Dimethylbis(oleoyloxy)stannane

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.

Reason / purpose for cross-reference:

other: read across: target

Objective of study:

absorption

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

The present work was undertaken to determine whether the organic tin was absorbed by the dam and crossed the placenta to pup blood and brain, and to determine when and how rapidly tin passes from dam to pup. This was accomplished in three phases:
(1) a comparison of absorption of organic and inorganic tin,
(2) a comparison of prenatal and postnatal levels of tin in the pups, and
(3) a tracer study to determine if the organic tin passed to the pup in-tact.

GLP compliance:

no

Radiolabelling:

yes

Remarks:

Phase III only

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles Rivers breeding laboratory
- Age at study initiation: 70 days old
- Housing: animals were housed one per cage with sawdust bedding in a room
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Purina Lab Chow ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C
- Humidity (%): 54 %:

Route of administration:

other: drinking water (phases I and II); oral:gavage (phase III)

Vehicle:

water

Duration and frequency of treatment / exposure:

Two weeks prior to breeding and continued through breeding and gestation.

Dose / conc.:

40 other: mg tin/L

Remarks:

Phases I and II

Dose / conc.:

100 other: µCi/L (specific activity 6.9 mCi/mM)

Remarks:

Phase III

No. of animals per sex per dose / concentration:

Thirteen females (phases I and II); 19 pregnant females (phase III)

Control animals:

yes, concurrent vehicle

Details on study design:

In Phases I and II animals received test material as 40 mg/l in solution two weeks prior to breeding and through breeding and gestation.

In Phase III animals received a 0.9 M NaCI solution containing 100 µCi/l. Four animals were sacrificed by decapitation at each of 5, 15 and 30 minutes, 1, 2, 6 and 24 hours after dosing.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood and brains from pups removed from dams and blood from dams from phases I and II; brains and blood from dams and foetuses from phase III
- Time and frequency of sampling: pups removed from dams prior to first nursing in both phases

Statistics:

Data for the first phase were analysed using a Kruskal-Wallis test, and the means were compared with a non-parametric multiple comparisons procedure based on Kruskal-Wallis ranked sums. Data for the cross-fostering phase were analysed using an analysis of variance (ANOVA). Drinking-water consumption data were analysed using a two-way nested ANOVA.

Details on absorption:

not measured

Details on distribution in tissues:

The majority of the tin received as dimethyltin is transferred to the pups during gestation rather than lactation.

Transfer type:

blood/brain barrier

Observation:

distinct transfer

Transfer type:

blood/placenta barrier

Observation:

distinct transfer

Details on excretion:

not measured

Metabolites identified:

not measured

Details on metabolites:

not measured

Phase I

In the dams' blood there were significant differences among dosage groups. A non-parametric multiple comparison showed the tin content from treated animals given DMDC was significantly higher than the control. Analysis of pup blood and brain yielded similar results. The tin content in blood from pups of treated dams was significantly higher than blood from pups of the control. The tin content from the brains of pups of treated dams was significantly higher than controls. Dam body weights did not differ throughout the experiment. Dams exposed to test material drank significantly less than controls (see Table 1).

Phase II

The level of tin in the blood of dams remained constant and the levels in test material exposed dams was significantly higher than that of the controls. The highest levels of tin in blood at any time in any age group were demonstrated at birth in gestationally exposed animals. By 10 day post-natal age, blood tin levels decreased rapidly in both prenatally exposed groups. Pups exposed only postnatally (CT/DM) had blood levels of tin significantly lower than the DM/DM and the DM/CT animals. Both the CT/CT and CT/DM groups were found to be statistically lower than the other two groups but not different from each other. At 21 days, all four groups were different from each other.

Tin levels in the brains of prenatally exposed pups were again highest at birth and different from controls. At 10 days, the DM/DM pups demonstrated significantly higher levels of tin in the brain than the other groups. The DM/CT group was also different from the other groups. At 21 days, the DM/DM group was significantly higher than the CT/DM group, which was higher than either the CT/CT or DM/CT group.

Phase III

The highest measured level of labelled material in the dam blood was recorded at 1 hour, while the level in the brain continued to increase through 24 hours when measurements were stopped. The label in the pup blood reached its highest measured level at 6 hours and in the brain the highest concentration measured was the last sample taken at 24 hours after exposure. The level of DPM/g in dam brain at 24 hours post dosing were equivalent to DPM/g in pup brain at 6 hour post dose.

Table 1: Results of the Kruskal-Wallis Multiple Comparison for Tissue Tin Content

Dose (mg tin/l)	Dam blood		Pup blood		Pup brain
	Mean (µg/g)	Group^a	Mean (µg/g)	Group^a	Mean (µg/g)	Group^a
Dimethyltin dichloride (40 mg/l)	10.68	A	14.63	A	1.17	A
Distilled water control	0.14	B	0.20	B	0.32	B
Overall	X² = 23.8, df = 2, p < 0.0001		X² = 24.7, df = 2, p < 0.0001		X² = 23.1, df = 2, p < 0.0001

^aMeans with the same group letter are not statistically different

Conclusions:

Interpretation of results: bioaccumulation potential cannot be judged based on study results.
This study shows (1) that DMDC is absorbed in the gastrointestinal tract of the dam much more rapidly than Sn2+ (results not presented), and consequently that higher concentrations of tin are found in pup blood and brain from DMDC than from Sn2+, and (2) that the majority of the tin received as dimethyltin is transferred to the pups during gestation rather than lactation. DMDC dosing of dam results in both tin and methyl carbon absorption by the dam, transplacental transfer to foetal blood, and localization in foetal brain. These data indicate that at least part of the increased central nervous system toxicity of DMDC over inorganic tin in drinking-water exposure could be the result of the increased availability of DMDC to the central nervous system of the dam and pup.

Executive summary:

Studies were conducted with female Sprague-Dawley rats to determine whether DMDC was absorbed by the dam and transferred across the placenta to foetal blood and brain tissue. This was accomplished in three phases: (1) measurement of absorption of organic and tin from drinking water, (2) a comparison of prenatal and postnatal levels of tin in the pups in cross-fostering studies and (3) a [14C]dimethyltin dichloride tracer study to determine whether organic tin passed to the pup intact. Major findings include: (1) DMDC is absorbed in the gastrointestinal tract of the dam much more rapidly than Sn²⁺ (results not presented); (2) the more rapid absorption of DMDC results in higher concentration of tin in foetal blood and brain; and (3) in foetuses that receive tin as DMDC, both tin and the methyl carbon are absorbed by the dam and transferred to the blood and brain of the foetuses.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material

Justification for type of information:

Read-across to structurally similar substance dimethyltin dichloride (DMTC) (EC Number 212-039-2, CAS Number 753-73-1), see attached justification.

Reason / purpose for cross-reference:

read-across source

Details on distribution in tissues:

The majority of the tin received as dimethyltin is transferred to the pups during gestation rather than lactation.

Key result

Transfer type:

blood/brain barrier

Observation:

distinct transfer

Key result

Transfer type:

blood/placenta barrier

Observation:

distinct transfer

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

22 August 2000 - 30th November 2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

other: read across target

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

(see overall remarks for further detail)

Principles of method if other than guideline:

To determine the absorption and urinary elimination profiles of dimethyltin dichloride in rats after a single oral dose as compared to an intravenous dose.

