cis-2-methyl-4-propyl-1,3-oxathiane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Oral: NOAEL (rat – reproductive/developmental toxicity): 300 mg/kg bw/day ; male/female, OECD TG 422, 2018

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study is GLP compliant and of a high quality (Klimisch 1); The available information as a whole meets the tonnage driven information requirements of REACH.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive/developmental screening study:

Key study: Oral: OECD TG 422, 2018 : The study was performed according the requirements of OECD TG 422 guideline under GLP conditions. Following a previously conducted 14-day sighting study, the systemic toxic potential of the test item in rats, including a screen for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints was conducted by oral gavage administration for at least five weeks with additional subgroups used to assess reversibility, persistence or delayed effects for 14 days post treatment. Three toxicology treatment groups with a control was conducted, each comprising five or ten male and five female rats which received oral gavage test item at doses of 0 (Control), 150, 300 or 600 mg/kg bw/day test item formulated in corn oil vehicle. Ten males were treated in the 150 and 300 mg/kg bw/day doses for pairing purposes with the reproductive phase females. Recovery phase groups included five males and females treated at 0 (Control) and 600 mg/kg bw/day. Reproductive phase females, ten per group (10) were treated at doses of 0 (Control), 150, 300 or 600 mg/kg bw/day. Toxicity phase males were treated for two weeks before pairing up to necropsy after six weeks. Toxicity phase females were treated for six weeks. Recovery phase males were treated for two weeks before pairing up to necropsy after six weeks followed by a 2-week recovery period. Recovery phase females were treated for six weeks followed by a 2-week recovery period. Reproductive phase females were treated for two weeks before pairing, throughout pairing, gestation and until Day 12 of lactation. The offspring received no direct administration of the test item; any exposure was in utero or via the milk. Selected F1 offspring were sampled and killed on Day 4 or Day 13 of age for analysis of blood thyroid hormone levels. The remaining F1 offspring were killed on Day 13 of age. A similarly constituted Control group was assigned to each phase, and received, the vehicle: corn oil at the same dose volume as treated groups. There were no treatment-related premature mortalities among adult animals during the course of the study. There was no adverse effect on clinical condition, sensory reactivity and grip strength, motor activity, ophthalmic changes and/or pre-coital interval, mating performance gestation length on the adult animals. Body weight gain was variable throughout the treatment period in males and non-mated females at 600 mg/kg bw/day. Overall gains were similar to control in both. Following cessation of treatment, females showed body weight loss, compared with body weight stasis in the Control. Body weight gain was variable during both gestation and lactation, but again overall gains in treated animals were similar to Control. Food consumption was similarly affected by treatment in all study phases, but was noticeably low during Days 4-10 of lactation. Water consumption was consistently high in males and non mated females at 300 or 600 mg/kg bw/day, during gestation at 600 mg/kg bw/day and lactation at 300 or 600 mg/kg bw/day. There were no toxicologically significant changes in haematology, blood chemistry and plasma parameters following five weeks of treatment in males and unmated females and on Day 13 of lactation except for minor elevated plasma cholesterol concentration in non-mated females and plasma urea concentration in males and minor change in creatinine concentrations in males/females receiving 600 mg/kg bw/day. These changes were attributed to changes in microscopic changes observed in male kidney and/or male/female liver. At the end of treatment liver weight and kidney weight were high in males/females at 300 and 600 mg/kg bw/day and 600 mg/kg bw/day, respectively. Urinalysis indicated a high urinary volume as a result of the higher water intake in males/females at 600 mg/kg bw/day. This may be attributed to higher plasma and urinary protein concentrations. Macroscopic examination performed after 5 weeks of treatment or 2 weeks recovery or reproductive females after day 13 lactation revealed no test item treatment related lesions. Microscopic examination revealed a dose-dependent hepatocellular periportal vacuolation in males and females treated at 150, 300 or 600 mg/kg/day that correlated at 600 mg/kg/day with increased storage of lipids within the cytoplasm of the hepatocytes and minor elevation of plasma cholesterol and elevated urea concentration in females or males in Week 5. This metabolic alteration may also be reflected by the presence of an increase in urinary ketones in all males at 600 mg/kg/day. The presence of periportal vacuolation correlated with the statistically significant increase in liver weights in males and females at 600 mg/kg/day. Examination of the liver in males and females at 600 mg/kg/day, following two weeks without treatment indicated partial recovery of the hepatocellular periportal vacuolation and normalisation of plasma cholesterol and urea concentrations. This treatment related change was not accompanied by inflammation or necrosis of the hepatocytes, therefore changes were considered unlikely to be adverse. A dose-dependent accumulation of hyaline droplets and basophilic tubules was evident in males receiving 300 or 600 mg/kg/day. Hyaline droplets are composed of poorly catabolized α2µ globulin probably binding to the test item and accumulating within the phagolysosomes of the renal tubular cells. The presence of increased α2µ globulin in males was confirmed immunohistochemically. Examination of the kidneys from Control and males previously treated at 600 mg/kg/day revealed resolution of the hyaline droplets however basophilic tubules persisted in the previously treated males. Basophilic tubules were only present focally and were consistent with background levels of this finding. Only partial recovery was evident following two weeks without treatment. Relevance for toxicity in humans through this α2µ globulin mechanism is considered unlikely. At 600 mg/kg/day, two females were not pregnant. Three litters indicated mortality by Day 2, that was attributed to the reduced secretory activity of the mammary gland in the adults. Two females exhibited irregularities of the estrous cycle before mating. Of the three females with total litter loss, one showed extended estrus, and a second had an irregular cycle. The offspring from adults treated at 600 mg/kg/day were small on Day 1 of age and subsequent growth, especially during Days 4-7, to Day 13, correlated with clinical signs of poor maternal care. There was some evidence of poor maternal care at 300 mg/kg/day. Ano genital distance in the offspring was unaffected by maternal treatment. Male offspring did not develop nipples. T4 (thyroxine) levels were statistically low in males at 300 or 600 mg/kg bw/day but were comparable with control following two weeks without treatment. This change was reversible and with no pathological correlations was considered non-adverse.

