Registration Dossier

Administrative data

Description of key information

The key study for acute oral toxicity in rat reports an LD50 value of 11685 mg/kg in rat (Mellon 1963; rel 2). Clinical signs of toxicity were sluggishness and unsteady gait post-dosing. At necropsy, gross examination revealed congested lungs, mottled livers with prominent acini and some haemorrhage and congestion of the gastrointestinal tract. The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.

The key acute inhalation study reports an LC50 value of >42.1 mg/L (DCC 2006; rel 1). Clinical signs were urine staining, discoloured urine, fecal staining, head and muzzle soiling. Necropsy findings included urinary bladder calculi and kidney foci in both sexes, an enlarged kidney in one male, and abcessed prostrate glands in two males. The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP.

The key acute dermal LD50 is >9500 mg/kg (Mellon 1963; rel 2). There were no clinical signs of toxicity and no abnormalities were detected at necropsy. The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
11 685 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
42.1 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
9 500 mg/kg bw

Additional information

The acute oral LD50 of 12.3 ml/kg (equivalent to 11685 mg/kg) was determined for male rats in a reliable study conducted according to generally accepted scientific principles, but no in compliance with GLP (Mellon Institute, 1963). The animals were sluggish and unsteady in gait soon after dosing. At autopsy, gross examination revealed congested lungs, mottled livers with prominent acini and some haemorrhage and congestion of the gastrointestinal tract.

A supporting study reporting an LD50 value of 7000mg/kg bw in mouse was also available (Societe des Usines Chimiques Rhone-Poulenc, 1972). The study was conducted according to a protocol equivalent to current guideline, but not in compliance with GLP. At lethal doses (4, 6, 9 and 13.5 g/kg bw) the mice were unreactive, with loss of reflexes and dyspnea, and died within the first 15 minutes post administration. At the non lethal dose of 2.6 g/kg, the symptoms were similar but alleviated within 2 hours.

A second supporting study was also available for acute oral toxicity, reporting an acute oral LD50 value of >9500 mg/kg bw in rat which was determined in a reliable study conducted according to an appropriate test protocol, but not in compliance with GLP (Hazelton Labs, 1966). There were no deaths at any dosage level tested. Signs of toxicity were observed at 10 ml/kg body weight and included depression, labored respiration, ataxia, and excessive urination.  These signs had completely resolved by day 4 post-dosing. There were no findings at necropsy.

The study by Mellon Institute (1963) was chosen as the key study for acute oral toxicity instead of the more recent report by Societe des Usines Chimiques Rhone-Poulenc

(1972) because the newer report used mouse instead of rat as their test species. The current guideline recommends the use of rat for acute oral toxicity studies. Both studies were reliability 2 and equivalent to current guideline. The choice of key study therefore does not affect classification, as the LD50 values of all studies are well above the cut off point for classification. For the acute dermal and inhalation toxicity, the most recent and high reliability sources available were selected as key. The key study for acute inhalation determined an LC50 value of > 7605 ppm (42.1 mg/L) for rats in a reliable study conducted according to current guideline, and in compliance with GLP (Dow Corning Corporation, 2006). No mortalities were reported. Clinical signs included urine staining, discoloured urine, fecal staining, head and muzzle soiling, with all females returning to normal by post exposure day 4. Four of the 5 males were reported normal by post exposure day 5, and all males were normal by post exposure day 10. Body weights and body weight gains were within normal limits over the duration of the study for all females. Two of the five males demonstrated weight loss during the first week post-exposure, with a return to normal weight gain during the second week. Necropsy findings included urinary bladder calculi and kidney foci in both sexes, an enlarged kidney in one male, and abcessed prostrate glands in two males. Urinary tract and prostate disease was attributed to urolithiasis of uncertain primary aetiology; a direct role for the test article in the formation of urinary calculi could neither be confirmed nor denied as a result of this study. A supporting study was also available for acute inhalation, reporting an LC50 value of >26,000 ppm in rat, which was determined in a reliable study conducted according to an appropriate test protocol but not in compliance with GLP (Mellon Institute 1963). In this study, one group of 6 rats (sex not specified) was exposed to concentrated vapor generated at 22,000 to 27,000 ppm with the following results; 8 hours killed 5 of 6 animals, 4 hours killed 3 of 6 animals and 2 hours killed 1 of 6 animals. All animals appeared to be anaesthetized when removed from the inhalation chambers and most deaths occurred within the ensuing 24 hour period. However, several animals had died before termination of the inhalation period. At autopsy, the victims had diffuse hemorrhage of the lungs. Most of the survivors gained weight during the subsequent 2 week observation period and had no gross pathology evident at sacrifice on the 14th day. A second group of 6 rats (sex not specified) was exposed to metered concentrations for 4 hours, where 26,000 ppm killed 0 of 6 animals. Metered concentration at either 26000ppm or 24000 ppm caused no mortality after a 4 -hour inhalation period. The animals appeared to be anesthetized when removed from the chambers but most gained weight (at a normal rate) during the ensuing 2 week observation period. Gross pathology was minimal at sacrifice on the 14th day. A third inhalation toxicity study is available (Dow Corning Corpopration, 1982) which has been deemed not reliable. The key study for acute dermal toxicity reports an LD50 value of >10 ml/kg (equivalent to >9500 mg/kg) for rabbits in a reliable study conducted according to an appropriate protocol, but not in compliance with GLP (Mellon Institure, 1963). There were no mortalities. Little skin irritation was observed but some desquamation was found after 14 days. Necropsy findings were not reported.

Justification for classification or non-classification

Based on the available data trimethoxy(methyl)silane does not require classification for acute toxicity

according to Regulation (EC) No 1272/2008.