Registration Dossier

Administrative data

Description of key information

The registration substance induced liver effect, possibly via metabolic overload. The NOAEL of 40 mg/kg bw/day  was obtained in the 28-day toxicity study for the registration substance  and also in the combined repeated dose and reproductive/developmental toxicity screening test for the read-across supporting substance.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
One key study and one supporting study are available. The results of both studies are consistent, indicating a sound robustness of the database.

Additional information

Repeated dose toxicity assessment

The repeated dose toxicity of the registration substance was assessed based on the results of the 28 -day oral toxicity and the combined repeated dose toxicity with the reproduction/developmental toxicity screening test. The first study was performed on the registration susbtance and the latter one on the read-across supporting substance.

a) Justification for use of (Pentapropenyl succinimido)-hexanoate, sodium and triethanolamine salts as read-across supporting substance:

The read-across substance is a salt of (Pentapropenyl succinimido)-caproic acid. When dissolved in water or in biological fluid, an immediate dissociation occurs, resulting into the systemic exposure to (Pentapropenyl succinimido)-caproic acid.

(Pentapropenyl succinimido)-caproic acid and the registration substance (Tetrapropenyl succinimido)-caproic acid belong to the homologous series of (Polypropenylsuccinimido)-caproic acid and can thus be considered as to belong to a "chain length category". Similar metabolite fates and the same mode of action can be presumed.

b) Summary of the available data.

b1)(Tetrapropenyl succinimido)-caproic acid were investigated according to the OECD Guideline 407. Rats were treated via gavage with the test material at doses of 0, 8, 40, 200 and 1000 mg/kg bw. Recovery groups were established for the 1000 and 200 mg/kg groups and the solvent control group.

No deaths occurred. No effects due to administration of the test substance were seen on body weight and feed consumption during the period of administration or on the urinalysis.

Salivation, decrease in spontaneous movement, decrease in respiratory rate, increase in leukocyte counts, decrease in blood sugar, decrease in chlorine, increase in liver weight and increase in eosinophilic bodies in the liver attributable to administration of the test substance were seen in the groups of 200 mg/kg or higher.Further hematology alteration was observed in males and females and effects on forestomach and kidney in males. The observed effects were either fully reversible within the observation period of 14 days or the degree of severity decreased significantly.

On the basis of the foregoing results, it can be concluded that the principal effects of this substance are on the liver in males and females and on the proventriculus and kidneys in males. The NOEL of 40 mg/kg bw was obtained.

b1) (Pentapropylensuccinimido)-hexanoic acid, sodium and triethanolamine salts was investigated for its repeated dose toxicity according to the OECD Guideline 422. The applied doses were 0, 40, 200 and 1000 mg/kg bw. No mortality and no apparent signs for the clinical observation was found as well as no effect in the functional observational battery. Effects on food consumption and body weight development were observed dose dependently. At dose of 1000 mg/kg bw, changes in clinical chemistry and hematology parameters comprised increased prothormbin time, increased potassium level and increased total protein. No comparable effects were found for 200 or 40 mg/kg bw. At dose of 1000 mg/kg bw, increased liver and spleen weights were found. No comparable effects were found for 200 or 40 mg/kg bw. There was no macroscopic finding for all treated animals. The histopathological alteration comprised central to diffuse hepatocellular hypertrophy in males and females of 1000 mg/kg bw, hyaline droplets in the kidney epithelium in males of 1000 mg/kg bw,follicular cell hypertrophy in thyroid at 1000 mg/kg bw and squamous hyperplasia of the forestomach that occurred down to the 40 mg/kg bw group. The NOALE of 40 mg/kg bw was obtained.

c) Presumed mode of action

The structural feature of N-alkylated imide in the center of molecule and highly branched alkenyl moiety imply a certain degree of reluctance to undergo degradation process. A metabolic overload effect can be predicted in case of an extensive metabolism. The liver was identified as the target organ in both studies mentioned above and the observed alteration pattern of the findings (liver weight increase, hepatocellular hypertrophy, follicular cell hypotrophy in thyroid gland, prolonged bleeding time, altered values of glucose and cholesterols) are indicative of adaptation/metabolic overload/functional impairment. As mode of action the metabolic overload can be reasonably introduced.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Recently performed Guideline study, GLP study

Justification for classification or non-classification

Rationale for assigning no classification for the endpoint repeated dose toxicity

In the provided key study and also in the supporting study, the liver was identified as the target organ. Based on that the NOEL of 40 mg/kg bw was derived. It should be pointed out that at dose of 200 mg/kg bw the only effect found was the liver enlargement in females without any further indications of functional impairment. Therefore, no classification is assigned for the endpoint repeated dose toxicity.