GLP compliance:

yes

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC
- Age at study initiation: 8 weeks (males); 9 weeks (females)
- Weight at dose administration: 226-247 g (males); 212-245 g (females)
- Housing: individually in suspended wire-mesh cages
- Individual metabolism cages: yes (animals designated for urine collection)
- Diet (e.g. ad libitum): PMI Nutrition International, Inc. Certified Rodent LabDiet® 5002 ad libitum.
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: approximately 1 week.

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71-79
- Humidity (%): 48-71
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

other: oral and intravenous

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The dosing formulation was prepared by dissolving 0.25 g of the test substance in 50 mL of sterile water for injection, U.S.P. in a plastic, autoclaved injection vial. The vial was sealed with a septum cap and inverted until the solution appeared uniform. Three 1 mL samples were removed from the vial, placed in plastic sample containers, and transferred to the Analytical Chemistry Department at WTI, Research for analysis of total tin. The formulation was homogeneous and contained the appropriate concentration of tin (94.5% of target).

DOSE ADMINISTRATION:
On the day of dose administration, each animal was weighed. The amount of dosing formulation needed for each animal was calculated based on a dose volume of 2 mL/kg. The dose for Groups 1 and 2 was administered as a bolus intravenous dose into a tail vein; the dose for Groups 3 and 4 was administered orally by gavage.

Duration and frequency of treatment / exposure:

Single dose

Dose / conc.:

10 mg/kg bw (total dose)

Remarks:

orally and intravenously

No. of animals per sex per dose / concentration:

Three

Control animals:

yes

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: plasma, urine
- Time and frequency of sampling: Groups 1 (intravenous) and 3 (oral), approximately 0.3 mL of blood was collected from a tail vein of each animal at 10 and 30 minutes and 1, 2, 4, 8, 12, 18, 24, 48, 72, and 96 hours after dose administration. For Groups 2 (intravenous) and 4 (oral), urine was collected from each animal over the following intervals after dose administration: 0-8, 8-16, 16-24, 24-48, 48-72 and 72-96 hours.

Statistics:

All calculations for this report were performed with Microsoft® Excel spreadsheets using full floating decimal point calculations. Equations other than those used for toxicokinetic data analysis and for standard statistical parameters (e.g., mean, standard deviation [SD], percent coefficient of variation [%CV], and linear regression) are presented with the tables. Slightly different results can be expected if calculations are based on the values as presented in the tables because some numbers have been rounded for display.

Type:

absorption

Results:

Based on the mean AUC0-∞ values, comparative bioavailability was 0.52 for males and 0.71 for females.

Type:

distribution

Results:

For males, mean (±SD) apparent volume of distribution was 44.3 (±26.7) L/kg and 52.7 (±31.7) L/kg following intravenous and oral administration, respectively. For females, mean (±SD) values were 109 (±92.9) L/kg and 138 (±98.1) L/kg.

Type:

excretion

Results:

For males, renal clearance was 0.105 and 0.0816 L/hr/kg following intravenous and oral administration, respectively. For females, renal clearance was 0.559 and 0.282 L/hr/kg following intravenous and oral administration, respectively.

Toxicokinetic parameters:

Cmax: Intravenous dosage to males: 3834 (±2983) ng/ml

Toxicokinetic parameters:

Cmax: Intravenous dosage to females: 1088 (±656) ng/ml

Toxicokinetic parameters:

Cmax: Oral dosage to males: 1255 (±917) ng/ml

Toxicokinetic parameters:

Cmax: Oral dosage to females: 481 (±189) ng/ml

Toxicokinetic parameters:

AUC: Intravenous dosage to males: 51327 (±53673) ng-hr/ml

Toxicokinetic parameters:

AUC: Intravenous dosage to females: 11032 (±306) ng-hr/ml

Toxicokinetic parameters:

AUC: Oral dosage to males: 26675 (±4301) ng-hr/ml

Toxicokinetic parameters:

AUC: Oral dosage to females: 7868 (±794) ng-hr/ml

Toxicokinetic parameters:

half-life 1st: Intravenous dosage to males: 184 (±73) hr

Toxicokinetic parameters:

half-life 1st: Intravenous dosage to females: 157 (±137) hr

Toxicokinetic parameters:

half-life 1st: Oral dosage to males: 173 (±80) hr

Toxicokinetic parameters:

half-life 1st: Oral dosage to females: 146 (±114) hr

Metabolites identified:

not measured

Details on metabolites:

not measured

Concentrations of tin were generally higher in males than in females following the single intravenous dose. Inter-animal variability in the plasma concentrations of tin was high, with coefficients of variation frequently near or exceeding 100%. Concentrations of tin in both males and females typically fluctuated during the first 8 hours after dose administration; tmax ranged from 10 minutes to 4 hour post dosing. Mean (±SD) Cmax values were 3834 (±2983) µg/mL for males and 1088 (±656) µg/mL for females. Mean (±SD) AUC0-∞ values were 51.3 (±53.7) µg-hour/mL for males and 11.0 (±0.31) µg-hour/mL for females.

Concentrations of tin were also generally higher in males than in females following the single oral dose. Inter-animal variability in the plasma concentrations of tin tended to be less following oral administration than following intravenous administration. There was also less fluctuation in the concentrations of tin following dosing although the range for tmax was high: 10 minutes to 8 hour post-dosing. Mean (±SD) Cmax values were 1255 (±917) µg/mL for males and 481 (±189) µg/mL for females. Mean (±SD) AUC0-∞ values were 26.7 (±4.3) µg-hour/mL for males and 7.87 (±0.79) µg-hour/mL for females. Based on the mean AUC0-∞ values, comparative bioavailability was 0.52 for males and 0.71 for females.

Table 1: Summary of Pharmacokinetic Parameters for Tin in Rat Plasma following Administration of 10 mg/kg Dimethyltin Dichloride

Cmax(ng/mL)
	Intravenous		Oral
	Mean	SD	Mean	SD
Males	3834	2983	1255	917
Females	1088	656	481	189

 

AUC0-∞(ng-hr/mL)
	Intravenous		Oral
	Mean	SD	Mean	SD
Males	51327	53673	26675	4301
Females	11032	306	7868	794

 

Following the distribution phase, which lasted at least 8 hours regardless of the route of administration, plasma concentrations of tin at 12 hour post-dosing had decreased by approximately an order of magnitude. After this rapid clearance phase, tin was cleared from plasma more slowly. Plasma concentrations of tin during the terminal elimination phase were higher for males than for females, but were similar between the two routes of administration. Terminal elimination rate constants were similar between the two routes of administration. For males, mean (±SD) terminal half-lives were 184 (±73) hours and 173 (±80) hours following intravenous and oral administration, respectively. For females, mean (±SD) terminal half-lives were 157 (±137) hours and 146 (±114) hours following intravenous and oral administration, respectively. The rapid decrease after the distribution phase and the long terminal half-life suggests that some fraction of tin is retained within the animal that is capable of maintaining an equilibrium with the plasma, at least over the duration examined in this study.

