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Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: Assessment based upon available information.
Adequacy of study:
key study
Study period:
May 2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Information selected for the toxicokinetic assessment is primarily study data. Studies were conducted inaccordance with recognised testing guidelines.

Data source

Reference
Reference Type:
other: Assessment
Title:
Unnamed
Year:
2018

Materials and methods

Results and discussion

Any other information on results incl. tables

The physical state of the substance,Molybdenum trioxide, reaction products with bis[O,O-bis(2-ethylhexyl)] hydrogen dithiophosphate,is blue-green viscous, opaque liquid and therefore, potential inhalation of the substance is negligible.

 

The substanceis an unknown or variable composition, complex reaction products and biological materials (UVCB substance) containing molybdenum and is essentially insoluble in water.  QSAR calculations provide water solubility values below10-6mg/L.  The partition coefficient (Log Pow)of the substance was estimated to be18.94 using EPI SuiteTMsoftware.  The UVCB substance includes a fraction that does not contain molybdenum.  The water solubility and Log Powofthe fraction without molybdenumare5 x 10-5mg/mL at 20 °C and 5.84, respectively.  The typical molecular mass of the substance (C32H68Mo2P2O6S6) is 995.11 Daltons.  These data indicate that the substance is relatively large (> 500 Daltons), has very low water solubility (< 0.1 mg/L), and is a highly lipophilic (Log Pow > 5.6) molecule, and thus the substance is not bioavailable via the oral route in accordance with Lipinski's rule of five.  Although the substance was not tolerated at 10 and 21.5 ml/kg in acute oral toxicity study in rats with oral LD50of 6.81 ml/kg body weight, equivalent to 7709 mg/kg (relative density of 1.132), the observations were largely local gastrointestinal effects due to overload of highly hydrophobic substance in gastrointestinal tract, diarrhea with the test substance in stools, and corresponding poor clinical conditions. Lower thymus weight and higher liver weight were noted at 1000 mg/kg/day, the highest dose tested, in a 6-day repeated dose oral range-finding toxicity study in rats. Systemic effects were also notedin the combined repeated dose oral toxicity study with the reproductive/developmental toxicity screening test in rats, which are hepatocellular hypertrophy, thyroid follicular cell hypertrophy and mucosal hyperplasia with erosion or ulceration in the nonglandular stomach.  The thyroid follicular cell hypertrophy was likely secondary to the liver effect and the mucosal hyperplasia may be secondary to direct irritation of the mucosa.  However, no information is currently available on possible degradation products produced in the gastrointestinal tract.

 

The very low water solubility, high lipophilicity, and relatively large molecular mass of the substance also indicate that it is not expected to be absorbed via the dermal route.  The acute dermal LD50in rabbits was 10 ml/kg body weight, equivalent to 11320 mg/kg. 

 

Additionally, the ready biodegradability test of the substance showed that it was less than 11% after 28 days and was not considered readily biodegradable.  The measured test concentrations of the substance in aquatic medium were low, approximately 1 mg/L in the acute toxicity tests in aquatic organisms (algae, daphnia, and fish).  The substance is therefore expected to have low potential for bioaccumulation in aquatic organisms although the substance is persistent and its Log Pow exceeds 5.

 

In conclusion, based upon the available data, bioavailability ofthemolybdenum-containingsubstance, Molybdenum trioxide, reaction products with bis[O,O-bis(2-ethylhexyl)] hydrogen dithiophosphate,is expected to be limited and the systemic effects of the UVCB substance were likely due to induction of microsomal xenobiotic-metabolizing enzymes.

Applicant's summary and conclusion

Conclusions:
In conclusion, based upon the available data, bioavailability ofthemolybdenum-containingsubstance, Molybdenum trioxide, reaction products with bis[O,O-bis(2-ethylhexyl)] hydrogen dithiophosphate,is expected to be limited and the systemic effects of the UVCB substance were likely due to induction of microsomal xenobiotic-metabolizing enzymes.

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