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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was performed to provide preliminary data on the rate and extent of absorption and excretion of radioactivity after oral, intravenous or dermal administration of the potassium, copper or aluminium salt of 14C-N-Cyclohexyl-hydroxi-diazeniumoxide (14C-HDO; 14C-K-HDO; 14C-Cu-HDO; 14C-AL-HDO) to male rats. The test material was administered in aqueous solution, suspension or technical preparation (Wolmanit CX 50). In order to gain further information on the routes of excretion, the biliary excretion was checked using bile duct cannulated rats and the exhalation of 14C CO2 was checked in a closed chamber system.
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Cyclohexylhydroxydiazene 1-oxide, potassium salt
EC Number:
613-953-8
Cas Number:
66603-10-9
Molecular formula:
C6H11KN2O2
IUPAC Name:
Cyclohexylhydroxydiazene 1-oxide, potassium salt
Test material form:
solid: particulate/powder
Details on test material:
Test item: (N-Cyclohexyl-diazeniumdioxy)-potassium
IUPAC name: Cyclohexylhydroxydiazene 1-oxide, potassium salt
Chemical name: Cyclohexylhydroxydiazene 1-oxide, potassium salt; synonyma: (N-Cyclohexyl-diazeniumdioxy)-potassium, K-HDO, K-NCH, Xyligen K powder, Xyligen K
Molecular formula: C6 H11 K N2 O2
Molecular mass: 182.27
Specific details on test material used for the study:
Potassium salt: K-HDO

14C labelled K-HDO:
the cyclohexyl group contains the 14C-label
Lot/Batch number: 266/3
Radiochemical purity: > 99%
Origin: Synthesis: Isotope laboratory of BASF
Aggregation state: solid; provided in aqueous solution
Stability in vehicle: stable in aqueous solution for at least 28 days
Storage: -4°C in the dark

Un-labelled Material:
To be used for: dilution of labelled material or for certain experiments
Note: the stability of the un-labelled materials has been proven by reanalysis.
Origin: Synthesis at BASF
Batch/Lot No.: Reu E 7350
Substance code: 88/744
Purity: 92 %
Aggregation state: solid
All other data: same as labelled material

Copper salt: Cu-HDO
Origin: Synthesis at BASF
Batch/Lot No.: Reu E 7339
Substance code: 88/124
Purity: 99.6%
Aggregation state: solid
Storage: 4°C in the dark
labelling of Cu-HDO by conversion of the labelled K-HDO


Aluminium salt: AL-HDO
Origin: Synthesis at BASF
Batch/Lot No.: Reu E 7353
Substance code: 88/760
Purity: 99%
Aggregation state: solid
Stability in solution: stable in organic solvents
Storage: 4°C in the dark
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Animals: Wistar rats
Strain: Chbb = Thom (SPF)
Origin: Dr. Karl Thomae GmbH; D-7960, Biberach/Riss
Sex: mal
Weight: about 300 g; was checked prior to dosing
Rationale: Other toxicity data are generated using the same species and strain. In order to relate the expected results to these data the same species and strain have to be used
Age at study initiation: At least 7 weeks at the date of administration
Sex:
male
Details on test animals or test system and environmental conditions:
HUSBANDRY:
Room: Animals were held under conventional hygienic conditions in an air-conditioned room at 20 - 24° and 30 - 70% relative humidity. These parameters are maintained under central control.

CAGING:
- During acclimatization and prior to the experiment in Makrolon cages Typ III
- During experiments in all glas metabolism cages Type Metabowl (Jensons Leighton Buzzard, UK)
- During topical application re­strained by metal rods in metabolism cages to prevent cross contamination from application area to other parts of the body

IDENTIFICATION: Individual number (tattooing) or colour markers

DIET:
Kliba-Labdiet for rat-mouse-hamster "A" GLP 343 either pelleted or granulated
Origin: Klingentalmühle AG, CH-4303 Kaiseraugst
unless otherwise stated ad libitum prior to and during experiment

WATER: Tap water ad libitum


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Concentration in vehicle (water): 0.562-2.61 % w/v
Duration and frequency of treatment / exposure:
see table below
No. of animals per sex per dose / concentration:
2 animals per test substance with the excemption of test 10
Positive control reference chemical:
not applicable
Details on study design:
see table below
Details on dosing and sampling:
see table below
Statistics:
Mean values were calculated

Results and discussion

Preliminary studies:
In the pre-test it was checked that test solution (20 mg/kg K-HDO) dissolved in 0.9% NaCl does not cause acute toxic effects during slow i.v. injection.
Main ADME resultsopen allclose all
Type:
absorption
Results:
Percutaneous absorption < 3%
Type:
excretion
Results:
see below