Clearance and apparent volume of distribution were lower for males than for females, but were similar between the two routes of administration. The differences in these parameters between the sexes are consistent with the differences in the AUC0-∞ values. For males, mean (±SD) clearance was 0.203 (±0.153) L/hour/kg and 0.204 (±0.033) L/hour/kg following intravenous and oral administration, respectively. For females, mean (±SD) clearance was 0.486 (±0.014) L/hour/kg and 0.685 (±0.069) L/hour/kg following intravenous and oral administration, respectively. For males, mean (±SD) apparent volume of distribution was 44.3 (±26.7) L/kg and 52.7 (±31.7) L/kg following intravenous and oral administration, respectively. For females, mean (±SD) apparent volume of distribution was 109 (±92.9) L/kg and 138 (±98.1) L/kg following intravenous and oral administration, respectively.

Elimination Rate Constant(hr-¹)
	Intravenous		Oral
	Mean	SD	Mean	SD
Males	0.00412	0.00133	0.00449	0.00208
Females	0.00712	0.00620	0.00685	0.00536

 

Half Life(hr)
	Intravenous		Oral
	Mean	SD	Mean	SD
Males	184	73	173	80
Females	157	137	146	114

 

Clearance(L/hr/kg)
	Intravenous		Oral
	Mean	SD	Mean	SD
Males	0.203	0.153	0.204	0.0328
Females	0.486	0.0135	0.685	0.0691

 

Apparent Volume of Distribution(L/kg)
	Intravenous		Oral
	Mean	SD	Mean	SD
Males	44.3	26.7	52.7	31.7
Females	109	92.9	138	98.1

Table 2: Mean Tin Plasma Concentrations and Pharmacokinetic Parmacokinetic Parameters Based on Mean Values in Rats following Intravenous or Oral Administration of 10 mg/kg Dimethyltin Dichloride

Group Summary
Route	Intravenous		Oral
Sex	Male	Female	Male	Female
Mean (±SD) Plasma Concentrations (ng/mL)*
10 min	2955 (3705)	334 (228)	702 (570)	387 (259)
30 min	1593 N/A	680 (455)	533 (406)	301 (67.1)
1 hr	2057 (2126)	330 (32.5)	547 (333)	327 (101)
2 hr	2213 (1889)	1032 (749)	685 (459)	376 (85.6)
4 hr	1545 (1616)	695 (468)	1396 (628)	382 (89.5)
8 hr	3874 (3883)	508 (262)	1169 (852)	285 (43.1)
12 hr	75.1 (55.3)	20.1 (3.14)	73.0 (65.3)	19.9 (2.12)
18 hr	94.1 (86.5)	21.4 (21.2)	77.0 (74.0)	21.7 (6.27)
24 hr	87.8 (63.7)	27.0 (9.69)	78.0 (62.5)	26.1 (18.5)
48 hr	51.9 (27.1)	13.5 (12.4)	71.7 (61.9)	16.9 (5.90)
72 hr	104 (112)	11.9 (10.3)	60.8 (49.4)	16.7 (8.55)
96 hr	59.2 (48.6)	5.94 (10.3)	59.2 (39.1)	15.3 (3.77)
Linear Regression of log Plasma Concentrations vs. Time**
Slope	-0.00146	-0.00745	-0.00168	-0.00253
Y-intercept (ng/mL)	91.2	34.1	84.1	25.6
Coefficient of Determination (r²)	0.130	0.919	0.943	0.745
Pharmacokinetic Parameters
Cmax(ng/mL)	3874	1032	1396	387
tmax(hr)	0.5	2	4	0.17
AUC0-∞ (ng-hr/mL)	50710	7941	31896	7557
Comparative Bioavailability	N/A	N/A	0.63	0.95
Kel(hr-¹)	0.00337	0.0172	0.00387	0.00583
Half-life (hr)	206	40	179	119
Cl (L/hr/kg)	0.106	0.675	0.168	0.709
Vd (L/kg)	31.4	39.4	43.5	122

 

* Individual vales below the limit of quantification were treated as zero

N/A = not applicable

** For terminal phase: 18 hr post dosing to last point above the quantification limit

Following the single intravenous dose, mean (±SD) percent of dose (as total tin) eliminated in the urine was 103 (±29.9)% for males and 112 (±43.4)% for females. Urinary elimination of tin appeared to be biphasic, with the initial phase occurring through 24 hour post-dosing. The terminal phase was slower than the initial phase and coincided with the low, relatively constant terminal plasma concentrations.

Following the single oral dose, mean (±SD) percent of dose (as total tin) eliminated in the urine was 40.1 (±4.08)% for males and 42.0 (±4.66)% for females. Percent of dose eliminated via the urine following oral dosing was lower than would be expected based on the comparative bioavailability of approximately 50-70%. Urinary elimination of tin following oral dosing appeared to be triphasic: the first phase coincided with the distribution phase, the second phase was similar to the initial phase following intravenous administration, and the third phase was similar to the terminal phase following intravenous administration.

The terminal elimination rate constants for urinary elimination of tin were similar between the sexes and routes of administration. For males, the urinary half-life, based on mean amounts of urine eliminated, was 13 and 11 hours following intravenous and oral administration, respectively. For females, the urinary half-life, based on mean amounts of urine eliminated, was 10 hours regardless of route of administration. Renal clearance was lower in males than in females and lower following oral administration than following intravenous administration because of the differences in the AUC0-∞ values. For males, renal clearance was 0.105 and 0.0816 L/hour/kg following intravenous and oral administration, respectively. For females, renal clearance was 0.559 and 0.282 L/hour/kg following intravenous and oral administration, respectively.

Table 3: Summary of Percent of Dose Eliminated in Urine following Administration of 10 mg/kg Dimethyltin Dichloride to Rats*

	INTRAVENOUS
Collection Interval	Mean % of Dose (±SD)
	Males	Females
0 – 8 hr	82.2 (27.7)	84.9 (38.3)
8 – 16 hr	17.8 (4.20)	18.0 (0.77)
16 – 24 hr	2.51 (1.21)	7.65 (4.40)
24 – 48 hr	0.71 (0.18)	1.08 (0.37)
48 – 72 hr	0.27 (0.10)	0.36 (0.10)
72 – 96 hr	BLQ N/A	BLQ N/A
TOTAL:	103 (29.9)	112 (43.4)

	ORAL
Collection Interval	Mean % of Dose (±SD)
	Males	Females
0 – 8 hr	13.0 (3.80)	17.8 (3.13)
8 – 16 hr	20.6 (0.33)	19.1 (3.15)
16 – 24 hr	5.75 (1.35)	4.01 (0.58)
24 – 48 hr	0.60 (0.05)	0.83 (0.17)
48 – 72 hr	0.17 (0.04)	0.20 (0.11)
72 – 96 hr	BLQ N/A	BLQ N/A
TOTAL:	40.1 (4.08)	42.0 (4.66)

 

* Means based on 3 animals per sex. BLQ = below the limit of quantification (5 ng/mL). N/A = not applicable

Table 4: Kinetics of the Urinary Elimination of Tin following Intravenous Administration of 10 mg/kg Dimethyltin Dichloride to Rats

