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EC number: 260-828-5 | CAS number: 57583-34-3
The NOAEL for general sub-chronic toxicity and maternal toxicity, fertility and developmental effects was placed at 150 mg trichloromethylstannane per kg diet.
The toxicity of trichloromethylstannane [CAS # 993-16-8] in Wistar rats was examined using continuous administration via the diet for 13 consecutive weeks (OECD Test Guideline 408). In satellite groups of female rats a reproduction/developmental screening test (OECD Test Guideline 421) was performed to provide initial data on possible reproductive and developmental effects of trichloromethylstannane. The main study used four groups of 10 rats/sex (13 -week study) and the satellite study used four groups of 10 female rats (reproduction/developmental screening study). For both studies the control group was kept on control diet and three test groups received experimental diets containing 30, 150 and 750 mg/kg [ppm] of the test substance. The dose levels used in both studies were based on the results of a preceding dose range finding study.
In the satellite study female rats were fed their respective test diets beginning 2 weeks prior to the mating period, and continued on test diets through mating, gestation, and up to PN 4 or shortly thereafter. Male rats from the main study were mated after a premating period of 10 weeks with female rats of the satellite groups which were fed the same dose of test diets.
Clinical observations, growth, food consumption, food conversion efficiency, neurobehavioural testing, ophthalmoscopy, haematology, clinical chemistry, renal concentration test, urinalysis, organ weights and gross examination at necropsy, microscopic examination of various organs and tissues and assessment of various reproductive and developmental parameters were used as criteria for detecting the effects of treatment.
The calculated doses during the pre-mating, gestation and lactation periods for the females receiving 30, 150, or 750 mg/kg trichloromethylstannane in the diet ranged from 1.2-2.0, 6.2-11.7 and 26.5-45.8 mg/kg body weight, respectively.
During the study one animal of the 750 mg/kg group was found dead on GD22. Most probably haemothorax caused by dystocia was the cause of death. No other mortalities or treatment-related clinical signs were observed in the female animals of the satellite groups.
Mean body weight, body weight change and food consumption was similar in the control and the 30 and 150 mg/kg groups. Mean body weight on PN 4 and mean body weight change PN 1-4 of the 750 mg/kg group was decreased, although not statistically significantly.
During the premating and gestation periods, mean food consumption of the female animals was similar in the control, 30 and 150 mg/kg groups. During the lactation period food consumption of the 750 mg/kg group was decreased (not statistically significantly).
No treatment-related effects on reproduction and development of the pups were observed in the 30 and 150 mg/kg groups.
In the 750 mg/kg group, a number of changes were seen indicative of a reproductive and developmental effect. One animal was found dead on GD22 (death was most probably caused by haemothorax caused by dystocia), post-implantation loss was 43 %, the number of pups delivered was 7.1 versus 11.2 in the control group, 3 females lost all pups between PN 1-4, and pup mortality between PN 1-4 in the 750 mg/kg group was 65 versus 16 % in the control group.
No treatment-related effects on pup weight and pup abnormalities were observed.
Absolute and relative organ weights (uterus, ovary and thymus) were similar among the groups. At microscopic examination of these organs no treatment-related histopathological changes were observed.
Based on reproductive and developmental effects (decreased number of pups delivered and increased post implantation loss and pup mortality) observed after mating of female animals of the 750 mg/kg satellite group with male animals of the main study, the mid-dose level 150 mg Trichloromethylstannane/kg diet (equivalent to 9.8 mg/ kg body weight/day in males and 6.2-11.7 mg/kg body weight for females) can be considered as a NOAEL for fertility and developmental effects.
Based on the effects on body weight and food consumption in the 750 mg/kg group, 150 mg Trichloromethylstannanel kg diet (equivalent to 6.2-11.7 mg/kg body weight/day) can be considered as a NOAEL for maternal toxicity.
When the substance was originally registered, it was supported by a complete dossier in which a number of toxicology data points, including reproductive toxicity, were filled with data from studies using trichloromethylstannane [CAS # 993-16-8]. This was justified at the time on the basis of the available data which showed MMTE hydrolysed to MMTC under simulated gastric conditions. The analytical methodology used for the in vitro metabolism [IVM or hydrolysis] study which was deemed to show MMTE hydrolysing to MMTC utilised an indirect chemical method, but it has been since shown to be that this methodology was flawed.
It was erroneously inferred from these data that MMTC was the major metabolite. This inference is now known to be incorrect. New data utilising a more advanced analytical methodology, ¹¹⁹Sn NMR Spectroscopy, and allowed intermediate hydrolysis products to be identified and quantified directly. The new data indicate that MMTC is not a metabolite, and therefore read-across from MMTC to MMTE is not toxicologically valid for mammalian in vivo studies. This creates possible data gaps in the dossier supporting MMTE for any data requirement which is currently fulfilled by read-across.
As per ECHA Decision number: CCH-D-2114373450-54-01/F of 13 November 2017 the registrant is intending to carry out an extended one generation reproductive toxicity study in rats (OECD 443).
The data that was originally presented on MMTC is still included in the registration dossier at this time. No other data is available on the substance itself until the new tests are conducted and it is therefore considered reasonable to continue using the MMTC data until such a time as the new studies are complete.
In a reproduction/developmental screening study following the OECD 421 guideline the NOAEL for general sub-chronic toxicity and maternal toxicity, fertility and developmental effects was placed at 150 mg trichloromethylstannane per kg diet.
In two Developmental Neurotoxicity (DNT) studies conducted by Moser, the results indicate that perinatal exposure to the test substance, even at concentrations which decrease maternal fluid intake, does not result in significant neurobehavioral or cognitive deficits.