 

Conclusion:

Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was considered to be 600 mg/kg bw/day. The α2µ globulin mediated kidney changes were deemed adverse, in the rat. However, toxicity to humans by this mechanism is considered unlikely. For reproductive / developmental toxicity for males and females a precautionary NOAEL is set at 300 mg/kg bw/day due to low pregnancy rate and high litter loss reported at 600 mg/kg bw/day. Applicant assessment indicates: that whilst the effects on lipid metabolism where not adverse in adults since they were deemed reversible, they may have led to adverse outcome in offspring via reduced secretory activity in female adults and consequential poor maternal care. On this basis a precautionary NOAEL has been adopted.

Effects on developmental toxicity

Description of key information

Oral: NOAEL (rat – reproductive/developmental toxicity): 300 mg/kg bw/day ; male/female, OECD TG 422, 2018

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study is GLP compliant and of a high quality (Klimisch 1); The available information as a whole meets the tonnage driven information requirements of REACH.

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

Reproductive/developmental screening study:

Key study: Oral: OECD TG 422, 2018 :The study was performed according the requirements of OECD TG 422 guideline under GLP conditions. Following a previously conducted 14-day sighting study, the systemic toxic potential of the test item in rats, including a screen for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints was conducted by oral gavage administration for at least five weeks with additional subgroups used to assess reversibility, persistence or delayed effects for 14 days post treatment. Three toxicology treatment groups with a control was conducted, each comprising five or ten male and five female rats which received oral gavage test item at doses of 0 (Control), 150, 300 or 600 mg/kg bw/day test item formulated in corn oil vehicle. Ten males were treated in the 150 and 300 mg/kg bw/day doses for pairing purposes with the reproductive phase females. Recovery phase groups included five males and females treated at 0 (Control) and 600 mg/kg bw/day. Reproductive phase females, ten per group (10) were treated at doses of 0 (Control), 150, 300 or 600 mg/kg bw/day. Toxicity phase males were treated for two weeks before pairing up to necropsy after six weeks. Toxicity phase females were treated for six weeks. Recovery phase males were treated for two weeks before pairing up to necropsy after six weeks followed by a 2-week recovery period. Recovery phase females were treated for six weeks followed by a 2-week recovery period. Reproductive phase females were treated for two weeks before pairing, throughout pairing, gestation and until Day 12 of lactation. The offspring received no direct administration of the test item; any exposure was in utero or via the milk. Selected F1 offspring were sampled and killed on Day 4 or Day 13 of age for analysis of blood thyroid hormone levels. The remaining F1 offspring were killed on Day 13 of age. A similarly constituted Control group was assigned to each phase, and received, the vehicle: corn oil at the same dose volume as treated groups. There were no treatment-related premature mortalities among adult animals during the course of the study. There was no adverse effect on clinical condition, sensory reactivity and grip strength, motor activity, ophthalmic changes and/or pre-coital interval, mating performance gestation length on the adult animals. Body weight gain was variable throughout the treatment period in males and non-mated females at 600 mg/kg bw/day. Overall gains were similar to control in both. Following cessation of treatment, females showed body weight loss, compared with body weight stasis in the Control. Body weight gain was variable during both gestation and lactation, but again overall gains in treated animals were similar to Control. Food consumption was similarly affected by treatment in all study phases, but was noticeably low during Days 4-10 of lactation. Water consumption was consistently high in males and non mated females at 300 or 600 mg/kg bw/day, during gestation at 600 mg/kg bw/day and lactation at 300 or 600 mg/kg bw/day. There were no toxicologically significant changes in haematology, blood chemistry and plasma parameters following five weeks of treatment in males and unmated females and on Day 13 of lactation except for minor elevated plasma cholesterol concentration in non-mated females and plasma urea concentration