Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Except data obtained from the scientific literature, the studies performed either on Isosorbide (LAB 3085) or on LAB 3822 were performed according OECD good laboratory practices.
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:

Data source

Reference
Reference Type:
other: analysis by an expert
Title:
Analysis of data available for Isosorbide risk assessment
Author:
Pf D.Marzin
Report Date:
2010

Materials and methods

Results and discussion

Results (fetuses)

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Isosorbide was tested for toxicokinetics and toxicology either as Isosorbide form or its precursor LAB 3822, which was demonstrated as quickly and completely metabolized into Isosorbide and into capric and caprylic acids.
After administration of LAB 3822 animals are exposed to Isosorbide. The level of exposure is proportional to the dose. Exposure to isosorbide is higher when administered alone than when it is administered as LAB 3822, but the isosorbide dose equivalent administered at the maximum dose of LAB3822 (0.67 mg/kg) is largely lower that when it was administered alone (2g/kg). The T1/2 (plasma and urine) and Tmax (plasma) of isosorbide was not different when isosorbide is administered as LAB3822 or as Isosorbide itself. In both cases males are more exposed than females. The excretion of isosorbide is almost in the urine as unchanged isosorbide. The metabolism and the pharmacokinetics were similar in all the species studied including human.
The acute toxicity is low in all the species tested including human by all the route tested including intravenous route. With such a low acute toxicity, Isosorbide need no classification. The symptoms were the same in all species including human and are limited, at high doses (> 10g/kg) to gastro-intestinal effects: nausea, vomiting and diarrhoea.
In the repeated toxicity doses isosorbide was tested in the rat in GLP studies up to 13 weeks by oral route by addition in the diet. No toxic effects were observed and the maximum daily doses tested which were the maximum feasible doses (3347 mg/kg/day for the males and 3970 mg/kg/day for the females) are the NOAEL in this species. Data from literature demonstrated that in the rat when administered in the diet at 10% up to 18 months or in the dog at 12g/kg/day up to 52 weeks no toxic effects were demonstrated.
Isosorbide was demonstrated as not irritant for the eye and the skin in vivo in the rabbit and not a skin sensitizer in the mouse in the LLNA test. Under these conditions, Isosorbide need no classification for local tolerance.
Isosorbide demonstrated no genotoxic potential in a battery of 3 in vitro tests able to demonstrate gene mutation in bacteria, gene mutation in mammal cells and clastogenic and aneugenic potential in mammal cells. These results are sufficient and there is no need for complementary data. In the absence of genotoxic potential, there is no need for a classification of Isosorbide.
In the absence of genotoxic potential and of abnormal signs of cells proliferation or hyperplasia in repeat doses toxicity studies there is no need for carcinogenicity studies and there is no need for a classification of Isosorbide.
Reproduction toxicity studies were performed in the rat using LAB 3822 the maximum administered dose was 0.81 g/kg isosorbide equivalent, this dose is weakly lower than the maximum recommended dose in the OECD guideline (1 g/kg/day). However, this study was considered as acceptable because the dose maximum dose tested is close to this maximum recommended dose, Isosorbide is highly bioavailable and high level of the systemic exposure was clearly demonstrated, because isosorbide is not metabolized and this fact explained the high level of systemic exposure and the study was not limited to this limit dose but 3 dose levels were tested and finally at this dose level the results demonstrated clearly the absence of toxicity for the dam and for the foetus. On the other hand data from literature, although limited, confirmed the absence of this type of toxic effects. In the absence of reproductive toxicity potential, there is no need for a classification of Isosorbide.
Due to the use of Isosorbide from several years as a drug, human data are available and demonstrated the good tolerance for long duration of treatment at high doses.
Under these considerations, the available data are sufficient to conclude that Isosorbide presents a very weak toxicity level that no complementary studies are needed for risk assessment and that isosorbide need no classification.