Dichlorodioctylstannane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

A screening study to investigate the reproductive/developmental effects of dioctyltin dichloride was conducted in accordance with OECD test method 421 (Appel & Waalkens-Berendsen, 2004). The low dose level of 10 mg Dihlorodioctylstannane/kg diet (10 ppm in diet - equivalent to 0.7 mg/ kg body weight/day in males and 0.5-0.7 mg/kg body weight for females) can be considered as a NOAEL for fertility effects. Based on the observed histological changes in the thymus (lymphoid depletion) of the 10 mg/kg female animals, 10 mg Dichlorodioctylstannane/ kg diet (10 ppm in diet - equivalent to 0.5-0.7 mg/kg body weight/day) was considered to be a LOAEL for maternal toxicity.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.5 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

reliable without restriction

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Short description of key information:

A screening study to investigate the reproductive/developmental effects of dioctyltin dichloride was conducted in accordance with OECD test method 421 (Appel and Waalkens-Berendsen, 2004).

Female Wistar rats were fed diets containing 10, 100 and 300 mg/kg (ppm) of the test substance. This began two weeks prior to the mating period, and continued through mating, gestation, and up to PN 4 or shortly thereafter. Male rats were mated after a premating period of 10 weeks with female rats of the satellite groups, which were fed the same dose of test diet. 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.

Results

Paternal Toxicity:

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)

No clinical signs were observed during the premating period. During the gestation period piloerection was observed in animal A115 (GD 21 -24) of the control group and animal D161 (GD 23-24) of the 300 mg/kg group. In addition, blepharospasm was observed in animal D161 (GD 23-24). During lactation piloerection was observed in animal C157 (PN 2-4) of the 100 mg/kg group and D163 (PN 2-4) and D167 (PN 1) of the 300 mg/kg group. Blepharospasm was observed in animal D167 of the 300 mg/kg group. Animals C149 (PN 4-5) and C157 (PN 4) of the 100 mg/kg group and animal D163 (PN 4) of the 300 mg/kg group were considered to be thin. In addition animals C149 and C159 showed a pale appearance. Some animals were sparsely haired during gestation and/or lactation; this finding is normal for this strain.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)

During the premating period no significant differences in mean body weight were observed. Mean body weight change was statistically significantly reduced in the 100 and 300 mg/kg groups during the first week of the premating period. During the gestation period, mean body weight was statistically significantly reduced from GD 7-21 in the 300 mg/kg group. Body weight change was statistically significantly reduced during the entire gestation period. During the lactation period, the mean body weight was statistically significantly reduced in the 300 mg/kg group.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)

During the premating period, mean food consumption (expressed as g/animal/day and as g/kg body weight/day) of the female animals of the 100 and 300 mg/kg groups was statistically significantly decreased. During the gestation period, food consumption (g/animal/day) of the females of the 100 mg/kg group was statistically significantly decreased from GD 7-14. Mean food consumption of the 300 mg/kg group (expressed as g/animal/day) was statistically significantly decreased during the entire gestation period and as g/kg body weight/day from GD 0-14. During the lactation period food consumption of the female animals of the 300 mg/kg group was statistically significantly decreased.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)

No effects

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)

No effects

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)

Animal 115 of the control group and animals D161, D171 and D173 of the 300 mg/kg group showed only implantation sites at necropsy. The female fecundity index, female fertility index and male fertility index were comparable among the control and Dichlorodioctylstannane-treated groups. The gestation index was 86, 100, 71 and 50% in the control, 10, 100 and 300 mg/kg groups, respectively. The number of females with liveborn pups was 6, 8, 5 and 4 for the control, 10, 100 and 300 mg/kg groups, respectively. The number of females with stillborn pups amounted to 1, 1, 4 and 3 for the control, 10, 100 and 300 mg/kg groups, respectively. The number of females with all stillborn pups was 0, 0, 2 and 1 in the control, 10, 100 and 300 mg/kg groups, respectively. The live birth index was 99, 95, 53 and 60% in the control, 10, 100 and 300 mg/kg groups, respectively. Post-implantation loss was 22.3, 21.0, 49.2 and 70.0% for the control, 10, 100 and 300 mg/kg groups, respectively.

ORGAN WEIGHTS (PARENTAL ANIMALS)

Absolute and relative uterus and ovary weight were similar in all groups. The absolute and relative thymus weight was statistically significantly decreased in the 100 (62 and 67%) and 300 mg/kg (31 and 38%) groups when compared to the control group.

