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Description of key information

In a 90 day dermal repeated dose study it has been shown that Bis(2-chloroethoxy)methane is cardiotoxic. The Lowest NOAEL for this effect is 100 mg/kg bw. Based on microscopic evidence of renal and hepatic pathology in males receiving 20 mg/kg/day, the no observed effect level (NOEL)  when administered orally to rats for three months under conditions of this study was 10 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
10 mg/kg bw/day

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
100 mg/kg bw/day

Additional information

In two range finding studies it was shown that the toxicity after oral administration of diformal is influenced by the concentration of the dosing solution and if the animals given the oral doses are fasted or unfasted. Based on the first range finding study it was concluded that 100 mg/kg of formal was lethal at concentrations of 100 mg/ml but essentially non toxic at a concentration of 10 mg/ml.

In the second range finding study the animals were dosed at concentration of 100 mg/ml.

The test substance, administered as a 100 mg/ml solution in corn oil, was initially administered to 60 Sprague-Dawley CD rats (5/sex/group) at dose levels of 20, 40, 50, 60, 80 and 100 mg/kg bw/day. Control animals (5/sex) received the vehicle at the same dose volume as administered to group VII animals (1.0 ml/kg bw/day). Because no signs of toxicity were seen after the first week, the two lower doses were raised from 20 and 40 mg/kg bw/day to 150 and 200 mg/kg bw/day, respectively, for the second week of the study.

Two additional (satellite) studies were performed to 1) clarify the effect of fasting on mortality at the 100 mg/kg dose level and 2) provide information on mortality, clinical signs and clinical laboratory values in animals receiving doses of 120 and 160 mg/kg bw/day (5/sex/dose) for up to seven days.

In the first satelite group all females in group I (fasted) died and all males in group I were moribund. All animals in group II (unfasted) survived.

The second satellite group showed results that are in line with the results found in the main group of the second range finding study.

Based on the apparent effects on blood urea nitrogen levels in females receiving doses as low as 50 mg/kg bw/day and on the elevated alkaline phosphatase level in males receiving 100 mg/kg bw/day, the NOEL for FORMAL in rats under conditions of this study was 40 mg/kg bw/day for females and 80 mg/kg bw/day for males.

In a 90 day oral repeated dose study the test substance, diluted in corn oil at a concentration of 100 mg per ml was administered to 100 Sprague-Dawley CD rats (10/sex/group) at dose levels of 10, 20, 40, 80 and 120 mg/kg/day. Cardiotoxicity was also observed causing mortality at 120 mg/kg bw.

Based on microscopic evidence of renal and hepatic pathology in males receiving 20 mg/kg/day, the no observed effect level (NOEL) for FORMAL when administered orally to rats for three months under conditions of this study was 10 mg/kg/day.

In a 90 day dermal repeated dose study it has been shown that Bis(2-chloroethoxy)methane is cardiotoxic. The Lowest NOAEL for this effect is 100 mg/kg bw. CEM cardiotoxicity is characterized by cytoplasmic vacuolation of myocytes, necrosis, and inflammation. The mechanism of cardiotoxicty has been investigated. It has been shown that CEM damages the mitochondria. The substance is metabolized to thiodiglycolic acid. Fatty acids are a major source of energy in the heart and because thiodiglycolic acid interferes with fatty acid metabolism, CEM mitochondria damage may be due in part to depletion of nutrients. Since heart tissue contains more mitochondria than other tissues due to a high energy demand the heart tissue is more susceptable to damage by CEM.

In a 16 day dermal study it has been shown that after the initial damage induced by CEM or its metabolite, thiodiglycolic acid, protective mechanisms within the heart are initiated, enabling it to cope with the continued exposure to the toxicant while eliminating some damaged myofibers. At day 16 if the study damage seen in the earlier phase of the study was repaired. However this protective mechanism cannot cope with longterm exposure to CEM since at the end of the 90 day study cardiotoxicity is observed.

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

Repeated dose toxicity: dermal - systemic effects (target organ) cardiovascular / hematological: heart

Justification for classification or non-classification

bis(2-chloroethoxy) methaneis classified STOT cat. 2 based on the following effects:

In a 90 day dermal repeated dose study it has been shown that Bis(2-chloroethoxy) methane is cardiotoxic. The Lowest NOAEL for this effect is 100 mg/kg bw.

Based on microscopic evidence of renal and hepatic pathology in males receiving 20 mg/kg/day, the no observed effect level (NOEL) when administered orally to rats for three months under conditions of this study was 10 mg/kg/day.

 

The LOAEL for degeneration of the olfactory epithelium and inflammation and ulcers of the forestomach in rats is 75 mg/kg bw/day.In the report (NTP TR 536, 2011) these effects are not explained. It seems unlikely that these effects have occurred via the dermal application of the test substance. However in the report no specific details on the application of the test substance on the skin can be found. If the study was performed in line with the general NTP protocol this means that the treatment was left area uncovered. In toxicokinetic studies it has been shown thatup to 50% of the total dose volatilized from the skin of some animals during 24-hour experiments (Black 2007).It therefore could the animals have ingested and/or inhaled the test substance leading to these effects.

                                                                                                                   

It can be concluded thatbis(2-chloroethoxy) methanemay cause specific target organ toxicity after repeated exposure. Based on the levels at which the effects occur bis(2-chloroethoxy) methaneis classified STOT cat. 2.