in males and minor change in creatinine concentrations in males/females receiving 600 mg/kg bw/day. These changes were attributed to changes in microscopic changes observed in male kidney and/or male/female liver. At the end of treatment liver weight and kidney weight were high in males/females at 300 and 600 mg/kg bw/day and 600 mg/kg bw/day, respectively. Urinalysis indicated a high urinary volume as a result of the higher water intake in males/females at 600 mg/kg bw/day. This may be attributed to higher plasma and urinary protein concentrations. Macroscopic examination performed after 5 weeks of treatment or 2 weeks recovery or reproductive females after day 13 lactation revealed no test item treatment related lesions. Microscopic examination revealed a dose-dependent hepatocellular periportal vacuolation in males and females treated at 150, 300 or 600 mg/kg/day that correlated at 600 mg/kg/day with increased storage of lipids within the cytoplasm of the hepatocytes and minor elevation of plasma cholesterol and elevated urea concentration in females or males in Week 5. This metabolic alteration may also be reflected by the presence of an increase in urinary ketones in all males at 600 mg/kg/day. The presence of periportal vacuolation correlated with the statistically significant increase in liver weights in males and females at 600 mg/kg/day. Examination of the liver in males and females at 600 mg/kg/day, following two weeks without treatment indicated partial recovery of the hepatocellular periportal vacuolation and normalisation of plasma cholesterol and urea concentrations. This treatment related change was not accompanied by inflammation or necrosis of the hepatocytes, therefore changes were considered unlikely to be adverse. A dose-dependent accumulation of hyaline droplets and basophilic tubules was evident in males receiving 300 or 600 mg/kg/day. Hyaline droplets are composed of poorly catabolized α2µ globulin probably binding to the test item and accumulating within the phagolysosomes of the renal tubular cells. The presence of increased α2µ globulin in males was confirmed immunohistochemically. Examination of the kidneys from Control and males previously treated at 600 mg/kg/day revealed resolution of the hyaline droplets however basophilic tubules persisted in the previously treated males. Basophilic tubules were only present focally and were consistent with background levels of this finding. Only partial recovery was evident following two weeks without treatment. Relevance for toxicity in humans through this α2µ globulin mechanism is considered unlikely. At 600 mg/kg/day, two females were not pregnant. Three litters indicated mortality by Day 2, that was attributed to the reduced secretory activity of the mammary gland in the adults. Two females exhibited irregularities of the estrous cycle before mating. Of the three females with total litter loss, one showed extended estrus, and a second had an irregular cycle. The offspring from adults treated at 600 mg/kg/day were small on Day 1 of age and subsequent growth, especially during Days 4-7, to Day 13, correlated with clinical signs of poor maternal care. There was some evidence of poor maternal care at 300 mg/kg/day. Ano genital distance in the offspring was unaffected by maternal treatment. Male offspring did not develop nipples. T4 (thyroxine) levels were statistically low in males at 300 or 600 mg/kg bw/day but were comparable with control following two weeks without treatment. This change was reversible and with no pathological correlations was considered non-adverse.

 

Conclusion:

Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was considered to be 600 mg/kg bw/day. The α2µ globulin mediated kidney changes were deemed adverse, in the rat. However, toxicity to humans by this mechanism is considered unlikely. For reproductive / developmental toxicity for males and females a precautionary NOAEL is set at 300 mg/kg bw/day due to low pregnancy rate and high litter loss reported at 600 mg/kg bw/day. Applicant assessment indicates: that whilst the effects on lipid metabolism where not adverse in adults since they were deemed reversible, they may have led to adverse outcome in offspring via reduced secretory activity in female adults and consequential poor maternal care. On this basis a precautionary NOAEL has been adopted.

Justification for classification or non-classification

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for reproductive/developmental toxicity.

 

References:

1. ECHA Guidance on Application on the CLP Criteria, (v5.0, July 2017)