GROSS PATHOLOGY (PARENTAL ANIMALS)

No effects

HISTOPATHOLOGY (PARENTAL ANIMALS)

Microscopic examination revealed moderate to very severe lymphoid depletion in the thymus, which was considered related to treatment. Lymphoid depletion was characterised by a decrease in the size of the thymic lobules which can be ascribed to extensive loss of cortical en medullary small lymphocytes. Consequently, the distinction between the cortical and medullary areas was blurred. Lymphoid depletion was observed in 5/10 animals of the 10 mg/kg group and in all animals of the 100 and 300 mg/kg groups. Surprisingly, one control animal (A115) also had very severe lymphoid depletion in the thymus. However, this was most probably associated with the fact that this animal was physiologically disturbed, as was demonstrated by 12 resorptions in the uterus and an abnormal kidney (gross changes: flabby and yellow patches). Some 10 mg/kg animals showed thymic involution as a result of pregnancy/lactation. This picture was similar to the thymic pregnancy/lactation involution in control animals and was characterised by a decreased size of thymic lobules exhibiting normal architecture. This phenomenon is a common observation in pregnant or lactating animals. However, the lymphoid depletion in the 10 mg/kg animals was similar to the thymic change in the 100 and 300 mg/kg animals. Therefore, lymphoid depletion in the 10, 100 and 300 mg/kg animals was considered related to treatment with the test substance. The other histopathological changes observed are common findings in rats of this strain and age or occurred in a single animal only.

Offspring toxicity

VIABILITY (OFFSPRING)

The mean number of pups delivered per litter amounted to 11.7, 11.0, 10.3 and 8.6 or the control, 10, 100 and 300 mg/kg groups, respectively. Pup mortality on PN 1 was 1.4, 4.5, 47, and 40% in the control, 10, 100 and 300 mg/kg groups, respectively. All pups of the following animals died between PN 1-4: B137 of the 10 mg/kg group, C145 and C159 of the 100 mg/kg group and D165, D175 and D177. Pup mortality on PN 4 was 5.8, 8.3, 26 and 88 %. Viability index (PN 1 -4) was 94, 92, 74 and 12% in the control, 10, 100 and 300 mg/kg groups, respectively. The number of live pups per litter on PN 1 amounted to 11.5, 10.5, 7.6, 6.5 for the control, 10, 100 and 300 mg/kg groups, respectively and on PN 4 the number of live pups per litter amounted to 10.8, 11.0, 9.3 and 3.0 for the control, 10, 100 and 300 mg/kg groups, respectively. Both in the 100 and 300 mg/kg groups, 4 litters were entirely stillborn or lost at PN 4. No difference was observed in the sex ratio between the groups.

CLINICAL SIGNS (OFFSPRING)

On PN 1 and 4, the number of runts was statistically significantly increased in the 100 and 300 mg/kg groups. In addition the number of cold pups was increased in the 300 mg/kg group on PN 1.

BODY WEIGHT (OFFSPRING) Mean pup weight and pup weight change were similar in the 10 and 100 mg/kg groups when compared to the control group. Pup weight of the 300 mg/kg group (PN 1, 3 litters and PN 4, 1 litter) was reduced. SEXUAL MATURATION (OFFSPRING) not examined

ORGAN WEIGHTS (OFFSPRING)

not examined

GROSS PATHOLOGY (OFFSPRING)

No effects

HISTOPATHOLOGY (OFFSPRING)

not examined

Based on reproductive and developmental effects observed after mating of 100 and 300 mg/kg female animals with male animals, the low dose level of 10 mg Dihlorodioctylstannane/kg diet (equivalent to 0.7 mg/ kg body weight/day in males and 0.5-0.7 mg/kg body weight for females) can be considered as a NOAEL for fertility and developmental effects.
Based on the observed histological changes in the thymus (lymphoid depletion) of the 10 mg/kg female animals, 10 mg Dichlorodioctylstannane/ kg diet (equivalent to 0.5-0.7 mg/kg body weight/day) was considered to be a LOAEL for maternal toxicity.