Table 1: Fluid intake (average and range of means, mL/day), body weight (average and range of means, g) and calculated MMT intake (mg/kg/day) for each concentration of MMT (ppm) throughout exposure
28.9 (27.0 - 30.4)
266.8 (253 - 271.1)
26.5 (24.5 - 27.7)
270.6 (254.9 - 274.6)
28.2 (27.1 - 29.1)
268.0 (255.5 - 271.6)
25.7 (23.6 - 26.8)
270 (256.0 - 274.3)
39.9 (36.1 - 48.1)
330.8 (274.5 - 418.1)
36.1 (30.7 - 43.5)
330.6 (280.8 - 414.5)
43.4 (35.1 - 50.6)
336.3 (276.4 - 420.3)
36.5 (30.8 - 44.7)
336.7 (278.4 - 422.3)
68.4 (48.2 - 92.9)
339.4 (336.2 - 346.3)
65.2 (44.7 - 86.8)
336.8 (322.6 - 348.3)
75.0 (51.4 - 95.9)
343.9 (332.3 - 356.6)
62.8 (47.8 - 82.1)
347.5 (335.8 - 352.3)
38.2 (33.1 - 44.0)
284.7 (231 - 346.9)
32.4 (28.5 - 37.4)
290.5 (233.9 - 356)
71.7 (40.8 - 96.3)
314.7 (304.0 - 328.8)
60.8 (36.9 - 85.1)
322.5 (310.9 - 333.8)
The objective of these studies was to replicate an earlier publication and further define the dose response characteristics of monomethylitn following perinatal exposure.
In Experiment 1, female Sprague-Dawley rats were exposed via drinking water to the test substance (0, 10, 50 and 245 ppm; equivalent to 0, 5, 25 and 120 mg Sn/L, respectively) before mating and throughout gestation and lactation (until weaning at postnatal day [PND] 21). Behavioural assessments of the offspring included a runway test (PND 11) in which the rat pups learned to negotiate a runway for dry suckling reward, motor activity habituation (PNDs 13, 17 and 21) and learning in the Morris water maze (as adults). Other endpoints in the offspring included measures of apoptosis (DNA fragmentation) at PND 22 and as adults, as well as brain weights and neuropathological evaluation at PND 2, 12, 22 and as adults.
In Experiment 2, pregnant rats were exposed from gestational day 6 until weaning to 500 ppm (245 mg Sn/L) in drinking water. The offspring behavioural assessments again included the runway task (PND 11), motor activity habituation (PND 17) and Morris water maze (as adults).
The results of Experiment 1 showed that there were no effects on any measure of growth, development, cognitive function or apoptosis following exposure to the test substance. There was a trend towards decreased brain weight in the high dose group. In addition, there was vacuolation of the neuropil in a focal area of the cerebral cortex of the adult offspring in all dose groups (1 -3 rats per treatment group).
In the second study, exposed females consumed significantly less water than the controls throughout both gestation and lactation, although neither dam nor pup weights were affected. As in Experiment 1, exposure did not alter pup runway performance, motor activity or cognitive function. These results indicate that perinatal exposure to the test substance, even at concentrations which decrease maternal fluid intake, does not result in significant neurobehavioral or cognitive deficits. While mild histological lesions were observed in the brain of adult offspring, the biological significance of this restricted finding in unclear.
When the substance was originally registered, it was supported by a complete dossier in which a number of toxicology data points, including developmental toxicity, were filled with data from studies using trichloromethylstannane [CAS # 993-16-8]. This was justified at the time on the basis of the available data which showed MMTE hydrolysed to MMTC under simulated gastric conditions. The analytical methodology used for the in vitro metabolism [IVM or hydrolysis] study which was deemed to show MMTE hydrolysing to MMTC utilised an indirect chemical method, but it has been since shown to be that this methodology was flawed.
As per ECHA Decision number: CCH-D-2114373450-54-01/F of 13 November 2017 the registrant is proposing to carry out a prenatal developmental toxicity study in the rat (OECD 414). The proposed developmental study is intended to address this endpoint with a standard approach.
A second species developmental toxicity test in rabbits is proposed in sequence only if adverse effects are observed in rats. There is no evidence that the methyltins are teratogenic and a second species test is not currently warranted for this plan.
When assessing for reproductive effects of MMTC, there are two studies to consider: an OECD 421 screening study and a published study in which two developmental neurotoxicity studies were carried out.
The experimental design of the OECD Guideline 421 screening study is considered to be limited; all potential toxic effects are not assessed in every phase of the study. Therefore a weight-of-evidence analysis should preferentially consider more robust studies in evaluating potential hazards. The Developmental Neurotoxicity [DNT] study is a more robust study than the OECD 421. The DNT is outlined under US EPA Guideline 870.6300 and is equivalent to OECD Guideline 426.
In a private communication [Moser, 2007] the author reiterated the lack of any reproductive effects in either study. She further indicated that it was uncertain if the brain changes in adult rats referred to in the published article were adverse. These findings did not appear in offspring at PND 1, 12, or 22, did not affect cognitive function as measured within the study.
In the weight-of-evidence analysis, maternal toxicity was evidenced by a slight indication of thymic involution and detriments in body weight and feed consumption at the highest dose in the OECD 421 study. Postnatal loss occurred at the highest dose in the OECD 421 study, but in the two more robust studies the postnatal loss could not be replicated, even at higher doses. The DNT studies clearly indicate that there are no reproductive effects of MMTC. Therefore, the weight-of-evidence analysis supports the conclusion that No Classification for reproductive toxicity is the appropriate decision.
In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to reproductive and developmental toxicity. However, in accordance with Annex VI of the Regulation, the substance has a harmonised classification and as such must be classified as a reproductive toxicant Category 2 (H361: Suspected of damaging fertility or the unborn child).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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