Amount Eliminated per Interval (µg)*
	Males				Females
Collection Interval	50040	50048	50053	Mean ( ±SD)	50058	50069	50071	Mean ( ±SD)
0 – 8 hr	664	1041	1348	1018 (343)	1526	997	591	1038 (469)
8 – 16 hr	164	266	232	220 (52.0)	227	223	209	220 (9.4)
16 – 24 hr	48.3	20.6	24.4	31.1 (15.0)	156	66.4	58.7	93.5 (53.8)
24 – 48 hr	6.26	9.60	10.3	8.74 (2.18)	17.2	8.39	14.2	13.3 (4.47)
48 – 72 hr	2.14	3.28	4.53	3.32 (1.20)	5.79	3.78	3.85	4.39 (1.22)
72 – 96 hr	BLQ	BLQ	BLQ	BLQ N/A	BLQ	BLQ	BLQ	BLQ N/A
Amount Remaining To Be Eliminated (ARE; µg)
0 hr	884	1340	1619	1281	1932	1299	877	1369
8 hr	221	299	271	264	406	301	286	331
16 hr	56.7	33.5	39.3	43.2	178	78.6	76.4	111
24 hr	8.40	12.9	14.9	12.1	23.0	12.2	17.8	17.6
48 hr	2.14	3.28	4.53	3.32	5.79	3.78	3.58	4.39
Elimination Kinetics (Linear Regression of log ARE vs. Time from 24-48 hr)
Slope (b)	-0.0247	-0.0247	-0.0215	-0.0233	-0.0249	-0.0212	-0.0290	-0.0290
Y-Intercept (µg)	33.0	50.6	48.9	43.8	91.0	39.2	88.4	88.4
Coefficient of Determination (r²)	1.00	1.00	1.00	1.00	1.00	1.00	1.00	1.00
Elimination rate Constant (hr-¹)	0.0570	0.0570	0.0495	0.0537	0.0574	0.0487	0.0668	0.0668
Half-life (hr)	12	12	14	13	23	14	10	10
Clr(L/hr/kg)**	N/A	N/A	N/A	0.105	N/A	N/A	N/A	0.559

 

* BLQ = below the limit of quantification (5 ng/mL).

** Renal clearance only calculated using mean values

N/A =not applicable

Table 5: Kinetics of the Urinary Elimination of Tin following Oral Administration of 10 mg/kg Dimethyltin Dichloride to Rats

Amount Eliminated per Interval (µg)*
	Males				Females
Collection Interval	50040	50048	50053	Mean ( ±SD)	50058	50069	50071	Mean ( ±SD)
0 – 8 hr	186	113	206	168 (49.1)	255	206	181	214 (37.6)
8 – 16 hr	264	263	271	266 (4.27)	258	187	244	230 (37.8)
16 – 24 hr	54.4	81.6	86.8	74.2 (17.4)	41.5	55.4	47.6	48.2 (6.98)
24 – 48 hr	7.62	8.57	7.25	7.82 (0.68)	9.15	8.44	12.2	9.93 (2.01)
48 – 72 hr	1.59	2.52	2.56	2.22 (0.55)	3.17	3.20	0.98	2.45 (1.28)
72 – 96 hr	BLQ	BLQ	BLQ	BLQ N/A	BLQ	BLQ	BLQ	BLQ N/A
Amount Remaining To Be Eliminated (ARE; µg)
0 hr	513	468	573	518	567	460	486	504
8 hr	327	355	367	350	312	254	305	290
16 hr	63.6	92.7	96.6	84.3	54	67.1	60.8	60.6
24 hr	9.22	11.1	9.8	10.0	12.3	11.6	13.2	12.4
48 hr	1.59	2.52	2.56	2.22	3.17	3.20	0.98	2.45
Elimination Kinetics (Linear Regression of log ARE vs. Time from 24-48 hr)
Slope (b)	-0.0318	-0.0268	-0.0243	-0.0273	-0.0246	-0.0233	-0.0471	-0.0293
Y-Intercept (µg)	53.3	48.9	37.6	45.3	47.9	42.3	178	62.6
Coefficient of Determination (r²)	1.00	1.00	1.00	1.00	1.00	1.00	1.00	1.00
Elimination rate Constant (hr-¹)	0.0732	0.0618	0.0560	0.0628	0.0566	0.0537	0.109	0.0675
Half-life (hr)	9.5	11	12	11	12	13	6.4	10
Clr(L/hr/kg)**	N/A	N/A	N/A	0.0816	N/A	N/A	N/A	0.282

 

* BLQ = below the limit of quantification (5 ng/mL).

** Renal clearance only calculated using mean values

N/A =not applicable

Conclusions:

Interpretation of results: bioaccumulation potential cannot be judged based on study results.
Except for differences in plasma concentrations, the toxicokinetics of tin in plasma of rats following a single intravenous or oral dose of 10 mg dimethyltin dichloride/kg were generally similar, however, there were sex-related differences. Concentrations of tin in plasma and AUC0-∞ values were higher in males than in females. Following the distribution phase, which lasted at least 8 hours regardless of 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 a terminal half-life ranging from 60-268 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 an equilibrium with the plasma, at least over the duration examined in this study.

Urinary kinetics of tin in rats following a single intravenous or oral dose of 10 mg dimethyltin dichloride/kg 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 approximately 100% of dose was eliminated in the urine following an intravenous dose. The amount eliminated in the urine following oral administration was lower than would be expected based on the comparative bioavailability of approximately 50-70%. Terminal urinary half-lives ranged from 6.4-14 hours.

Executive summary:

Dimethyltin dichloride was administered either intravenously or orally to rats at 10 mg/kg to determine the toxicokinetic parameters of tin in plasma and urine. Two groups of three male and three female rats received the test substance intravenously via a lateral tail vein and two groups of three male and three female rats received the test substance orally by gavage. One group from each route of administration was used for blood collections and the other group was used for urine collections. Blood samples were collected at target times of 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 separated by centrifugation and stored separately at approximately -20°C. Urine samples were collected at 0-8, 8-16, 16-24, 24-48, 48-72, and 72-96 hours post-dosing. Urine samples were stored at approximately -20°C. Plasma and urine samples were analysed for total tin by graphite furnace atomic absorption spectrometry. Data for tin concentrations in plasma and urine were subjected to toxicokinetic analysis.

Except for differences in plasma concentrations, the toxicokinetics of tin in plasma of rats were generally similar, however, there were sex-related differences. Concentrations of tin in plasma and AUC_{0 -∞} values were higher in males than in females. Following the distribution phase, which lasted at least 8 hours regardless of 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 a terminal half-life ranging from 60-268 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 an equilibrium with the plasma, at least over the duration examined in this study.

Urinary kinetics of tin in rats 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 approximately 100% of dose was eliminated in the urine following an intravenous dose. The amount eliminated in the urine following oral administration was lower than would be expected based on the comparative bioavailability of approximately 50-70%. Terminal urinary half-lives ranged from 6.4-14 hours.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material

Justification for type of information:

Read-across to structurally similar substance dimethyltin dichloride (DMTC) (EC Number 212-039-2, CAS Number 753-73-1), see attached justification.

Reason / purpose for cross-reference:

read-across source

Type:

absorption

Results:

Based on the mean AUC0-∞ values, comparative bioavailability was 0.52 for males and 0.71 for females.

Type:

distribution

Results:

For males, mean (±SD) apparent volume of distribution was 44.3 (±26.7) L/kg and 52.7 (±31.7) L/kg following intravenous and oral administration, respectively. For females, mean (±SD) values were 109 (±92.9) L/kg and 138 (±98.1) L/kg.

