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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18 Sept 2018 - 9 Oct 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
Dec 2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Appendix to Director General Notification, No. 12-Nousan-8147. Agricultural Production Bureau, Ministry of Agriculture, Forestry and Fisheries of Japan (JMAFF), November 2000, including the most recent revisions.
Version / remarks:
Nov 2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Remarks:
aquous solution
Details on test material:
Sodium salts of substituted amino acid (2) solution, FC-C 13588
Appearance: clear colorless solution

Test animals

Species:
rat
Strain:
other: Crl:WI (Han)
Sex:
female
Details on test animals or test system and environmental conditions:
ANIMALS
-Species: Rat
-Strain: Crl: WI (Han), Outbred, SPF-Quality
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 8-9 weeks old)
- Weight at study initiation: 136 to 148 g.
- Fasting period before study: Yes, animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and until 3-4 hours after administration of the test item. Water was available.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days
- It is considered that there were no known contaminants in the feed and the water that would interfere with the objectives of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 37 to 69%
- Air changes (per hr): approx 10
- Photoperiod (hrs dark / hrs light): 12/12
- For psychological/environmental enrichment, animals were provided with paper (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom), except when interrupted by study procedures/activities.

IN-LIFE DATES: From 25 Sept 2018 to 28 Nov 2018

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
GAVAGE METHOD: plastic feeding tubes.
Frequency: single dosage, on Day 1.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 mL/kg) body weight.
The dose volume for each animal was based on the body weight measurement prior to dosing.
Dose volume (mL/kg body weight) was calculated as follows:
Dose level (g/kg) / spec.gravity or density (g/mL).

DOSAGE PREPARATION:
- Sodium salts of substituted amino acid (2) solution FC-C 13588, was administered as received.
- The test item was stored in the freezer and was allowed to warm to room temperature for at least 30 minutes before dosing. To reduce the number of freezing/melting cycles the test item was melted once prior to initiation of the scheduled work and daily aliquots were prepared for all studies. The specific aliquots were then melted for use in the study, reducing the melting/freezing to the minimum.
- Adjustment was made for specific gravity of the test item. No correction was made for the purity/composition of the test item.
- The dosing formulations were stirred continuously during dose administration.

CLASS METHOD
- Rationale for the selection of the starting dose: The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines.
- The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.
- The first group was treated at a dose level of 2000 mg/kg body weight. Based on the results, one additional group was dosed at 2000 mg/kg body weight.
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, in the morning and at the end of the working day. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings.
Body weights: Animals were weighed individually on Day 1 (predose), 8 and 15. A fasted weight was recorded on the day of dosing.
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.
All the animals were examined for reaction to dosing. The onset, intensity and duration of these signs were recorded if appropriate.

- Terminal procedures: All animals surviving to the end of the observation period were sacrificed by oxygen/carbon dioxide procedure. All animals were subjected to necropsy and descriptions of all internal macroscopic abnormalities were recorded.

- Other examinations performed: none.
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:
Hunched posture, piloerection, ptosis and/or salivation were noted for the animals on Day 1.
Body weight:
The mean body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
In an acute oral toxicity study with rats, performed according to OECD/EC test guidelines, an LD50 >2000 mg/kg bw was determined. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg.
Executive summary:

An acute oral toxicity study was done for the test item Sodium salts of substituted amino acid (2) solution in Wistar Han rats, following the OECD test guideline 423 and following GLP principles. The test item was administered to 2 groups of 3 female rats via gavage on a single administration, and observed during 14 days. No mortality occurred during that period. Clinical signs like hunched posture, piloerection, ptosis and/or salivation were noted for the animals on day 1 after administration. The mean body weight gain was considered to be normal for animals at the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals. 

The oral LD50 value of Sodium salts of substituted amino acid (2) solution in Wistar Han rats was established to exceed 2000 mg/kg.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg. Therefore, Sodium salts of substituted amino acid (2) solution does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

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