Effects on developmental toxicity

Description of key information

Key study:

A prenatal developmental toxicity study with the registered substance Dioctyltin Dichloride (DOTC) was conducted in accordance with the OECD guideline 414 and GLP (Bioneeds, 2014). The NOAEL and the LOAEL for maternal toxicity to the dams and was determined to be 10 ppm (0.8 mg/kg bw/day) and 100 ppm (7.2 mg/kg bw/day), respectively based on a statistically significant decrease in maternal body weight and reduced thymus size. The NOAEL and the LOAEL for developmental toxicity was also determined to be 10 ppm (0.8 mg/kg bw/day) and 100 ppm (7.2 mg/kg bw/day), respectively, based on a statistically significant and treatment-related increase in the percentage of skeletal malformations associated with delayed fetal ossification. As the observed skeletal malformation associated with delayed fetal ossification was only noted at maternally toxic doses DOTC is regarded as not teratogenic in the rat but as fetotoxic at a maternally toxic doses.

Supporting study:

A screening study to investigate the reproductive/developmental effects of dioctyltin dichloride was conducted in accordance with OECD guideline 421 (Appel & Waalkens-Berendsen, 2004). The low dose level of 10 mg Dihlorodioctylstannane/kg diet (10 ppm in diet - equivalent to 0.7 mg/ kg body weight/day in males and 0.5-0.7 mg/kg body weight for females) can be considered as a NOAEL for fertility effects. Based on the observed histological changes in the thymus (lymphoid depletion) of the 10 mg/kg female animals, 10 mg Dichlorodioctylstannane/ kg diet (10 ppm in diet -equivalent to 0.5-0.7 mg/kg body weight/day) was considered to be a LOAEL for maternal toxicity.   

Overall conclusion:

The NOAELs for developmental toxicity derived from the available OECD 414 and OECD 421 are in a comparable range i.e., 100 ppm in diet. The corresponding NOAEL value calculated in “mg/kg bw/day” derived from the OECD 421 study was used as key value as it is to a minor extend lower than the respective value obtained from the OECD 414 study.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.5 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Reliable without restriction

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Key study:

A prenatal developmental toxicity study with the registered substance Dioctyltin Dichloride (DOTC) was conducted in accordance with the OECD Guideline 414 and GLP. The purpose of this study was to assess the effects of prenatal exposure of Test Article (DOTC) on the pregnant females and in the developing organisms and assessment of maternal toxicity as well as death, structural abnormalities, or altered growth in the fetuses when administered by a mixture with the diet to the mated females from gestation day 5 to 19. A total of 100 mated female Sprague Dawley rats were allocated to four groups. Each group consisted of 25 mated female Sprague Dawley rats (Dams). DOTC was administered by a mixture with the diet (using insignificant amounts of acetone as suitable vehicle) at dose levels of: Vehicle control: 0 ppm, Low dose group 10 ppm (0.8 mg/kg bw/day), Mid dose group: 100 ppm (7.2 mg/kg bw/day), High dose group: 300 ppm (22.4 mg/kg bw/day). Both the Test Article and vehicle control were administered by a mixture with the diet. All the animals were sacrificed on gestation day 20 by carbon dioxide exposure and subjected to detailed gross pathology. The gravid uterus was collected by hysterectomy and fetuses were removed by caesarean section. Examination of dams and fetuses was performed and the following results were obtained.

PREGNANCY DATA

A total number of 22, 21, 20 and 20 mated females were confirmed with pregnancy at a pregnancy rate of 88%, 84%, 80% and 80% at the time of caesarean section at 0, 10, 100 and 300 ppm respectively.

MATERNAL DATA

General Tolerability

No deaths and abortions were noted during the experimental period.

Body weight, Body Weight Change and Corrected body weight

There was a statistically significant decrease in maternal body weight for the period of gestation days (GD) 17-20 and maternal body weight change for the periods GD 5-8, GD 11-14, GD 14-17 and GD 17-19 for dams in the 300 ppm group was noted. There were no statistically significant decreases in maternal body weight and maternal body weight change for dams in the 10 or 100 ppm dose groups on any gestation day when compared to control dams.

No statistically significant decrease in body weight change GD 5-20 for dams in the 10 ppm and 100 ppm groups compared to controls was noted. A statistically significant decrease in body weight change GD 5-20 for dams in the 100 ppm (11.9%) and in 300 ppm (30.8%) groups as compared with controls was noted.

The corrected body weight change and the percent change were similar to controls in the 10 and 100 ppm groups. In the 300 ppm group the corrected body weight change and the percent change (75.6%) were both statistically significantly decreased compared to controls. Gravid uterine weight was similar to controls at all doses.