Type:

excretion

Results:

For males, renal clearance was 0.105 and 0.0816 L/hr/kg following intravenous and oral administration, respectively. For females, renal clearance was 0.559 and 0.282 L/hr/kg following intravenous and oral administration, respectively.

Reference 5

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

8th June - 13th August 1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

Version / remarks:

Draft dated 1996

Deviations:

not specified

Principles of method if other than guideline:

Purity: 89 % dimethyltin dichloride, 11 % monomethyltin dichloride

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

no

Species:

other: human skin and rat skin

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

Human skin:
Extraneous tissue was removed from human whole skin samples. The skin samples were immersed in water at 60°C for 40-45 seconds and the epidermis teased off the dermis. Each epidermal membrane was given an identifying number and stored frozen on aluminium foil until required for use.

Rat skin:
Skin was from male rats of the Wistar-derived strain (supplied by Charles River UK Ltd, Margate, Kent, UK.), aged 28 days ± 2 days. Fur from the dorsal and flank region was carefully shaved using animal clippers, ensuring that the skin was not damaged. The clipped area was excised and any subcutaneous fat removed. The skins were soaked for approximately 20 hours in 1.5M sodium bromide then rinsed in distilled water. The epidermis was carefully peeled from the dermis. Each epidermal membrane was given an identifying number and stored frozen on aluminium foil until required for use.

Type of coverage:

other: dermal absorption was determined under both occluded and unoccluded conditions

Vehicle:

ethanol

Duration of exposure:

24 hrs

Doses:

Based on results of three experiments to determine a non-damaging dosage, the methyltin chloride mixture was applied to both human and rat epidermal membranes at a rate of 100 µg/cm² as a 10 µl/cm² dose of a 10000 µg/ml solution in ethanol. This application was equivalent to a nominal dose rate for tin of 53.5µg/cm², based upon a tin content of 53.5% w/w in the methyltin chloride mixture, or 89 µg/cm² based on DMTC content.

No. of animals per group:

6 cells per species

Details on study design:

MEASUREMENT OF MEMBRANE INTEGRITY
Samples of epidermis were mounted in glass diffusion cells with an exposed area of 2.54 cm². The cells were placed in a water bath maintained at 32 ± 1 °C.

The integrity of the membranes was determined by measurement of their electrical resistance across the skin membrane. Membranes with a measured resistance <10 kΩ (human) or <2.5 kΩ (rat) were regarded as having a lower integrity than normal and not used for exposure to the test material.


ASSESSMENT OF SKIN BARRIER DAMAGE
This assessment was only performed for human epidermis.

The receptor chambers of 3 cells containing intact membranes were filled with a recorded volume of receptor fluid (water) and the cells placed in a waterbath maintained at 32 ± 1°C. The methyltin chloride mixture was applied undiluted to these cells at a rate of 0.1g/cm² and the cells occluded for the entire exposure period (24h). Concurrently with these experiments, 2 untreated control cells were assessed under identical conditions as the treated cells.

After the 24h contact period, the donor chamber were emptied and the surface of the membrane decontaminated by flushing with water (5 x 5 ml volumes), followed by physiological saline (5ml). The receptor chambers were emptied and rinsed with physiological saline (5ml).

The procedure used for the assessment of skin integrity was repeated and a damage ratio calculated by dividing the pre-treatment resistance measurement by the post treatment resistance measurement. If the membrane has been damaged by the test material, the electrical resistance falls, compared to the initial measurement. When the change to the barrier properties of the membrane is more than 3-fold, this is regarded as significant impairment. Damage ratios <3 are regarded as insignificant. In this experiment with the methyltin chloride mixture, the mean damage ratio for the treated cells was 24 (versus a control value of 1.4), which clearly indicated significant damage to the barrier function of the epidermis.

The experiment was repeated using the minimum amount that could practically weighed onto the cells (0.002 g/cm²). This dose level gave a mean damage ratio of 6.8 (versus a control value of 1), which again was regarded as have significantly damaged the epidermal barrier.

In a further attempt to find a non-damaging dose to human epidermis, a third series of experiments were designed. Three solutions of the methyltin chloride mixture 10000, 50000 and 100000 µg/ml) were prepared in ethanol and each applied to three replicate epidermal membranes at a rate of 10 µl/cm² (a, 100, 500 or 1000 µg methyltin chloride mixture /cm²). For control purposes, ethanol only was applied to 2 cells at a rate of 10 µl/cm². The applications were not occluded until the ethanol vehicle had evaporated naturally and then remained covered until the end of the 24h contact period, when the cells were decontaminated and post-treatment resistance measurements taken, as previously described. The determined mean damage ratios were 1.33, 5.1 and 9.7 for the 100, 500 or 1000 µg methyltin chloride mixture /cm² applications respectively (versus 0.93 for the control applications), indicating that a non-damaging dose of methyltin chloride mixture would lie between 100 and 500 µg/cm².


MEASUREMENT OF TEST SUBSTANCE ADSORPTION
The receptor chambers of cells containing intact human and rat epidermal membranes (6 cells per species) were filled with a recorded volume of receptor fluid (water) and placed in a water bath maintained at 32 ± 1°C, A pre-treatment sample (0.5 ml) was taken from each receptor chamber for analysis by ICP-MS. An equal volume of fresh receptor fluid was added to each receptor chamber to replace the volume removed.

From information gained from the above experiments to define a non-damaging dose of the test material, the methyltin chloride mixture was applied to both human and rat epidermal membranes at a rate of 100 µg/cm² as a 10 µl/cm² dose of a 10000 µg/ml solution in ethanol. This application was equivalent to a nominal dose rate for tin of 53.5µg/cm², based upon a tin content of 53.5% w/w in the methyltin chloride mixture. For the cells designated to be occluded, as soon as the ethanol vehicle had evaporated naturally, the cells were occluded for the remainder of the 24h contact period.

At recorded intervals, samples (0.5ml) of the receptor fluid were taken for analysis by ICP-MS. The volume of fluid in the receptor chamber was maintained by the addition of (0.5ml) of fresh receptor fluid to the chamber immediately after the removal of each sample.


MASS BALANCE DETERMINATION
After the final sample of receptor fluid had been taken at the end of the exposure period, the remaining fluid in the receptor chamber was discarded and the chamber rinsed with fresh receptor fluid (5 ml) which was also discarded. The donor chambers were carefully removed and washed with water (10 ml) and the washings retained for analysis.

The surface of the epidermis was rinsed with water (5 x 5 ml) and the rinsings were combined prior to analysis.
The epidermis was carefully removed from the receptor chamber and placed in a glass scintillation vial.
All samples were stored refrigerated while awaiting analysis.

Absorption in different matrices:

Human skin - unoccluded application (Mean of 6 replicates - % of dose recovered)
Donor chamber 2.43
Skin wash 8.02
Epidermis 20.15
Absorbed (receptor fluid) 0.25
TOTAL RECOVERY 30.85

Human skin - occluded application (Mean of 5 replicates - % of dose recovered)
Donor chamber 6.71
Skin wash 3.45
Epidermis 43.26
Absorbed (receptor fluid) 1.39
TOTAL RECOVERY 54.80

Rat skin - unoccluded application (Mean of 5 replicates - % of dose recovered)
Donor chamber 2.19
Skin wash 11.89
Epidermis 24.18
Absorbed (receptor fluid) 9.95
TOTAL RECOVERY 48.21

Rat skin - unoccluded application (Mean of 6 replicates - % of dose recovered)
Donor chamber 2.41
Skin wash 4.01
Epidermis 51.08
Absorbed (receptor fluid) 10.04
TOTAL RECOVERY 67.54

Total recovery:

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.

