Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2010-10-20
Reliability:
1 (reliable without restriction)
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
other: expert statement
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Expert statement based on available physical/chemical and toxicological data.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate
- CAS no. 858036-65-4


Radiolabelling:
not specified

Test animals

Details on test animals and environmental conditions:
Not applicable

Administration / exposure

Details on exposure:
Not applicable
Duration and frequency of treatment / exposure:
Not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
Not applicable
No. of animals per sex per dose:
Not applicable
Positive control:
Not applicable
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable
Statistics:
Not applicable

Results and discussion

Preliminary studies:
Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulphate is a solid at room temperature with a molecular weight of 453.643 g/mol. The substance is poorly soluble in water (2.5 mg/L). The logPow of the substance was measured to be 3.5 (HPLC method). A BCF of 9.1 was measured in zebra fish. The substance has a very low vapour pressure of < 10-6 hPa at 20°C.
Oral absorption is favoured for molecular weights below 500 g/mol. Based on the very low water solubility and the moderate logPow value the substance is not expected to be readily absorbed via the GI tract and if absorbed to cause very low oral toxicity as administration in an acute toxicity study caused no mortalities up to the limit dose of 5000 mg/kg bw.
Based on the low vapour pressure of < 10-6 hPa inhalation exposure is not likely. Thus, it is very unlikely, that relevant amounts of the substance reach the lung. Furthermore, if the substance reaches the lung, it is also not very likely that the substance is taken up rapidly (see discussion based on physical and chemical parameters for the oral route above). Together, this indicates low systemic availability after inhalation and if bioavailable, no systemic toxicity effects via this route of administration.
Similarly, based on physical – chemical properties, the substance is not likely to penetrate skin to a large extent due to the low water solubility of 2.5 mg/L. The logPow of 3.4 would favour dermal absorption, but the substance is not sufficiently water soluble. Furthermore, application of the substance to skin of rats and rabbits did not cause significant irritation or corrosion nor systemic effects (mortality) in a skin irritation/corrosion study and an acute dermal toxicity study up to 5000 mg/kg bw. In addition no skin sensitizing properties were detected in an LLNA test in mice.
Details on distribution in tissues:
When reaching the body, the substance will not be easily distributed in body liquids due to its very low water solubility. Based on its low BCF value of 9.1, the substance is very unlikely to bioconcentrate in the human body.
Details on excretion:
Based on the low water solubility and the relatively high logPow value, excretion via the bile is most likely. In addition, as the substance has a molecular weight above 300 g/mol the excretion via the bile is likely, especially if phase-II conjugation takes place e.g. with formation of glucoronid derivates.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Based on the structure of the molecule and its nature, metabolism in the human body will mainly consist on phase-I and phase-II metabolising steps, leading to better water solubility for excretion. Metabolic activation leading to more toxic metabolites is thus not very likely. This is in compliance with the results obtained in the genotoxic tests showing no effects with and without metabolising system. In addition available studies do not indicate any sex difference with regard to the toxicity of the substance.

Any other information on results incl. tables

no remarks

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: no bioaccumulation potential based on a toxicokinetic assessment
Based on physical-chemical characteristics, particularly water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption and bioavailability by the oral, dermal and inhalation routes is expected, which is further supported by the oral and dermal acute and repeated dose toxicity studies results. Bioaccumulation is not likely to occur based on the physical-chemical properties and the determined low BCF value. Excretion is expected to occur most likely via the faeces. No metabolic activation to critical metabolites is expected. No sex differences with regard to toxicity are expected based on data from repeated dose toxicity tests.
Executive summary:

Toxicokinetics

Toxicological profile

In one acute oral toxicity study according to OECD 401 and GLP, the LD50 in Wistar rats was determined to be greater than 5000 mg/kg bw. Bodyweight development was not impaired. No deaths occurred in the study. An acute dermal toxicity study with Wistar rats also revealed an LD50-value of greater than 5000 mg/kg bw.

In a preliminary in vitro study using the EpiDerm human skin model test, it was concluded, that 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate does not show a corrosive potential. Skin irritation/corrosion of 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate was also investigated in an in vivo test in rabbits. Mean scores over 24, 48 and 72 hours for each animal were 1.0, 0.3 and 0.7 for erythema and 0.0 for edema. Thus, the test substance is not irritating to the skin.

In a preliminary in vitro HET-CAM test and an Isolated Chicken Eye (ICE) test 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate was shown to be not severely irritating to the eye. The negative results of the in vtro eye irritation tests were confirmed by an in vivo eye irritation study in rabbits 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulphate also showing no indication of eye irritation.

A Local Lymph Node Assay (LLNA) revealed that the test substance did not induce delayed contact hypersensitivity and is thus not regarded as skin sensitizer.

