Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
secondary literature

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
1994
Report date:
1994

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
In the review article no reference to the above mentioned guideline is made.
Deviations:
not specified
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no

Test material

1
Reference substance name:
Ichthammol
EC Number:
232-439-0
EC Name:
Ichthammol
Cas Number:
8029-68-3
Molecular formula:
unspecified
IUPAC Name:
Ichthammol (UVCB substance)
Details on test material:
Trademark substance Ichthyol® (Ammoniumbituminosulfonat DAB, dark sulfonated shale oil, CAS 8029-68-3) is subject of the review article by Cholcha et al. Another valid synonym fitting in this listing is Ichthammol. Test material is pharmaceutical grade manufactured by the registrant. The authors subsume sodium and ammonium types of bituminosulfonates under the umbrella term of "dark sulfonated shale oil" (SSD):"The sulfonation (with concentrated sulfuric acid) of a medium shale oil fraction at temperatures of less than 120 °C and the subsequent neutralization of the intermediate product (with either ammonia or sodium hydroxide solution) yields dark sulfonated shale oil as ammonium or sodium salt." Both types are treated equally independent of the cation actually used in a specific toxicological study, i.e. although a sodium type of dark sulfonated shale oil was used in evaluation of "acute oral toxicity", the results are applicable to Ichthammol (which is of ammonium type) according to the authors.
Specific details on test material used for the study:
Trademark substance Ichthyol® (Ammoniumbituminosulfonat DAB, dark sulfonated shale oil, CAS 8029-68-3) is subject of the review article by Cholcha et al. Another valid synonym fitting in this listing is Ichthammol. Test material is pharmaceutical grade manufactured by the registrant. The authors subsume sodium and ammonium types of bituminosulfonates under the umbrella term of "dark sulfonated shale oil" (SSD):"The sulfonation (with concentrated sulfuric acid) of a medium shale oil fraction at temperatures of less than 120 °C and the subsequent neutralization of the intermediate product (with either ammonia or sodium hydroxide solution) yields dark sulfonated shale oil as ammonium or sodium salt." Both types are treated equally independent of the cation actually used in a specific toxicological study, i.e. although a sodium type of dark sulfonated shale oil was used in evaluation of "acute oral toxicity", the results are applicable to Ichthammol (which is of ammonium type) according to the authors.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Sprague-Dawley rats (Lippische Versuchstierzucht Hagemann GmbH & Co., Extertal, FRG) with body weights of 160-175 g were used. The animals were kept singly in makrolon cages (Type II). The animals were held in air-conditioned rooms (24 ± 0.5 °C, 60 % relative humidity). All animals were fed with the appropriate Altromin feed (Altromin GmbH, Lage/Lippe, FRG). Food and water were offered ad libitum. Feeding was discontinued 15-16 h before administration.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
For the oral administration, SSD (7900 and 10000 mg/kg b.w.) was diluted with distilled water and administered once by gavage at a volume of 20 ml/ kg b.w.
Doses:
7900 and 10000 mg/kg b.w.
No. of animals per sex per dose:
Each dose was tested in 10 (oral administration) rats per sex.
Control animals:
no
Details on study design:
The rats of both studies wer observed for 2 weeks following administration.
Statistics:
No description of any statistical method in the review article.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 10 000 mg/kg bw
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
There was no mortality observed in this study.
Clinical signs:
After oral application of SSD (7900 and 10 000 mg/kg b.w.), ataxia as signs of toxicity were observed from 7900 mg/kg b.w. upwards as well as sedation at 10 000 mg/kg b.w.; there was no mortality. The animals recovered within 24 h after administration.
Body weight:
no indication about gain or loss of body weight in the review article
Gross pathology:
No pathological changes were found during the macroscopic examination.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The review article referred to with regard to "acute oral toxicity" deals with the general toxicological profile of dark sulfonated shale oil (abbreviated as SSD including Ichthammol) and concludes with following discussion:

The animal experiments under discussion were conducted to understand the toxic effects of SSD after dermal and oral application, to establish the corresponding toxic dose range as well as to determine the expected therapeutic window for humans by comparing the toxic doses found in animal testing with the human therapeutic dose.
The single application of SSD to rats by gavage caused only intolerance reactions at a dosage of 7900 mg/kg b.w. upwards. No intolerance reactions were observed after dermal application up to the highest tested dose-level of 21500 mg/kg b.w.
The test substance proved to be only mildly toxic after repeated long-term substance administration. In the dog, toxic effects occurred only in the extremely high dose range (990 mg/kg b.w./d) with oral adminsitration. There were indications of a certain load on the liver with an increase in alanine and asparate aminotransferase as well as reversible cell enlargement and a disturbance in differentiation, in part with cloudy swelling.
The rats also showed signs of intolerance after 6 months of treatment only at the high dose of 3000 mg/kg b.w./d in the form of an inhibition of body weight gain. No substance-related changes were found by histological examination.
In a study on the local tolerance in rabbits slight erythema were found from a concentration of 12.5 % onwards. After application of the 100 % sample as well as a concentration of 50 % corrosive effects on the skin were observed.
No signs of embryotoxic or teratogenic properties were found up to the toxic range for dams.
The in vitro and in vivo mutagenicity studies provided no indication of mutagenic properties. This can also be attributed to the low benzo[a]pyrene content in SSD. At least 5 pg benzo[a]pyrene/plate are needed in the Ames test for the indication of a mutagenic effect; SSD introduces less than 0.001 pg benzo[a]pyrene onto the plate when a maximum tested concentration of 10 mg SSD/ plate and the values stated in paragraph 3.8 are considered.
There were no indications of substance-related neoplastic changes found in the cancerogenicity study in the rat. These findings coincide with the decicively low concentrations of polycyclic aromatic hydrocarbons found in SSD by gas chromatography/mass spectrometry.
A comparison of the toxic doses in animal testing and the human therapeutic dose can provide a basis to judge the anticipated “therapeutic window”. This quotient, the therapeutic ratio, varies according to animal species, frequency of administration, dose-level and the toxicological problem; the therapeutic ratio of SSD for dermal application is > 7.
Therefore, a sufficient therapeutic window for human use of SSD is given. Another advantage of topical use is the lack of photosensitizing properties of SSD in humans.