Parameter:

percentage

Absorption:

20 %

Remarks on result:

other: 24 hours

Remarks:

unoccluded human - amount remaining in epidermis considered potentially absorbable

Parameter:

percentage

Absorption:

34 %

Remarks on result:

other: 24 hours

Remarks:

unoccluded rat - - amount remaining in epidermis considered potentially absorbable

Preliminary Study:

During preliminary assessments, the direct application of a non-damaging occluded dose of the methyltin chloride mixture to the epidermis could not be achieved, however a dose of 100 µg/cm² (applied as a 10000 µg/ml solution in ethanol at a rate of 10 µl/cm² and occluded only after the ethanol had evaporated), was determined not to damage the epidermis (damage ratio = 1.33). Ethanol itself was determined not to affect the barrier function of the epidermis.

This same regime was used in experiments to determine the absorption through human and rat epidermis and the distribution of tin within the test system. Similar experiments were also carried out where the applications were left unoccluded throughout the 24h exposure period.

Absorption through human epidermis:

From the occluded applications to human epidermis, an initial rate of tin absorption of 0.015 µg/cm²/h measured during the first 6h of exposure. Between 6-24h a maximum absorption rate of 0.037 µg/cm²/h was achieved. From the unoccluded application a similar pattern of absorption was seen, except that the tin absorption rates were 5-6 times slower during the 0-6h and 6-24h periods (0.003 µg/cm²/h and 0.006 µg/cm²/h). In terms of percent of applied tin, 1.4% was absorbed from the occluded dose, while only 0.25% was absorbed from the unoccluded dose after 24h exposure.

Absorption through rat epidermis:

Absorption of tin through rat epidermis was much faster than through human epidermis. From the occluded application, tin absorption maintained an essentially constant rate (0.233 µg/cm²/h) throughout the entire 24h exposure. From the unoccluded application, the absorption process was essentially complete within the first 3h of exposure, with a maximum mean absorption rate of 1.07 µg/cm²/h during this period. From both applications, 10% of the applied tin was determined to have been absorbed by 24h after dosing.

Distribution of dose and mass balance:

The overall recovery of tin from the test system after 24h exposure was low with 55% and 67% of applied tin being recovered from the occluded applications to human and rat epidermis respectively, while only 31% and 48% was recovered from the unoccluded applications. Since (a) more tin was recovered from the occluded experiments than from the unoccluded exposures and (b) the methyltin chloride mixture is volatile, the assumption is that the losses of tin from the occluded experiments (essentially a sealed system) occurred during the period that the ethanol vehicle was evaporating prior to occlusion. If this is the case, then recovery would be expected to be lower from the unoccluded experiments compared to those that were occluded. This hypothesis is also supported by the fact that tin absorption is faster through rat epidermis than through human epidermis, thus allowing less time for tin to volatilise from the surface of rat epidermis during this early stage of the absorption process, giving rise to the higher recovery values from the rat experiments.

A high proportion of the recovered tin was present in the epidermis for both human and rat. For the occluded applications this amounted to about half of the dose and about fifth of that applied to unoccluded experiments. The amounts determined to have been absorbed into the receptor fluid were low (0.25% and 1.4% from human experiments and 10% from both rat experiments). Approximately 10% for human and 6.4% - 14% for rat was washed off the surface of the epidermis and the donor chamber.

Conclusions:

1. Following 24h dermal contact with the methyltin chloride mixture, amounts >100 µg/cm² can alter the barrier function of human epidermis.
2. The results indicate that at a dose level of 100 µg/cm² of the methyltin chloride mixture (89% as DMTC), 70% of the tin dose probably evaporates from the surface of human skin under unoccluded conditions.
3. At this 100 µg/cm² dose level, the absorption of tin from this methyltin chloride mixture through human epidermis is very slow, and a significant amount remains in the epidermis.
4. The absorption of tin from this methyltin chloride mixture through rat epidermis significantly overestimated absorption through human epidermis.
5. Absorption of tin through human epidermis after 24h exposure under unoccluded conditions is estimated to be 20%, considering the remaining in epidermis as potentially absorbable. Through rat epidermis, 34% of the applied tin was absorbed by 24h under similar conditions.

The non-irritating concentration of the methyltin chloride mixture can be quoted as 100 µg/cm², 89 µg/cm² based on DMTC content.

Executive summary:

Study design:

The absorption of a methyltin chloride mixture containing 53.5% w/w tin as monomethyltin trichloride (11%w/w) and dimethyltin dichloride (89% w/w) has been measured in vitro through human and rat epidermis. The tin species absorbed were not individually identified; absorption determinations were based on measurements of total tin in the samples analysed. The first phase of the study was to identify the highest dose that could practically be applied, which was also determined to be non-damaging to human epidermis. During the second phase of the study the absorption of tin was determined from both occluded and unoccluded applications of this non-damaging dose to human and rat epidermis (10 µl/cm² of a 10000 µg methyltin chloride mixture /ml in ethanol, which was equivalent to a dose of 100 µg methyltin chloride mixture /cm²).

Results:

Determination of a non-damaging dose to human epidermis

A non-damaging occluded dose of the methyltin chloride mixture could not be applied directly to the epidermis, however a dose of 100 µg/cm² (applied as a 10000 mg/ml solution in ethanol at a rate of 10 µl/cm² and occluded only after the ethanol had evaporated), was determined not to damage the epidermis. The non-irritating concentration of the methyltin chloride mixture can therefore be quoted as 100 µg/cm². The dimethyltin dichloride content of this mixture is 89%.

This same regime was used in experiments to determine the absorption of tin through human and rat epidermis and its distribution within the test system, from both occluded and unoccluded applications of the methyltin chloride mixture.

Absorption through human epidermis

From the occluded applications to human epidermis, an initial rate of tin absorption of 0.015 µg/cm²/h was measured during the first 6h of exposure. Between 6-24h a maximum absorption rate of 0.037 µg/cm²/h was achieved. From the unoccluded application, tin

absorption rates were 5-6 times slower during the 0-6h and 6-24h periods (0.003 µg/cm²/h and 0.006 µg/cm²/h). In terms of percent of applied tin, 1.4% was absorbed into the receptor fluid from the occluded dose, while only 0.25% was absorbed from the unoccluded dose after 24h exposure. Percentages remaining in the epidermis accounted to 43.26 and 20.15%, respectively, under occluded and unoclluded conditions.

Absorption through rat epidermis

Absorption of tin through rat epidermis was much faster than through human epidermis. From the occluded application, tin absorption maintained an essentially constant rate (0.233 µg/cm²/h) throughout the entire 24h exposure. From the unoccluded application, the absorption process was essentially complete within the first 3h of exposure, with a maximum mean absorption rate of 1.07 µg/cm²/h during this period. From both applications, 10% of the applied tin was determined to have been absorbed into the receptor fluid by 24h after dosing. Percentages remaining in the epidermis accounted to 51.08 and 24.18%, respectively, under occluded and unoccluded conditions.

