N-glycyl-L-tyrosine

Endpoint summary

Description of key information

- acute oral toxicity with N-glycyl-L-tyrosine dihydrate, LD50 > 2150 mg/kg bw corresponding to 2000 mg/kg bw N-glycyl-L-tyrosine, OECD guideline 401, GLP, Wistar rats, observation period after oral application 14 days,

- acute toxicity: other routes: LD50 > 5956 mg/kg bw, non-guideline study, either 20 or 25 mmol/kg bw at 250 ml/kg bw N-glycyl-L-tyrosine was intravenously administered to Sprague Dawley rats within 8h, observation period after administration 14 days

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

study according to OECD guideline 401 and GLP, therefore the data is of high quality.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2021-12-24 - 2022-04-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity: Fixed Dose Procedure)

Version / remarks:

2017

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

Species:

rat

Strain:

other: Crl: WI(Han)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approximately 8-10 weeks old
- Weight at study initiation: 188 to 195 g
- Fasting period before study: no
- Housing: individually housed in polycarbonate cages (Makrolon MIII type; height 18 cm.) containing sterilized wooden fibers as bedding material equipped with water bottles.
- Diet: Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was
provided ad libitum
- Water: Municipal tap-water was freely available to each animal via water bottles
- Method of randomisation in assigning animals to test and control groups: all animals within ± 20% of the sex mean body weights

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C (target 20-24°C)
- Humidity (%): 50-56% (target 40-70%)
- Air changes (per hr): >10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 06 January 2022 To: 28 January 2022

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Remarks:

The samples were applied after moistening with 0.5. mL water (Elix), to ensure close contact to the skin.

Details on dermal exposure:

TEST SITE
- Area of exposure: 5 x 7 cm
- % coverage: 18 cm2 for females
- Type of wrap if used: surgical gauze patch (Surgy 1D), successively covered with Coban elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with water
- Time after start of exposure: 24 hours

Duration of exposure:

24 hours

Doses:

2300 mg/kg bw (dihydrate form; test item; CAS 39630-46-1) equivalent to
2000 mg/kg bw (anhydrous form; CAS 658-79-7)

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: post-dose observations were performed at periodic intervals on the day of dosing (at least three times) and once daily thereafter; animals were weighed individually on Days 1 (pre-dose), 8 and 15
- Necropsy of survivors performed: yes
- Irritation: skin reactions were assessed at least once daily after removal of the dressing and test
item

Preliminary study:

A range finding study was performed in order to select the dose causing no mortality or significant toxicity to be used in the main study. One animal was dosed at 2000 mg/kg.

Sex:

female

Dose descriptor:

LD50 cut-off

Effect level:

> 2 300 mg/kg bw

Based on:

test mat.

Remarks:

dihydrate form (CAS 39630-46-1; test item

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Key result

Sex:

female

Dose descriptor:

LD50 cut-off

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Remarks:

anhydrous form (CAS 658-79-7)

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

No mortality occured.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

The body weight gain shown by the surviving animals during the observation period was within the range expected for rats used in this type of study.

Gross pathology:

No abnormalities were found at macroscopic postmortem examination of the animals.

Interpretation of results:

GHS criteria not met

Remarks:

Based on these results, N-Glycyl-L-tyrosine does not have to be classified and has no obligatory labelling requirement for acute dermal 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).

Conclusions:

The dermal LD50 value of Glycyl-L-tyrosine dihydrate (CAS 39630-46-1) in Wistar Han rats was established to exceed 2300 mg/kg body weight, equivalent to 2000 mg/kg body weight of the anhydrous form Glycyl-L-tyrosine (CAS 658-79-7).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 1) study with the registered substance. The selected studies are thus sufficient to fulfil the standard information requirements of Regulation (EC) No. 1907/2006 (REACH).

Additional information

In a study according to OECD guideline 401, GLP, Wistar rats were administered N-glycyl-L-tyrosine dihydrate at either 1000 mg/kg bw or 2150 mg/kg bw by gavage. The maximum dose was chosen in order to achieve the limit dose of 2000 mg/kg bw N-glycyl-L-tyrosine. After an observation period of 14 days the animals were sacrificed and underwent necropsy, no alterations were found in all parameters observed. The LD50 was determined to be > 2150 mg/kg bw, i.e. > 2000 mg/kg bw N-glycyl-L-tyrosine.

In a non-guideline study either 20 or 25 mmol/kg bw at 250 ml/kg bw N-glycyl-L-tyrosine was intravenously administered via the tail vein within 8 hours to female and male Sprague-Dawley rats. During infusion and for +2 h post infusion the animals were monitored continuously and observations recorded at 30 min intervals, in the 14 days post administration period the animals were observed twice daily and body weight recorded daily. The animals were sacrificed on day 15 and necropsies were performed (organ weights of brain, liver, kidneys, heart, lungs, spleen and testes/ovaries).

No treatment related changes occurred during the 14 days observation period. Thus, the LD50 is considered to be > 5956 mg/kg bw. The study is sufficiently documented, therefore the provided data is considered to be reliable. The results confirm a low acute toxicity of N-glycyl-L-tyrosine dihydrate.

One study was performed to determine the potential toxicity of N-Glycyl-L-tyrosine dihydrate , when given by a single dermal dose.

The study was carried out according to OECD TG 402 (2017). Initially, N-Glycyl-L-tyrosine dihydrate was administered to a single female Wistar Han rat by a single dermal application at 2000 mg/kg bw for 24 hours in a range finder study. Based on the results, the main study was performed by dosing two females at 2000 mg/kg bw. A factor 1.15 was used to correct for the purity of the test item and the corrected dose concentration was calculated to be 2300 mg/kg bw. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred. No clinical signs of systemic toxicity and no irritation was noted. The body weight gain shown by the surviving animals during the observation period was within the range expected for rats used in this type of study. No abnormalities were found at macroscopic postmortem examination of the animals.

The dermal LD50 value of N-Glycyl-L-tyrosine dihydrate (CAS 39630-46-1) in Wistar Han rats was established to exceed 2300 mg/kg body weight, equivalent to 2000 mg/kg body weight of the anhydrous form N-Glycyl-L-tyrosine (CAS 658-79-7).

 

Justification for classification or non-classification

Based on the provided relevant and reliable data N-glycyl-L-tyrosine does not need to be classified according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS) with respect to acute toxicity.