Tetrasodium N,N-bis(carboxylatomethyl)-L-glutamate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

in-life part February -March 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well performed GLP study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Objective of study:

other: absorption and excretion

Test guideline

Qualifier:

according to guideline

Guideline:

other: ICH M3 (R2): Note for guidance on non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals, December 2009

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

GLDA-Na4

IUPAC Name:

GLDA-Na4

Constituent 2

Reference substance name:

Tetrasodium N,N-bis(carboxylatomethyl)-L-glutamate

EC Number:

257-573-7

EC Name:

Tetrasodium N,N-bis(carboxylatomethyl)-L-glutamate

Cas Number:

51981-21-6

Molecular formula:

C9H9NO8Na4

IUPAC Name:

tetrasodium 2-[bis(carboxylatomethyl)amino]pentanedioate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Identification: GLDA-Na4
Chemical Name: Tetrasodium-N,N-bis(carboxylatomethyl)-L-glutamate
Molecular formula: C9H9NO8.4Na
Molecular weight: 351.163
CAS Number: 51981-21-6
Description: White powder
Batch: FC-C 10943
Purity: 87.3wt% as GLDA-Na4
Test substance storage: at room temperature in the dark
Stability under storage conditions: Stable
Expiry date: 19 April 2015
Hygroscopic: Yes, store in well-sealed container
Volatile: No, vapour pressure: 0.08 KPa at 20C
Reactivity: Reactive to moisture
Specific Gravity / Density: 1.466 (relative density)
pH: 11.5 at concentration of 1%
Stability at higher temperatures: Yes, maximum temperature: 120 degr. C
Maximum duration: 2 hours

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Randomization:
By computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean.
Acclimatisation period:
At least 5 days under laboratory conditions.
Conditions:
Environmental controls for the animal room were set to maintain 18 to 24°C(actual range 19.0-20.3°C), a relative humidity of 40 to 70% (actual
range 30-51%), approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were recorded in the raw data and were considered not to have had any effect on the outcome of the study.
Accommodation:
Before dosing animals were group housed 4 animals per sex per cage. Housed in labeled Macrolon cages (type IV; height 18 cm.) with sterilized
sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lilico & Son (Wonham Mill Ltd), Surrey, United Kingdom). Group1: The day prior to dosing and following administration, the rats were individually housed in stainless steel metabolism cages (LxWxH = 18.5x19x20 cm) with a grid. Groups 2-6: on the day of dosing and following administration, the rats were individually housed in stainless steel metabolism cages (LxWxH = 18.5x19x20 cm) with a grid. The urine and feces collection assembly of the metabolism cage was cooled using dry ice.
Diet:
Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
Water: Free access to tap-water.

Administration / exposure

Route of administration:

other: gavage or intraperitineal injection

Vehicle:

water

Details on exposure:

Group 1, 2 and 5: Oral gavage, using a plastic feeding tube.
Group 3, 4 and 6: Intraperitoneal injection.
The animals were not deprived of food overnight.

Duration and frequency of treatment / exposure:

Frequency: once on Day 1.

Doses / concentrations

Remarks:

Doses / Concentrations:
Dose Level Oral: 100, 300 and 1000 mg/kg
Intraperitoneal: 5, 15 and 50 mg/kg

No. of animals per sex per dose / concentration:

4

Control animals:

other: urine and feces were also sampled from animals from group 1 prior to dosing (control values)

Positive control reference chemical:

No

Details on study design:

Single dose on day 1.
Duration of follow-up 72 hours.

Details on dosing and sampling:

Single dose on day 1. Dose Volume: 5 mL/kg
Actual dose volumes were based on the latest individual body weights.
For urine and feces collection the rats were individually housed in stainless steel metabolism cages (LxWxH = 18.5x19x20 cm) with a grid. The urine and feces collection assembly of the metabolism cage was cooled using dry ice.
Urine and feces were collected over the following intervals:
Predose once, only for Group 1: -24 to 0 hr
0-24 hr
24-48 hr
48-72 hr
Urine and feces samples were weighed and stored in labeled polypropylene tubes (Greiner Bio-One GmbH, Frickenhausen, Germany) at approximately ≤ -75°C until dispatch on dry-ice to the test site for bioanalysis. Samples were sent to Akzo Nobel NV, Arnhem, The Netherlands, on 11 March
2013.

Statistics:

Not applicable

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

<5% following oral administration

Main ADME results 2

Type:

excretion

Results:

GLDA-Na4 is excreted unmetabolized and when a limited amount of GLDA-Na4 is being absorbed, on average >85% is rapidly (first 24 hours) excreted via urine/faeces

Toxicokinetic / pharmacokinetic studies

Details on excretion:

In samples from animals subjected to single oral administration (groups 1, 2 and 5), the test substance was largely detected in faeces (92.7 – 99.1%). Only a small part was detected in urine (0.9 – 7.3%), while the overall recovery of GLDA-Na4 in orally dosed animals (PO) ranged from 95.8 – 103.0%. For the samples from animals subjected to intraperitoneal administration (IP) (groups 3, 4 and 6), the results were less clear. In 2 out of 12 animals (both sexes) higher levels of GLDA-Na4 were found in the faeces compared to the urine. Nevertheless, after IP dosing, the test substance was mainly detected in urine (in 83% of the animals), with an overall recovery of GLDA-Na4 in the IP dosed animals ranging from 74.6 – 103.3% (see tables attached).

Applicant's summary and conclusion

Conclusions:

In the orally dosed rats, most GLDA-Na4 was found in the faeces. This indicates that only a limited amount of GLDA-Na4 is being absorbed, i.e. <5% on average, when GLDA-Na4 is dosed orally. In the IP dosed rats, GLDA-Na4 was mainly detected in urine (83% of the animals). This indicates that (a) GLDA-Na4 is excreted unmetabolized and (b) when a limited amount of GLDA-Na4 is being absorbed, on average >85% is rapidly (first 24 hours) excreted via urine/faeces by the animal.

Executive summary:

In the present study, rats were dosed with GLDA-Na4 either orally or via intraperitoneal administration. In the orally dosed rats, most GLDA-Na4 was found in the faeces with an overall recovery ranging from 95.8 – 103.0%.This indicates that only a limited amount of GLDA-Na4 is being absorbed, i.e. <5% on average, when GLDA-Na4 is dosed orally. In the IP dosed rats, GLDA-Na4 was mainly detected in urine (83% of the animals), with an overall

recovery ranging from 74.6 – 103.3%. This indicates that (a) GLDA-Na4 is excreted unmetabolized and (b) when a limited amount of GLDA-Na4 is being absorbed, on average >85% is rapidly (first 24 hours) excreted via urine/faeces by the animal.