Distribution of dose and mass balance

The overall recovery of tin from the test system after 24h exposure was low with 55% and 67% of applied tin being recovered from the occluded applications to human and rat epidermis respectively, while only 31% and 48% was recovered from the unoccluded applications. The data indicate that the unaccounted portion of the dose probably volatilised from the surface of the skin and was not captured by this test system.

A high proportion of the recovered tin was present in the epidermis for both human and rat. For the occluded applications this amounted to about half of the dose and about fifth of that applied to unoccluded experiments. The amounts determined to have been absorbed into the receptor fluid were low (0.25% and 1.4% from human experiments and 10% from both rat experiments). Approximately 10% for human and 6.4% - 14% for rat was washed off the surface of the epidermis and the donor chamber.

Conclusion:

1. Following 24h dermal contact with the methyltin chloride mixture, amounts >100 µg/cm² can alter the barrier function of human epidermis.

2. The results indicate that at a dose level of 100 µg/cm² of the methyltin chloride mixture (89% as DMTC), 70% of the tin dose probably evaporates from the surface of human skin under unoccluded conditions.

3. At this 100 µg/cm² dose level, the absorption of tin from this methyltin chloride mixture through human epidermis is very slow, and a significant amount remains in the epidermis.

4. The absorption of tin from this methyltin chloride mixture through rat epidermis significantly overestimated absorption through human epidermis.

5. Absorption of tin through human or rat epidermis after 24h exposure under unoccluded conditions is estimated to be 0.25% or 10% respectively. However, if it is assumed that the remaining tin in the epidermis as potentially absorbable, the percentage of absorbed tin through human or rat epidermis after 24 h exposure under unoccluded conditions rises to approximately 20% or 34%, respectively.

Reference 6

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material

Justification for type of information:

Read-across to structurally similar substance dimethyltin dichloride (DMTC) (EC Number 212-039-2, CAS Number 753-73-1), see attached justification.

Reason / purpose for cross-reference:

read-across source

Key result

Time point:

24 h

Dose:

unnocluded human

Parameter:

percentage

Absorption:

20 %

Remarks on result:

other: amount remaining in epidermis considered potentially absorbable

Key result

Time point:

24 h

Dose:

unoccluded rat

Parameter:

percentage

Absorption:

34 %

Remarks on result:

other: amount remaining in epidermis considered potentially absorbable

Reference 7

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 September 2016 to 07 November 2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Objective of study:

other: hydrolysis

Qualifier:

according to guideline

Guideline:

other: OECD 111

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EU Method C.7

Deviations:

no

GLP compliance:

no

Radiolabelling:

not specified

HYDROLYSIS AT PH 4,7 AND 9

- At pH 4 the 119Sn-NMR spectra of the extracted reaction products shows no signs of hydrolysis, whereas at pH 7 and to a greater extent at pH 9, new signals in the 119Sn-NMR spectra indicate the breakdown of the substance.

- The half-life time of the test material under the conditions of the study is > 1 year for the pH value 4 the substance can considered as hydrolytically stable.

- At pH 7 and 9 two signals appear at -187 and – 207 ppm in the 119Sn-NMR spectra of the extracted hydrolysate which can be attributed to the formation of a dimeric tetramethyl distannoxane structure. Those structures are formed following a stepwise hydrolysis of initially formed diorganotin hydroxides.

HYDROLYSIS AT PH 1.2

- The 119Sn-NMR spectrum of the organic extract shows no signal between 200 and -800 ppm.

- The 1H-NMR spectrum of the hexane extract is identical with the reference spectrum of oleic acid.

- The recovered mass of 0.79 g corresponds to 100% of oleic acid (M = 282.46 Da) bound as ligand in the test material.

- It can be concluded that under the conditions of the study the oleic acid ligand is hydrolysed from the tin atom and the remaining dimethyltin fragment forms a water soluble breakdown product.  

MASS BALANCE RECOVERY RATES

pH 4: 78 %

pH 7: 20 %

pH 9: 85 %

pH 1.2: 79 %

ATOMIC ABSORPTION SPECTOMETRY

- The aqueous phase of the low pH hydrolysis was analysed after extraction with hexane by AAS and contained 1530 mg/L  Sn (92% of Theory).

Conclusions:

Under the conditions of this study, the test material was is hydrolytically stable at pH 4. After 5 days of hydrolysis at 50°C less than 10% of the test material was hydrolysed (half life at 25 °C > 1 year). At pH 7 and to a greater extend at pH 9, the test material breaks down to a dimeric dimethyl distannoxane.
At simulated gastric conditions (0.1 M HCl /pH 1.2 /37°C/ 4 h) the only identifiable breakdown product was the ligand oleic acid, which was extracted in the hexane phase and identified by 1H-NMR spectroscopy. The lower recovery of test material in the hexane extract and the content of 1530 mg/L tin remaining in the aqueous phase indicate that the remaining dimethyltin fragment remains in a soluble form in water.

Executive summary:

The hydrolysis of the test material as a function of pH was investigated in accordance with the standardised guidelines OECD 111 and EU Method C.7.

The stability of the test material was investigated at pH 4, 7 and 9 and pH 1.2 using NMR spectroscopy.

Under the conditions of this study, the test material was is hydrolytically stable at pH 4. After 5 days of hydrolysis at 50°C less than 10% of the test material was hydrolysed (half life at 25°C > 1 year). At pH 7 and to a greater extend at pH 9, the test material breaks down to a dimeric dimethyl distannoxane.

At simulated gastric conditions (0.1 M HCl /pH 1.2 /37°C/ 4 h) the only identifiable breakdown product was the ligand oleic acid, which was extracted in the hexane phase and identified by 1H-NMR spectroscopy. The lower recovery of test material in the hexane extract and the content of 1530 mg/L tin remaining in the aqueous phase indicate that the remaining dimethyltin fragment remains in a soluble form in water.

Description of key information

Hydrolysis as a function of pH. Naßan (2017)

Under the conditions of this study, the test material was hydrolytically stable at pH 4. After 5 days of hydrolysis at 50°C less than 10% of the test material was hydrolysed (half life at 25 °C > 1 year). At pH 7 and to a greater extent at pH 9, the test material breaks down to a dimeric dimethyl distannoxane.

At simulated gastric conditions (0.1 M HCl /pH 1.2 /37°C/ 4 h) the only identifiable breakdown product was the ligand oleic acid, which was extracted in the hexane phase and identified by 1H-NMR spectroscopy. The lower recovery of test material in the hexane extract and the content of 1530 mg/L tin remaining in the aqueous phase indicate that the remaining dimethyltin fragment remains in a soluble form in water.

Read-across to DMTC (Dimethyltin dichloride), CAS 753-73-1

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.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Hydrolysis as a function of pH. Naßan (2017)

The hydrolysis of the test material as a function of pH was investigated in accordance with the standardised guidelines OECD 111 and EU Method C.7.

The stability of the test material was investigated at pH 4, 7 and 9 and pH 1.2 using NMR spectroscopy.

Under the conditions of this study, the test material was hydrolytically stable at pH 4. After 5 days of hydrolysis at 50°C less than 10% of the test material was hydrolysed (half life at 25°C > 1 year). At pH 7 and to a greater extent at pH 9, the test material breaks down to a dimeric dimethyl distannoxane.

