6-[(C10-C13)-alkyl-(branched, unsaturated)-2,5-dioxopyrrolidin-1-yl]hexanoic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

40 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

One valid study available

Additional information

Toxicity to reproduction

The assessment on the toxicity to reproduction is based on the combined repeated dose toxicity with the reproduction/developmental toxicity screening test that was performed 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 and thus justifying the proposed read-across approach.

b) Study summary:

(Pentapropenyl succinimido)-hexanoate, sodium and triethanolamine salts was investigated for its reproductive 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. The effects at 1000 and 200 mg/kg bw were considered to be indicative of adverse effects.

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, increased incidence and severity of hyaline droplets in the kidney epithelium in males of 1000 mg/kg bw, squamous hyperplasia of the forestomach that occurred down to the 40 mg/kg bw group and follicular cell hypertrophy in thyroid at 1000 mg/kg bw.

The NOALE of 40 mg/kg bw was obtained.

As for the fertility of the parental animals no effect was found on the reproduction organs in all treated animals.

At 1000 mg/kg bw, fertility index, conception rate and gestation index were reduced and the pre-implantation loss increased. At 200 mg/kg bw all relevant parameters for the assessment of the fertility (effects up to the implantation) were not affected.

As for the developmental toxicity, increased post-implantation loss and increased post natal loss were observed down to the lowest dose level of 40 mg/kg bw. The LOAEL of 40 mg/kg bw is assigned for the developmental toxicity.

Short description of key information:
The reproduction toxicity of the registration substance is assessed based on the data for the read-across supporting substance.
(Pentapropenyl succinimido)-hexanoate, sodium and triethanolamine salt was investigated for its reproduction toxicity potential according to the OECD Guidline 422. Down to dose level of 40 mg/kg bw clear fetotoxicities were found. The LOAEL of 40 mg/kg bw was obtained.

Justification for selection of Effect on fertility via oral route:
Guideline study; well-performed and well-documented

Effects on developmental toxicity

Description of key information

The read-across supporting substance (Pentapropylensuccinimido)-hexanoic acid, sodium and triethanolamine salts was investigated equivalent to the OECD Guideline 414.  Clear fetotoxicities were observed at doses that were associated with apparent maternal toxicity.   The LOAEL of 8 mg/kg bw was obtained.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

8 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

One valid study is available.

Additional information

Developmental toxicity /teratogenicity

The assessment was performed by the read-across approach.

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 and thus justifying the proposed read-across approach.

b) Study summary

The read-across supporting substance (Pentapropylensuccinimido)-hexanoic acid, sodium and triethanolamine salts was investigated for its developmental toxicity equivalent to the OECD Guideline 414 with the deviation that 5 pregnant animals per dose group were used. The application route was per gavage with water as vehicle. The applied doses were 0, 8, 40 and 200 mg/kg bw. The observations parameters were according to the Guideline as well.

No clinical effect was found for all treated animals. At 200 mg/kg bw the food consumption and the body weight gain were slightly reduced. No effect was found for animals of 40 and 8 mg/kg bw.

With respective to the reproduction performance of the treated animals, the investigated parameters such as number of corpora lutea, implantation sites and number of live fetuses were comparable to those of control animals.

During examination of fetuses, increased frequency of a small spleen was noted down to the dose level of 8 mg/kg bw/day. Increased number of supernumerary ribs (rudimentary) was noted at the dose levels of 200 and 40 mg/kg bw/day. In addition, changes in the size or shape of the nasopharyns, nasal septum incompletely fused to the palate as well as several abnormalitiers and variations in skeleton were noted at the dose level of 200 mg/kg bw/day.

Based on the fetotoxicity found down to dose of 8 mg/kg bw, the LOAEL of 8 mg/kg bw was established.

c) Use of the obtained NOAEL/LOAEL for the DNEL derivation:

The proposed read-across substance is a salt of a weak acid and is expected dissociate immediately when dissolved in aqueous system or in biological fluid, resulting into the release of (Pentapropenyl succinimido)-caproic acid and counter ions. The given structural difference being only in the number of propenyl unit, a significantly deviating bioavailbilities or chemical reactivities cannot be expected. Based on the molar dose, no potency difference is expected.

In order to derive the NOEAL for the registration substance the NOAEL obtained in the key study should be corrected in that the molecular mass difference should be taken into account (530 vs. 378). In the presented key study, the applied doses were 8, 40 and 200 mg/kg bw, corresponding to 6, 30 and 160 mg/kg bw for the acid form. For the DNEL derivation the dose levels of 6 mg/kg bw as LOAEL will be used.

Justification for selection of Effect on developmental toxicity: via oral route:
Guideline study; well-performed and well-documented

Justification for classification or non-classification

The registration substance should be classified according to DSD 67/548/EEC as

T, Reprotox, Cat2; R1

Rationale for assigning Cat 2: R61 for the endpoint developmental toxicity

In the available developmental toxicity study equivalent to OECD 414, clear fetotoxicities were observed at doses that were not associated with apparent maternal toxicity. The assignment of Cat 2:R61 is justified according to 67/548/EEC (DSD).

 

Rationale for  “no classification” for the endpoint fertility

In the available OECD 422 study, no significant effect was found on the reproduction organs in all treated animals.

At 1000 mg/kg bw, fertility index, conception rate and gestation index were reduced and the pre-implantation loss increased. At 200 mg/kg bw all relevant parameters for the assessment of the fertility (effects up to the implantation) were not affected.

Since the impairment of the body weight development in the pre-mating phase was apparent at 200 and 1000 mg/kg bw, “no classification” is justified.