Feed Consumption and Test Article Consumption

There were no treatment related differences in average feed consumption at any of the tested dose.

Test Article consumption for each dose was calculated as 0.8, 7.2 and 22.4 mg/kg/day for the low, mid and high dose groups, respectively.

Gross Pathology

Macroscopic observations of reduced size of thymus in 7 of 25 females at 100 ppm and in all females (25 of 25) at 300 ppm were observed. These observations were judged to be treatment-related. No gross pathological observations were noted in 10 ppm animals.

Maternal Data (Uterine Observations)

No treatment related differences in mean gravid uterus weight, number of corpora lutea per dam, number of implantation sites per dam, incidence of early and late resorptions, number of dead and live fetuses, pre and post-implantation losses and male/female sex ratio were noted at all the doses.

The occurrence of early resorptions at 100 ppm, late resorptions at 10 and 300 ppm, pre-implantation loss at 300 ppm and post-implantation loss at 10, 100 and 300 ppm were judged as incidental and not treatment related.

FETAL DATA

Fetal Sex Ratio, Average Fetal Weight and Average Crown Rump Length

No treatment related effects on the fetal sex ratio, average fetal weight and average crown-rump length were noted at any of the dose.

External Examination

No gross external abnormalities were noted within any group after external examination of fetuses.

Visceral Examination

No treatment related malformations and variations were observed at all doses. The noted observations, abnormal liver lobation and dilation of the renal pelvis, are common findings for rat fetuses and were judged as incidental occurrences. 

Skeletal Examination

Statistically significant and treatment related increase in percentage of malformations of missing metacarpal No. 5 (11.4% at 100 ppm and 34.6% at 300 ppm as compared with 0.8% in control), proximal phalanx No. 3 bilateral (14.3% at 100 ppm and 28.0% at 300 ppm as compared with 0.8% in control) and proximal phalanx No. 4 (13.3% at 100 ppm and 27.1% at 300 ppm as compared with 0.8% in control) were noted.

Statistically significant and treatment related increase in percentage variations of poor ossification of sternum No. 5 and No. 6 (6.5% and 14.0% as compared with 0% in control) was noted at 300 ppm. A dose dependent and treatment related increase in poor ossification of metacarpal No. 5 was observed at 100 ppm (1.0%) and at 300 ppm (3.7%) as compared with 0% in control.

CONCLUSION

The results of the experiment support the conclusion that the NOAEL (No Observed Adverse Effect Level) of DOTC for the maternal toxicity endpoint was 10 ppm (0.8 mg/kg bw/day). The LOAEL (low observed adverse effect level) for the maternal toxicity endpoint was 100 ppm (7.2 mg/kg bw/day) based on a statistically significant decrease in corrected body weight change from gestation day 5-20 and a decrease in thymus size at 100 ppm. A statistically significant decrease in maternal body weight, maternal body weight gain, corrected maternal body weight change from gestation day 5-20, and corrected maternal weight occurred at the 300 ppm dose.

The results of the experiment support the conclusion that the NOAEL of the Test Article DOTC for the developmental toxicity endpoint was 10 ppm (0.8 mg/kg bw/day). The LOAEL (low observed adverse effect level) was 100 ppm (7.2 mg/kg bw/day)

The results of the experiment also support the conclusion that the NOAEL (No Observed Adverse Effect Level) and LOAEL (low observed adverse effect level) of the Test Article DOTC for the maternal and developmental toxicity endpoints are the same. Hence, DOTC is regarded as not teratogenic in the rat but is fetotoxic at a maternally toxic dose.

Supporting study:

A screening study to investigate the reproductive/developmental effects of dioctyltin dichloride was conducted in accordance with OECD test method 421. Female Wistar rats were fed diets containing 10, 100 and 300 mg/kg (ppm) of the test substance. This began two weeks prior to the mating period, and continued through mating, gestation, and up to PN 4 or shortly thereafter. Male rats were mated after a premating period of 10 weeks with female rats of the satellite groups, which were fed the same dose of test diet. 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.