At simulated gastric conditions (0.1 M HCl /pH 1.2 /37°C/ 4 h) the only identifiable breakdown product was the ligand oleic acid, which was extracted in the hexane phase and identified by 1H-NMR spectroscopy. The lower recovery of test material in the hexane extract and the content of 1530 mg/L tin remaining in the aqueous phase indicate that the remaining dimethyltin fragment remains in a soluble form in water.

Toxicokinetic assessment

No experimental studies of the absorption, distribution, metabolism or elimination of Dimethylbis(oleoyloxy)stannane (synonym: DMT-Ol; EC Number 223-384-3; CAS Number 3865-34-7) in mammals are available. However, the physical chemical properties and the existing toxicity studies on the substance, as well as data and toxicity studies on the read-across substance Dimethyltin dichloride (synonym: DMTC; EC Number 212-039-2, CAS Number 753-73-1) have been used to infer as far as possible, its potential toxicokinetics.

 

The substance DMT-Ol is a pale yellow liquid. Its molecular weight (MW) is 711.693 g/mol. As estimated by predictive models, the substance is not water-soluble (1.718-10 mg/L), has a partition coefficient (Log Kow/Log Pow) of 13.1524, and a vapour pressure of 3.63 Pa at 25°C.

In a hydrolysis as a function of pH study, DMT-Ol was found to be hydrolytically stable at pH 4. After 5 days of hydrolysis at 50°C less than 10% of the test material was hydrolysed (half life at 25°C > 1 year). At pH 7 and to a greater extend at pH 9, the test material was found to break down to a dimeric dimethyl distannoxane.

At simulated gastric conditions (0.1 M HCl; pH 1.2; 37°C for 4 h) the only identifiable breakdown product was the ligand oleic acid, which was extracted in the hexane phase and identified by 1H-NMR spectroscopy. The lower recovery of test material in the hexane extract and the content of 1530 mg/L tin remaining in the aqueous phase indicate that the remaining dimethyltin fragment remains in a soluble form in water.

 

Absorption

In a hydrolysis as a function of pH study, the only identifiable breakdown product was the ligand oleic acid, while the dimethyltin fragment remained in a soluble form in water. It is therefore expected that the ligand oleic acid will be subjected to absorption and metabolism as a fatty acid, while the dimehtyltin toxophore will behave as for the read-across substance DMTC. Toxicokinetic studies on DMTC determined oral bioavailability to be approximately 50%. For the purposes of human health risk assessment, 50% oral absorption is assumed for DMT-Ol by read-across.

The high molecular weight (MW 711.793 g/mol) and high estimated Log Pow (13.1524) indicates that micellar solubilisation would play a major role for absorption by inhalation. In the absence of any quantitative data for human health risk assessment purposes absorption by inhalation of DMT-Ol is assumed to be 100%.

As the molecular weight of DMT-Ol is > 500 g/mol, it is insoluble in water and the estimated Log Pow is > 4, a default value of 10% dermal absorption is considered appropriate for human health risk assessment.

Based on the in vitro dermal absorption test conducted on DMTC (Ward, 1999), absorption of tin content through human or rat epidermis after 24h exposure under unoccluded conditions was estimated to be 0.25% or 10%, respectively. However, if it is assumed that the remaining tin in the epidermis as potentially absorbable, the percentage of absorbed tin through human or rat epidermis after 24 h exposure under unoccluded conditions rises to approximately 20% or 34%, respectively.

 

Distribution

By reading-across from DMTC, wide distribution within the body is assumed for DMT-Ol. Micellar solubilisation and preferential partition to tissues with high lipid content are expected to occur.

 

Metabolism and Excretion

As mentioned above, the ligand oleic acid will be subjected to metabolism as a fatty acid for the production of energy within the body. The dimehtyltin toxophore will be excreted at least partially via the urine while excretion of unchanged DMT-Ol, if any, is expected to occur mainly via the faeces.

The partition coefficient for DMT-Ol was a predicted value and therefore in the absence of experimental log Kow data, the potential for bioaccumulation is considered low.

 

 

Read-across Justification

The target substance Dimethylbis(oleoyloxy) stannane (EC Number 223-384-3, CAS Number 3865-34-7) is a mono-constituent organotin substance that consists of a tin central metal element with two methyl ligands and two oleic acid ligands. The source substance Dimethyltin Dichloride (DMTC) (EC Number 212-039-2, CAS Number 753-73-1) is also an organotin compound and has the identical structure elements as the target substance in respect of the tin-alkyl moiety.

According to WHO IPCS CIRCAD (2006) organotin compounds are characterized by a tin–carbon bond and have the general formula RxSn(L)(4−x), where R is an organic alkyl or aryl group and L is an organic (or sometimes inorganic) ligand. The organotin moiety is significant toxicologically. The anionic ligand influences physicochemical properties but generally has little or no effect on the toxicology. Applying this WHO characterization to target and source, they can be described (CH3)2SnL, with L source = Cl2- and L target = (C18H33O2)2-.

Since the target substance and the source substance share the identical organotin moiety, and the organotin moiety is generally recognized as the relevant toxophore of organotins and the toxicity estimates (AE) respectively toxicity limits for organotins are expressed as tin, the overall ecotoxicity/systemic toxicity of the target can be interpolated by assessing the (eco-)toxicity of the source (WHO IPCS CIRCAD, 2006, BAUA AGS TRGS 900, 2014, Summer KH, Klein D and Greim H, 2003). As the source has a higher relative amount of tin based on molecular weight (source 54.0%, target 16.6%) the read-across approach to DMTC can be assessed as conservative (worst case).

The purity of the source and target substance are expected to be high, based on the manufacturing method. The impurity profile is not expected to have strong effects on substance properties and any impurity of (eco-)toxicological relevance of the source substances is expected to be present in the target substance. Consequently, the hazard profiles of the source substances, including those of their impurities, are intrinsically covered. Differences in impurities are not expected and thus do not have an impact on the (eco-)toxic properties. The dominating intrinsic property of oleic acid the moiety of the target substance, which is not covered by the source substance and thus may pose a source specific impurity - is its irritation. However this is a local effect covered by studies on the target substance itself and thus excluded from the read- across approach.

The bioavailability of both substances varies in a predictable manner and is assumed to be dependent on the water solubility. The prediction of the effects of the target substance based on the relationship between solubility and (eco-)toxicity or on a worst-case basis. The respective ligands of source and target are expected to be of no (eco-)toxic importance based on intrinsic properties but may have an effect on solubility respectively bioavailability.

 

References

• BAUA (Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (Federal Institute for Occupational Safety and Health)) AGS (Ausschuss für Gefahrstoffe (Committee on Hazardous Substances)) TRGS (Technical Rules for Hazardous Substances) 900 (2014). Begründung zu n-Octylzinnverbindungen, April 2014.
• Summer KH, Klein D, Griem H (2003). Ecological and toxicological aspects of mono- and disubstituted methyl-, butyl-, octyl-, and dodecyltin compounds - Update 2002. GSF National Research Center for Environment and Health, Neuherberg, for the Organotin Environmental Programme (ORTEP) Association.
• World Health Organization (WHO) International Programme on Chemical Safety (IPCS) Concise International Chemical Assessment Document (CICAD) 73 Mono- and disubstituted methyltin, butyltin, and octyltin compounds (2006). Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals. World Health Organization ISBN 978 92 4 153073.