Initial Assessment Report For SIAM 23