Results

Paternal Toxicity:

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)

No clinical signs were observed during the premating period. During the gestation period piloerection was observed in animal A115 (GD 21 -24) of the control group and animal D161 (GD 23-24) of the 300 mg/kg group. In addition, blepharospasm was observed in animal D161 (GD 23-24). During lactation piloerection was observed in animal C157 (PN 2-4) of the 100 mg/kg group and D163 (PN 2-4) and D167 (PN 1) of the 300 mg/kg group. Blepharospasm was observed in animal D167 of the 300 mg/kg group. Animals C149 (PN 4-5) and C157 (PN 4) of the 100 mg/kg group and animal D163 (PN 4) of the 300 mg/kg group were considered to be thin. In addition animals C149 and C159 showed a pale appearance. Some animals were sparsely haired during gestation and/or lactation; this finding is normal for this strain.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)

During the premating period no significant differences in mean body weight were observed. Mean body weight change was statistically significantly reduced in the 100 and 300 mg/kg groups during the first week of the premating period. During the gestation period, mean body weight was statistically significantly reduced from GD 7-21 in the 300 mg/kg group. Body weight change was statistically significantly reduced during the entire gestation period. During the lactation period, the mean body weight was statistically significantly reduced in the 300 mg/kg group.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)

During the premating period, mean food consumption (expressed as g/animal/day and as g/kg body weight/day) of the female animals of the 100 and 300 mg/kg groups was statistically significantly decreased. During the gestation period, food consumption (g/animal/day) of the females of the 100 mg/kg group was statistically significantly decreased from GD 7-14. Mean food consumption of the 300 mg/kg group (expressed as g/animal/day) was statistically significantly decreased during the entire gestation period and as g/kg body weight/day from GD 0-14. During the lactation period food consumption of the female animals of the 300 mg/kg group was statistically significantly decreased.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)

No effects

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)

No effects

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)

Animal 115 of the control group and animals D161, D171 and D173 of the 300 mg/kg group showed only implantation sites at necropsy. The female fecundity index, female fertility index and male fertility index were comparable among the control and Dichlorodioctylstannane-treated groups. The gestation index was 86, 100, 71 and 50% in the control, 10, 100 and 300 mg/kg groups, respectively. The number of females with liveborn pups was 6, 8, 5 and 4 for the control, 10, 100 and 300 mg/kg groups, respectively. The number of females with stillborn pups amounted to 1, 1, 4 and 3 for the control, 10, 100 and 300 mg/kg groups, respectively. The number of females with all stillborn pups was 0, 0, 2 and 1 in the control, 10, 100 and 300 mg/kg groups, respectively. The live birth index was 99, 95, 53 and 60% in the control, 10, 100 and 300 mg/kg groups, respectively. Post-implantation loss was 22.3, 21.0, 49.2 and 70.0% for the control, 10, 100 and 300 mg/kg groups, respectively.

ORGAN WEIGHTS (PARENTAL ANIMALS)

Absolute and relative uterus and ovary weight were similar in all groups. The absolute and relative thymus weight was statistically significantly decreased in the 100 (62 and 67%) and 300 mg/kg (31 and 38%) groups when compared to the control group.

GROSS PATHOLOGY (PARENTAL ANIMALS)

No effects

HISTOPATHOLOGY (PARENTAL ANIMALS)

Microscopic examination revealed moderate to very severe lymphoid depletion in the thymus, which was considered related to treatment. Lymphoid depletion was characterised by a decrease in the size of the thymic lobules which can be ascribed to extensive loss of cortical en medullary small lymphocytes. Consequently, the distinction between the cortical and medullary areas was blurred. Lymphoid depletion was observed in 5/10 animals of the 10 mg/kg group and in all animals of the 100 and 300 mg/kg groups. Surprisingly, one control animal (A115) also had very severe lymphoid depletion in the thymus. However, this was most probably associated with the fact that this animal was physiologically disturbed, as was demonstrated by 12 resorptions in the uterus and an abnormal kidney (gross changes: flabby and yellow patches). Some 10 mg/kg animals showed thymic involution as a result of pregnancy/lactation. This picture was similar to the thymic pregnancy/lactation involution in control animals and was characterised by a decreased size of thymic lobules exhibiting normal architecture. This phenomenon is a common observation in pregnant or lactating animals. However, the lymphoid depletion in the 10 mg/kg animals was similar to the thymic change in the 100 and 300 mg/kg animals. Therefore, lymphoid depletion in the 10, 100 and 300 mg/kg animals was considered related to treatment with the test substance. The other histopathological changes observed are common findings in rats of this strain and age or occurred in a single animal only.

