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Toxicological information

Basic toxicokinetics

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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:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2014
Report Date:
2014
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:
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. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 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:
4
Control animals:
other: urine and feces were also sampled from animals from group 1 prior to dosing (control values)
Positive control:
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 resultsopen allclose all
Type:
absorption
Results:
<5% following oral administration
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.