The test substance was examined in three different in vitro mutagenicity studies, all three with and without metabolic activation. The test item did not induce gene mutations by frameshift or base-pair substitution in the examined strains in the Ames test. 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate tested up to cytotoxic concentrations did not induce structural chromosome aberrations in Chinese Hamster ovary cells and was therefore not considered clastogenic in the tested system. Finally the test substance showed no mutagenic effect in a mammalian cell test, the HPRT assay. Overall, the substance was considered non genotoxic.

In a 28-day repeated dose toxicity study, 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate was administered to male and female Wistar rats by gavage at dose levels of 0 (vehicle control), 100, 300 and 1000 mg/kg body weight per day over a period of 4 weeks. No treatment-related adverse findings concerning clinical pathology were noted. Moreover, regarding pathology, there were no substance-related weight changes, gross lesions or microscopic findings in male and female Wistar rats observed after 4 weeks of treatment. In addition, during the recovery period also no effects were noted. In conclusion, under the conditions of the present study no substance-related adverse findings were obtained. Therefore, the no-observed-adverse-effect level (NOAEL) was 1000 mg/kg body weight per day in both sexes.

In a reproduction/toxicity screening test, 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulphate was administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at doses of 100, 300 and 1000 mg/kg body weight/day (mg/kg bw/d) in order to detect possible effects of the test substance on the integrity and performance of the reproductive system of both sexes. The duration of treatment covered a two-weeks premating period and mating period in both sexes, approximately one week post-mating in males and the entire gestation period and 4 days of lactation in females. No test substance-related, relevant findings were observed in F0 parental animals and F1 pups at all doses applied. Thus, under the conditions of this reproduction/developmental toxicity screening test the NOAEL (no observed adverse effect level) for reproductive performance and fertility was equal to the limit dose of 1000 mg/kg bw/d recommended in the respective guideline for the F0 parental rats. The NOAEL for general, systemic toxicity of the test substance was also 1000 mg/kg bw/d for the F0 parental male and female animals. Treatment with the test article did not lead to any pathomorphological changes with respect to the tissue and organs examined during necropsy, organ weight determination and light microscopy. The NOAEL for developmental toxicity in the F1 progeny of the test substance-treated groups was found to be 1000 mg/kg bw/d.

Toxicokinetic analysis

1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulphate is a solid at room temperature with a molecular weight of 453.643 g/mol. The substance is poorly soluble in water (2.5 mg/L). The logPow of the substance was measured to be 3.5 (HPLC method). A BCF of 9.1 was measured in zebra fish. The substance has a very low vapour pressure of < 10-6 hPa at 20°C.

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the very low water solubility and the moderate logPow value the substance is not expected to be readily absorbed via the GI tract and if absorbed to cause very low oral toxicity as administration in an acute toxicity study caused no mortalities up to the limit dose of 5000 mg/kg bw.

Based on the low vapour pressure of < 10-6 hPa inhalation exposure is not likely. Thus, it is very unlikely, that relevant amounts of the substance reach the lung. Furthermore, if the substance reaches the lung, it is also not very likely that the substance is taken up rapidly (see discussion based on physical and chemical parameters for the oral route above). Together, this indicates low systemic availability after inhalation and if bioavailable, no systemic toxicity effects via this route of administration.

Similarly, based on physical – chemical properties, the substance is not likely to penetrate skin to a large extent due to the low water solubility of 2.5 mg/L. The logPow of 3.4 would favour dermal absorption, but the substance is not sufficiently water soluble. Furthermore, application of the substance to skin of rats and rabbits did not cause significant irritation or corrosion nor systemic effects (mortality) in a skin irritation/corrosion study and an acute dermal toxicity study up to 5000 mg/kg bw. In addition no skin sensitizing properties were detected in an LLNA test in mice.

When reaching the body, the substance will not be easily distributed in body liquids due to its very low water solubility. Based on its low BCF value of 9.1, the substance is very unlikely to bioconcentrate in the human body.

Based on the structure of the molecule and its nature, metabolism in the human body will mainly consist on phase-I and phase-II metabolising steps, leading to better water solubility for excretion. Metabolic activation leading to more toxic metabolites is thus not very likely. This is in compliance with the results obtained in the genotoxic tests showing no effects with and without metabolising system. In addition available studies do not indicate any sex difference with regard to the toxicity of the substance.

Based on the low water solubility and the relatively high logPow value, excretion via the bile is most likely. In addition, as the substance has a molecular weight above 300 g/mol the excretion via the bile is likely, especially if phase-II conjugation takes place e.g. with formation of glucoronid derivates.

Summary

Based on physical-chemical characteristics, particularly water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption and bioavailability by the oral, dermal and inhalation routes is expected, which is further supported by the oral and dermal acute and repeated dose toxicity studies results. Bioaccumulation is not likely to occur based on the physical-chemical properties and the determined low BCF value. Excretion is expected to occur most likely via the faeces. No metabolic activation to critical metabolites is expected. No sex differences with regard to toxicity are expected based on data from repeated dose toxicity tests.