Offspring toxicity

VIABILITY (OFFSPRING)

The mean number of pups delivered per litter amounted to 11.7, 11.0, 10.3 and 8.6 or the control, 10, 100 and 300 mg/kg groups, respectively. Pup mortality on PN 1 was 1.4, 4.5, 47, and 40% in the control, 10, 100 and 300 mg/kg groups, respectively. All pups of the following animals died between PN 1-4: B137 of the 10 mg/kg group, C145 and C159 of the 100 mg/kg group and D165, D175 and D177. Pup mortality on PN 4 was 5.8, 8.3, 26 and 88 %. Viability index (PN 1 -4) was 94, 92, 74 and 12% in the control, 10, 100 and 300 mg/kg groups, respectively. The number of live pups per litter on PN 1 amounted to 11.5, 10.5, 7.6, 6.5 for the control, 10, 100 and 300 mg/kg groups, respectively and on PN 4 the number of live pups per litter amounted to 10.8, 11.0, 9.3 and 3.0 for the control, 10, 100 and 300 mg/kg groups, respectively. Both in the 100 and 300 mg/kg groups, 4 litters were entirely stillborn or lost at PN 4. No difference was observed in the sex ratio between the groups.

CLINICAL SIGNS (OFFSPRING)

On PN 1 and 4, the number of runts was statistically significantly increased in the 100 and 300 mg/kg groups. In addition the number of cold pups was increased in the 300 mg/kg group on PN 1.

BODY WEIGHT (OFFSPRING) Mean pup weight and pup weight change were similar in the 10 and 100 mg/kg groups when compared to the control group. Pup weight of the 300 mg/kg group (PN 1, 3 litters and PN 4, 1 litter) was reduced. SEXUAL MATURATION (OFFSPRING) not examined

ORGAN WEIGHTS (OFFSPRING)

not examined

GROSS PATHOLOGY (OFFSPRING)

No effects

HISTOPATHOLOGY (OFFSPRING)

not examined

Conclusion

Based on reproductive and developmental effects observed after mating of 100 and 300 mg/kg female animals with male animals, the low dose level of 10 mg Dihlorodioctylstannane/kg diet (equivalent to 0.7 mg/ kg body weight/day in males and 0.5-0.7 mg/kg body weight for females) can be considered as a NOAEL for fertility and developmental effects.
Based on the observed histological changes in the thymus (lymphoid depletion) of the 10 mg/kg female animals, 10 mg Dichlorodioctylstannane/ kg diet (equivalent to 0.5-0.7 mg/kg body weight/day) was considered to be a LOAEL for maternal toxicity.

Toxicity to reproduction: other studies

Additional information

Additional information also related to classification and labeling:

For DOTC there are three studies available relating the endpoints reproduction / development:

-         Smialowicz et al., J Toxicol Environ Health ;25,4 (1988) 403-22

-         Appel et al., TNO V3964 (OECD TG 408/421)

-         Tonk, Menke (OECD 443)

·        Tonk et al., Reproductive Toxicology 32 (2011) 341-348

·        Tonk et al., Toxicology Letters 204 (2011) 156-163

·        Menke et al., Toxicologic Pathology 40 (2012) 255-60

 

In several acute studies it was shown that toxicity to the lymphoid cells of the thymus is an acute effect (see endpoint immunotoxicity). The adverse effects in CD4-/CD8- occurs 24 h after a one time exposure, the thymus atrophy after 72 h.The adverse effect relating to the lymphoid cells of the thymus is regarded as maternal toxicity. Apple reported a dose of 0.3 mg DOT /kg bw/day for adverse effects relating to the immune system and found effects relating to pup weight at 14.8 mg DOT /kg bw/day. Tonk and Menke found only a suppressed immune system in juvenile rats. But it was shown, that this effect in juvenile rats is completely reversible after approximately 7 weeks recovery time by Smialowicz.

Justification for classification or non-classification

In the available reproductive and developmental toxicity studies conducted with the registered substance, all the noted effects were observed at maternally toxic doses only. It is generally accepted that such developmental effects are produced by a non-specific secondary consequence of general toxicity.

Therefore, the registrant classifies the registered substance as a Reproductive Toxicant Category 2 (H361) as instructed in the ECHA guidelines on the Application of the CLP Criteria and according to Regulation (EC) No 1272/2008 (CLP).