N'-(1,3-dimethylbutylidene)-3-hydroxy-2-naphthohydrazide

Endpoint summary

Description of key information

Toxicokinetic Assessment by a certified toxicologist.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The acute oral and dermal toxicity of the test substance is low, with the LD50 being higher than 2000 mg/kg body in both cases. The 28-day toxicity study also revealed that the substance has a low toxicity, with a NOAEL of 50
mg/kg/day. Therefore, an extensive toxicokinetic assessment is considered of limited value. Below, an assessment of the anticipated toxicokinetic behaviour of BMH is given.

The water solubility of BMH is relatively low (4.37 mg/l), and therefore considered a rate-limiting factor for the absorption of the compound from the gastro-intestinal tract. Generally, the bioavailability of BMH from the gastro-intestinal tract is anticipated to be low. However, in the presence of food or bile salts, the bioavailability of BMH may well be enhanced. The compound will be positively charged on the amide group throughout the gastro-intestinal tract. Since the compound needs to pass the lipid membranes, the ionization of the compound will impair its uptake.

For risk assessment purposes oral absorption of BMH is set at 50%.

After absorption of BMH, several metabolic steps may take place. The bond between the two nitrogens may be split, forming the corresponding cyano compound and the free amide group, which can than be conjugated, most probably by acetylation or glucuronidation. Hydroxylation of the unsaturated ring in the molecule by the P450 enzyme system is anticipated. The hydroxy-metabolites will be conjugated and excreted via urine or bile. This P450-mediated enzymatic hydroxylation is a known pathway leading to induction of liver enzymes and liver hypertrophy as was also observed in the 28-day toxicity study. However, this finding should be considered an adaptive response to the presence of a xenobiotic, rather than a toxic response. The changes in plasma concentrations of ALAT and ASAT are a well-known phenomenon related to the liver hypertrophy.

Because of the low water solubility, the unchanged compound will hardly be excreted via the kidneys.

Distribution of BMH will be limited to total body water, because of the relatively low log P_o/w. Therefore, a volume of distribution of about 0.7l/kg is expected.Uptake via inhalation may well take place, because of the particle size distribution
(25% < 4.5 µm). For risk assessment purposes inhalation absorption is set at 100%.

Since the bioavailability of dermally applied compounds can be assumed to be zero for substances with a log P_o/wbelow -1 and over 5 or a relative molecular mass over 700, it is to be expected that BMH will be absorbed to some extent through the skin. For risk assessment purposes dermal absorption is set at 50%.

Based on the expected kinetic behaviour in the body, as described above, BMH will not be extensively absorbed form the gastro-intestinal tract and when absorbed, it will be extensively metabolised. Therefore, accumulation in the body during prolonged exposure is not anticipated.