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Diss Factsheets

Administrative data

Description of key information

In line with OECD Guideline No.407, Repeated Dose 28-day Oral Toxicity Study in Rodents, 2008, Wistar rats were treated with GR-50-1408 for 28 consecutive days by dietary administration at dose levels of 0, 1000, 3000 and 10000 ppm, followed by a 14-day treatment-free recovery period. The dietary administration up to 10000 ppm was well tolerated by the animals. No mortality occurred in this study and no toxicologically relevant changes were noted in clinical appearance and functional observations.

There were no toxicologically relevant changes in males and females treated at 1000 and 3000 ppm. Based on the morphological changes in the kidneys, a No Observed Adverse Effect Level (NOAEL) for GR-50-1408 of 3000 ppm (corresponding to an actual test article intake of 296 and 300 mg/kg for males and females, respectively) was established.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015
Reliability:
1 (reliable without restriction)
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes (incl. QA statement)
Limit test:
yes
Specific details on test material used for the study:
GR-50-1408 is the Givaudan identification code which was employed for ROSYFOLIA during the early, developmental and testing period.
Species:
rat
Strain:
other: Crl:WI(Han) (outbred, SPF-Quality).
Sex:
male/female
Details on test animals or test system and environmental conditions:
Test system Rat: Crl:WI(Han) (outbred, SPF-Quality).
Rationale: Recognized by international guidelines as the recommended test system (e.g. EPA, FDA, OECD and EC).
Source: Charles River Deutschland, Sulzfeld, Germany.
Total number of animals: 30 males, 30 females (females were nulliparous and non-pregnant).
Age at start of treatment: Approximately 6 weeks.
Identification: Earmark and tattoo.
Randomization: By computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean.
Acclimatization period: At least 5 days before the start of treatment under laboratory conditions.
Health inspection Upon receipt of the animals.

Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.
Group housing of 5 animals per sex in in polycarbonate cages type 2000P (height 21.5 cm) with sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lilico & Son (Wonham Mill Ltd), Surrey, United Kingdom). During locomotor activity monitoring, animals were housed individually in a Hi-temp polycarbonate cage (Ancare corp., USA; dimensions: 48.3 x 26.7 x 20.3 cm) without cage-enrichment, bedding material, food and water.
Free access to standard powder rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
During motor activity measurements, animals had no access to food. The diet was provided in stainless steel containers, covered by a stainless steel grid to prevent spillage. The same diets remained in the food hopper for a maximum of 4 days, and on the day of weighing the remaining food in the food hopper was replaced with new room temperature-acclimated diet retained from the freezer. Food hoppers were shaken on a daily basis to divide any sawdust equally over the diet in order to facilitate food consumption.
Free access to tap water except during motor activity measurements.
Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study
Route of administration:
oral: feed
Details on route of administration:
The oral route was selected as it is a possible route of human exposure during manufacture, handling or use of the registration substance.
Vehicle:
unchanged (no vehicle)
Remarks:
the tested substance is directly mixed with diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Dose / conc.:
0 ppm
Remarks:
diet
Dose / conc.:
1 000 ppm
Remarks:
Diet
Dose / conc.:
3 000 ppm
Remarks:
Diet
Dose / conc.:
10 000 ppm
Remarks:
Diet
No. of animals per sex per dose:
30 males, 30 females (females were nulliparous and non-pregnant).
Control animals:
yes
Observations and examinations performed and frequency:
At least once daily from start of treatment onwards, detailed clinical observations were made in all animals. Once prior to start of treatment and at weekly intervals, this was also performed outside the home cage in a standard arena. The time of onset, grade and duration of any observed signs were recorded.
Sacrifice and pathology:
On the scheduled day of necropsy, animals were deeply anaesthetized using isoflurane (Abbott B.V., Hoofddorp, The Netherlands) and subsequently exsanguinated and subjected to a full post mortem examination. Animals were deprived of food overnight (with a maximum of 24 hours) prior to scheduled necropsy. All animals assigned to the study were necropsied and descriptions of all macroscopic abnormalities recorded.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No clinical signs were noted during the observation period that were considered to be toxicologically relevant. No abnormalities were noted during weekly arena observations.

Clinical signs noted during the observation period occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and/or did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment.
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study period.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Body weights and body weight gain of males and females at 10000 ppm were slightly lower compared to controls (statistically significant on Days 4, 7 and/or 10 only). During the recovery period, the males showed high body weights and body weight gain (statistically significant on Day 15 of Recovery).
Males at 3000 ppm showed slightly higher body weight and body weight gain compared to controls from Day 13 onwards (statistically significant for body weight on Days 16 and 19 only). No body weight changes were noted in animals at 1000 ppm and females at 3000 ppm.
Since all the changes in body weights and food consumption were slight and/or reversible these findings were considered not toxicologically relevant.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
A slightly lower food consumption was noted for males and females at 10000 ppm during the first 4 days of treatment, which recovered to levels similar to those seen in controls thereafter.
Higher food consumption was observed for males at 10000 ppm during Days 8-15 of the Recovery period.
No apparent treatment-related changes in food consumption before or after correction for body weight were recorded for animals treated at 1000 and 3000 ppmx.
Since all the changes in body weights and food consumption were slight and/or reversible these findings were considered not toxicologically relevant.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The following statistically significant changes in haematology parameters distinguished treated from control animals:
− Lower red blood cell count in males and females at 10000 ppm.
− Lower haemoglobin level in males at 10000 ppm (also appeared lower for females but not statistically significant).
− Lower haematocrit level in males at 10000 ppm (also appeared lower for females but not statistically significant).
At the end of recovery all treatment related findings recovered. In addition slightly higher red blood cell distribution width (RDW) and mean corpuscular volume (MCV) were observed in females (also appeared higher for males but not statistically significant).
Any other statistically significant changes in haematology parameters were considered to be unrelated to treatment as these occurred in the absence of a dose-related trend or occurred only at the end of recovery period.
These changes in haematologic and clinical biochemical parameters were slight and/or recovered after a 14-day recovery period and were not supported by any related morphological changes and therefore not considered to be adverse.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
The following statistically significant changes in clinical biochemistry parameters distinguished treated from control animals at the end of treatment period:
− Lower total protein and albumin level in males at 10000 ppm.
− Lower total bilirubin in males and females at 3000 and 10000 ppm.
− Lower glucose in males at 10000 ppm.
− Lower bile acid level in males at 10000 ppm.
− Higher cholesterol level in females at 10000 ppm.
At the end of recovery all treatment related findings recovered, except for total bilirubin level, which remained lower in females at 10000 ppm compared to controls.
A lower calcium level was observed in males and females at 1000 and 10000 ppm. These changes occurred in absence of a clear dose related trend and without any corresponding morphological changes. Therefore this change was considered not toxicologically relevant.
Any other statistically significant changes in clinical biochemistry parameters were considered to be unrelated to treatment as these occurred in the absence of a dose-related trend, occurred at the end of recovery phase only and/or were within the range expected for rats of this strain and age.
Key result
Dose descriptor:
NOAEL
Effect level:
296 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: morphological changes in the kidneys
Key result
Critical effects observed:
not specified
Conclusions:
Based on the morphological changes in the kidneys, a No Observed Adverse Effect Level (NOAEL) for GR-50-1408 of 3000 ppm (corresponding to an actual test article intake of 296 and 300 mg/kg for males and females, respectively) was established.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
296 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP compliance

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification