Pentanedioic acid, 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-, (2S)-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 April 2015 - 30 April 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study has been performed according to OECD and/or EC guidelines and according to GLP principles.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

(2001)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

Official Journal of the European Union No. L142, May 2008, including the most recent amendments

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

(2002)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000; including the most recent partial revisions.

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(2S)-2-(1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-2-YL)PENTANEDIOIC ACID

EC Number:

608-945-6

Cas Number:

340-90-9

Molecular formula:

C13H11NO6

IUPAC Name:

(2S)-2-(1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-2-YL)PENTANEDIOIC ACID

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): Phthalyl-L-Glu
- Substance type: Organic
- Physical state: White powder
- Storage condition of test material: At room temperature
- pH (1% in water, indicative range): 2.46 – 2.41 (determined by WIL Research Europe)

Test animals

Species:

rat

Strain:

other: Crl:WI (Han)

Sex:

female

Details on test animals or test system and environmental conditions:

- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 10 weeks old)
- Weight at study initiation: 165-187g
- Fasting period before study: yes (o/n before dosing and 3-4 hours post-dose)
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet, except overnight prior to dosing and until 3-4 hours after administration of the test substance
- Water: Free access to tap water
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.8 – 21.4
- Humidity (%): 48 – 61
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From 14 April 2015 to 30 April 2015

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

GAVAGE METHOD: plastic feeding tubes

Frequency: single dosage, on day 1

VEHICLE
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at WIL Research Europe and on test substance data supplied by the Sponsor. There was no information available regarding the solubility or stability in vehicle.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 mL/kg) body weight.

DOSAGE PREPARATION: The preparations (w/w) were kept at room temperature and were dosed within 4 hours after adding the vehicle to the test substance. Homogeneity was obtained to visually acceptable levels and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies. No correction was made for purity of the test substance.

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

6 (2 groups of three females in a stepwise manner)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily
Body weights: Days 1 (pre-administration), 8 and 15
Clinical signs: At periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15.
- Necropsy of survivors performed: At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.

Statistics:

No statistical analysis was performed (the method used is not intended to allow the calculation of a precise LD50 value).

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture was noted for all animals on day 1. Additionally, piloerection was noted for one animal on day 1.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:

not classified

Conclusions:

In an acute oral toxicity study with female rats, performed according to OECD/EC test guidelines and GLP principles, an oral LD50 >2000 mg/kg bw was determined for Phthalyl-L-Glu.

Executive summary:

An acute oral toxicity study was performed with female rats, according to OECD/EC test guidelines and GLP principles. Two groups of three females were exposed in a stepwise manner to 2000 mg/kg bw. No mortality occurred. Hunched posture was noted for all animals on the day of exposure, accompanied by piloerection in one animal. No unexpected changes in body weight gain occurred, no macroscopic effects were seen at necropsy after 14 days. Based on these results, an oral LD50 >2000 mg/kg bw was determined for Phthalyl-L-Glu.