Toxicokinetic / pharmacokinetic studies

Details on absorption:
- Dermal application of the test material either in suspension or in technical preparation did not result in any considerable resorption. Cumulated yields are below 3 %. Recovery from skin or skin wash including wool swap after 8 h exposure is around 100 % (suspension)
Details on excretion:
- After oral administration of the test substance via gavage between 60 and 82 % of the dose are excreted in urine within the first 24 hours. After simulated feed intake about 95 % of the dose is found in urine within this time period. Total recovery ranges from 63-98 % of the dose.
- The total recovery from faeces is always below 3 % of the dose indicating a rather fast and extensive absorption of the HDO part of the administered salt.
- As far as it can be concluded from data of two animals, plasma level is always below 0.1 %. After 8 or 24 hours in most cases the amount of radioactivity is close to the detection limit.
- After oral administration of the test material in the technical preparation (Wolmanit CX-50) results were found to be similar to the test material preparations.
- Intravenous application of 14C-Cu-HDO (dose 2 mg/kg) resulted in an excretion in urine as it was found in the gavage experiments. Within the first 24 hours 88 % of the dose is found there.
- After oral administration, a biliary excretion in the range of 21 –32 % of the dose is found which is considerably higher than any faecal excretion found in the other experiments Therefore enterohepatic circulation has to be anticipated.

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Comparison of the different salts of HDO 

With respect to differences in solubility in aqueous media (known from other studies) and differences in their acute toxicity it could be expected that also differences might be found for the rate and extent of the adsorption and excretion or the general bioavailability of the various diazeniumoxides. Although the study provides only data from a limited number of animals, it can be seen that there is virtually no difference in the amounts of radioactivity in body fluids or excreta. This indicates that the bioavailability of the organic anion (HDO-) is not –or only to a minor extent- influenced by the type of cation bound to it.

Structure

Water solubility

LD50

K-HDO

Soluble

136 mg/kg

Cu-(HDO)2

Low

500 mg/kg

Al-(HDO)3

Very low

> 5000 mg/kg

 

As can be seen from these data the organic anion of all three diazeniumoxides salts is well resorbed and excreted mainly in urine at a relatively fast rate following oral or intravenous administration to male rats. There is virtually no resorption after dermal application. Administration of the test material in a technical preparation (Wolmanit CX-50) instead of aqueous suspensions or solutions did not influence the results of absorption or excretion. With respect to differences in solubility in aqueous media and differences in their acute toxicity, it was expected that differences might be found for the rate and extent of absorption and excretion or general bioavailability of the diazeniumoxides. As can be seen from these data is virtually no difference with respect to the above parameters indicating that a dissociation of the salts might occur prior or during absorption. This would lead to the expectation that adverse effects in toxicity studies with such test materials might in part be due to the corresponding cations.

 

Applicant's summary and conclusion

Conclusions:
Low dermal absorption of K-HDO; excretion mainly via urine.
Executive summary:

 The study was performed to provide preliminary data on the rate and extent of absorption and excretion of radioactivity after oral, intravenous or dermal administration of the potassium, copper or aluminium salt of 14C-N-Cyclohexyl-hydroxi-diazeniumoxide (14 C-HDO; 14 C-K-HDO; 14 C-Cu-HDO; 14C-Al-HDO) to male rats. The test material was administered in aqueous solution, suspension or technical preparation (Wolmanit CX 50). In order to gain further information on the routes of excretion the biliary excretion was checked using bile duct cannulated rats and the exhalation of 14C CO2was checked in a closed chamber system.

Following oral administration (starving overnight) of the three salts in various preparations at a nominal dose level of 20 mg/kg between 63 and 86% of the radioactivity dose are excreted in urine. 95% of the radioactivity dose is found in urine following simulated feed intake (starving overnight, diet access for 90 - 120 min before administration via gavage) of the test materials. Total recovery in feces was in all experiments at or below 3% of the radioactivity dose. Since biliary excretion is found to be between 20-30% of radioactivity dose enterohepatic circulation must be anticipated. As far as it can be concluded from these preliminary experiments plasma level after oral administration was always below 0.1% radioactivity dose. No radioactivity above background was found in expired air following oral administration.

Following intravenous application of the copper salt at a dose level of 2 mg/kg excretion in urine was found to be approx. 88% of the radioactivity dose within 24 hours. Dermal application of the test material in aqueous suspension or technical preparation (Wolmanit CX 50) did not result in any considerable absorption. After 8-hour exposure cumulated resorption was below 3% of the radioactivity dose.

As can be seen from these preliminary data the organic anion of all three N-Cyclohexyl-hydroxy-diazenium salts is well resorbed and excreted mainly in urine at a relatively fast rate following oral or intravenous administration to male rats. There is virtually no resorption after dermal application. Administration of the test material in a technical preparation (Wolmanit CX 50) instead of aqueous suspensions or solutions did not influence the results of absorption or excretion. With respect to differences in solubility in aqueous media and differences in their acute toxicity it was expected that also differences might be found for the rate and extent of absorption and excretion or general bioavailability of the Cyclohexyldiazeniumoxides.

As can be seen from these preliminary data there is virtually no difference with respect to the above parameters indicating that a dissociation of the salts might occur prior or during absorption. This would lead to the expectation that adverse effects in toxicity studies with such test materials might in part be due to the corresponding cations.