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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Compilation of available data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Compilation and estimations.
Cross-reference
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
other: compilation and estimations
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Objective of study:
other: Compilation of available data and estimations based on phys.-chem. properties.
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
adipic acid dihydrazide
IUPAC Name:
adipic acid dihydrazide

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No systemic (or local) effects were detected in the acute oral and the acute inhalation studies. No indications on a possible absorption of the test substance in the gastrointestinal tract or the respiratory tract, and no indications on a possible distribution in the body were therefore obtained. Repeated dose toxicity studies are not yet available. Based on the Section R.7.12.2.1 of the 'Guidance on information requirements and chemical safety assessment' some of the relevant physical-chemical properties for an oral absorption are:- A relatively low molecular mass of 174 for adipic acid dihydrazide (ADH). Generally the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption.- A high water solubility of 102 g/L for ADH. Water-soluble substances will readily dissolve into the gastrointestinal fluids. Absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. However, if the molecular weight is low (less than 200) the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.- A low n-octanol/water partition coefficient of log Pow = -2.7 for ADH. Moderate log P values (between -1 and 4) are favourable for absorption by passive diffusion.- ADH is in the non-ionised state between pH ca. 4 and 12, which favours an absorption through biological membranes.These data, especially the low log Pow and the high water solubility, do not favour a crossing of biological membranes. It is therefore not expected that an oral absorption will occur to a relevant degree. This is in agreement with no observed toxic effects in the acute oral toxicity studies.For inhalation the relevant parameters for absorption are not very different to those for oral absorption:- n-octanol/water partition coefficient:Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion.- Water solubility: Low water solubility, like small particle size enhances penetration to the lower respiratory tract. Vapours of very hydrophilic substances may be retained within the mucus. For absorption of deposited material similar criteria as for GI absorption apply. Again, much the same as for the oral case, the physico-chemical properties of ADH do not favour a crossing of biological membranes in the case of inhalation.For dermal absorption an even lesser absorption is predicted compared to the oral or inhalation route, based on the following criteria:- Molecular Weight:Less than 100 favours dermal uptake. - n-octanol/water partition coefficient:For substances with log P values <0, poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Values <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low.- Water Solubility:The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Between 1-100 mg/l absorption is anticipated to be low to moderate and between 100-10000 mg/l moderate to high. However, if water solubility is above 10000 mg/l and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low.
Details on distribution in tissues:
No hint is obtained from the available data that a distribution occurs, in case adipic acid dihydrazide should be absorbed.
Details on excretion:
No relevant data are available, which provide evidence on the route of excretion.

Any other information on results incl. tables

The toxicokinetic behaviour of adipic acid dihydrazide was estimated from available data.

Accumulation: No accumulation is expected, based on the low log Pow.

Metabolism: No relevant differences in genotoxicity was detected with and without the addition of a metabolising system. Therefore no indication of the importance of the metabolism of the test substance was obtained from the mutagenicity studies.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:

No evidence of an oral or inhalation absorption was obtained from the available toxicity tests. Only low oral and inhalation absorptions are predicted from the phys.-chem. properties of adipic acid dihydrazide.

The dermal absorption is predicted to be even lower compared to the oral or inhalation route.

No evidence of a distribution or of the way of excretion was obtained, possibly also based on the predicted low absorption.

No evidence of metabolisation was obtained from the mutagenicity tests with and without metabolising systems.

No accumulation is expected, based on the low log Pow.

No relevant data are available, which provide evidence on the route of excretion.

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