2-Propenoic acid, 2-methyl-, tris(1-methylethyl)silyl ester

Endpoint summary

Description of key information

Repeated dose toxicity summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

In the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (Kubaszky, 2011), TIS-M was administered daily 7 days per week by oral gavage to Wistar (CRL:(WI)BR) rats at 3 dose levels, 50, 250 and 1000 mg/kg bw/day (12 males and 12 females per dose group). A control group (12 males and 12 females) received the vehicle only (dried sunflower oil). Males were dosed for 28 days and females were dosed for 14 days pre-mating, for up to 14 days mating period, through gestation and up to and including the day before necropsy (at least 4 days post-partum dosing). Females showing no-evidence of copulation were sacrificed 24 to 26 days after the last day of the mating period.

 

There were no clinical signs or mortality considered related to TIS-M administration in animals dosed at 50 mg/kg bw/day or at 250 mg/kg bw/day. One male dosed at 1000 mg/kg was euthanized pre-terminally in moribund condition after treatment on Day 8 after displaying clinical signs including activity decreased, hunched back position, piloerection, lack of coordination, emaciation, vocalization and/or difficult respiration. In addition, activity decreased and/or hunched back position were noted for up to 17 days in 2 further males dosed at 1000 mg/kg bw/day. One female dosed at 1000 mg/kg bw/day was found dead on gestation day 22 (treatment Day 38); activity moderately decreased, piloerection and hunched back position were observed one day before death. Similar clinical signs were noted in a further female on Days 39 to 41; the animal recovered and underwent scheduled necropsy on Day 42.

 

Macroscopic examination of the euthanized male (dosed at 1000 mg/kg bw/day) showed diffuse, dark/red discoloration in all lobes of the lungs and bilateral, multifocal, pale discoloration in the kidneys, however, there were no findings from the microscopic examination. A specific cause of death was not determined for the female dosed at 1000 mg/kg bw/day found dead on Day 38; there were no macroscopic findings in this female however, microscopic examination showed minimal, perilobular, hepatocellular vacuolation in all lobes of the liver. Minimal/mild centrolobular hepatocellular vacuolation potentially related to TIS-M was noted in all lobes of the liver in the 5/11 surviving female animals dosed at 1000 mg/kg bw/day with no similar findings noted in the male animals, or any findings in the organs examined of animals dosed at 50 and 250 mg/kg bw/day. Liver enlargement and pale mottling of the liver, potentially associated with TIS-M and correlated with the microscopic findings were noted in 3/11 surviving females dosed at 1000 mg/kg bw/day. Therefore, in total, there were 6/12 females with liver findings (all dosed at 1000 mg/kg bw/day).  

 

Animals in the 1000 and 250 mg/kg bw/day dose groups had statistically significant lower than control mean body weight and mean body weight gain values. At 1000 mg/kg bw/day, both male and female animals had statistically significant lower mean food consumption at most of the timepoints evaluated, which correlated with the body weight values. Statistically significant higher absolute and/or relative liver and/or kidney weights were observed at 250 and/or 1000 mg/kg bw/day, with an apparent dose response and considered related to TIS-M administration. These changes were considered to be correlated with the hepatic microscopic finding (noted in 6/12 females dosed at 1000 mg/kg bw/day only). An unusual clinical chemistry profile possibly associated with TIS-M was noted in one male dosed at 1000 mg/kg bw/day, which correlated with increases in the absolute and relative liver weight within this group and compared to the control animals, although no microscopic findings were recorded in this animal.

 

Based on the associated adverse effects including the body weight, food consumption, clinical pathology, organ weights and histopathology findings, the NOAEL for TIS-M in the parental generation for systemic toxicity was considered to be 50 mg/kg bw/day. 

The following information is taken into account for any hazard / risk assessment:

Assessment of repeated dose exposure by oral route is discussed above.

Value used for CSA (route: oral):

NOAEL: 50 mg/kg bw/day (subacute; rat)

Target organ: liver

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

The above study has both been ranked reliability 1 according to the Klimisch et al system. This ranking was deemed appropriate because the study was conducted to GLP an in compliance with agreed protocols. Sufficient dose ranges and numbers are detailed; hence it is appropriate for use based on reliability and animal welfare grounds. In this study, the histopathological changes in the liver (minimal/mild centrolobular hepatocellular vacuolation)occurred at the highest dose level (1000 mg/kg bw/day). At the mid dose level (250 mg/kg bw/day), increased liver and kidney weights and decreased body weights were seen, however, there were no adverse histopathological changes considered related to TIS-M at this dose level therefore no classification is proposed.

The above results triggered no classification under the Dangerous Substance Directive (67/548/EEC) and the CLP Regulation (EC No 1272/2008).