AVITERA ROSE SE

Endpoint summary

Description of key information

The median lethal dose (LD50) of FAT 40879/B after single oral administration to female rats (LD50 cut-off value) 5000 mg/Kg body weight and the estimated acute toxicity is between 2000 < ATE ≤ 5000.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Experimental Starting Date: 07 May 2021 and Experimental Completion Date: 08 June 2021

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

adopted 17th December 2001

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

Identification: FAT 40879/B TE
Appearance: Dark red powder, solid at 20 °C
Batch Number: BOP 05-20 (MC-0065114700/800 1:1)
Purity: 80.5 % all colored organic constituents; main constituent 66.9 %
pH: 6.7 at concentration of 2 % (w/w) in water
Manufacture Date: June 26, 2020
Expiry Date: September 08th, 2025
Storage Conditions: Freezer (-15 to -20 °C)

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Animal Breeding, RCC Laboratories India Private Limited, Genome Valley, Turkapally, Shameerpet (Mandal) Ranga Reddy District, Hyderabad – 500 078 India.
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
Yes
- Age at study initiation:
09 -12 weeks
- Weight at study initiation:
158.4 to 198.6 g
- Fasting period before study:
18.0 h
- Housing: Housed in groups of three animals, by dose, each in Polycarbonate cages
- Diet: Teklad Certified Global 14 % protein rodent maintenance diet (Batch No.2014C-091720MA) was provided ad libitum
- Water: UV purified water was provided ad libitum
- Acclimation period: Under laboratory conditions for 07 days for Step I, 12 days for Step II, 15 days for Step III and 06 days for Step IV animals, after veterinary examination.
- Microbiological status when known
- Method of randomisation in assigning animals to test and control groups

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.8 to 22.9
- Humidity (%): 61 to 69
- Air changes (per hr): The animal room was air-conditioned with adequate (above 10) air changes per hour.
- Photoperiod (hrs dark / hrs light): light cycle of 12 hours light and 12 hours dark.

IN-LIFE DATES: From: May 13, 2021 To: June 08 2021

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

The dose volume was 10 mL/kg body weight. The animals were gavaged using 15 G oral plastic feeding tubes.
ORDER
In Step I, 03 female rats received a single dose of the test item by oral gavage administration at 300 mg/Kg body weight. No mortality was observed in all three treated animals.
In Step II, 03 naive female rats were again treated with the same dose of 300 mg/Kg body weight. No mortality was observed in all three treated animals.
In Step III, 03 naive female rats were treated at the next higher dose of 2000 mg/Kg body weight. No mortality was observed in all three treated animals.
In Step IV, 03 naive female rats were again treated with the same dose of 2000mg/Kg body weight. No mortality was observed in all three treated animals.
As there was no mortality at the highest dose of 2000 mg/Kg body weight, hence no further testing was carried out.

Doses:

Step 1 and step 2: 300 mg/kg
Step 3 and step 4: 2000 mg/kg

No. of animals per sex per dose:

3 female animals per step.
2 steps per dose (Total 6 female animals per dose)

Control animals:

no

Details on study design:

Mortality / Viability: Twice Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 4 hours after administration on test day 0 (in common with the clinical signs) and twice daily during days 1-14 (once on the day of receipt, on holidays and days of terminal sacrifice).
Body weights: On the day of commencement of acclimatization, on test days 0 (prior to dose administration), day 07, and 14.
Clinical signs: Once daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 4 hours post test item administration on test day 0. Once daily during days 1-14

Statistics:

No statistical analysis was performed. Mean and Statistical Analysis was performed using validated Excel.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed in any of the treated animals of Step I, Step II , Step III and Step IV ( 300 and 2000 mg/Kg body weight)

Clinical signs:

other: All the animals of Step I (Animal No. 01, 02 and 03) and Step II (Animal No. 04, 05 and 06) treated at 300 mg/Kg body weight and all the animals of Step III (Animal No. 07, 08 and 09) and Step IV (Animal No. 10, 11 and 12) treated at 2000 mg/Kg body weigh

Gross pathology:

No gross pathological abnormalities were observed in any of the treated and surviving animals at terminal sacrifice, hence histopathologic analysis was not necessary.

MORTALITY / CLINICAL SIGNS

Dose	Step	Animal Number	Sex	Test day
				0*					1	2	3	4	5	6	7	8	9	10	11	12	13	14
				0.5	1	2	3	4
300 mg/Kg body weight	I	01	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
		02	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
		03	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
	II	04	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
		05	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
		06	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
2000 mg/Kg body weight	III	07	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
		08	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
		09	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
	IV	10	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
		11	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
		12	F	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1

 

BODY WEIGHT AND MEAN PERCENT BODY WEIGHT CHANGES

A.No	Sex	Body weight (g)				Body weight Change (%)
		Acclimatization	Day 0	Day 7	Day 14	(Day 0-7)	(Day 0-14 )
1	Female	168.6	188.0	203.2	224.4	8.1	19.4
2	Female	170.0	186.2	201.4	221.4	8.2	18.9
3	Female	166.5	182.4	197.6	218.8	8.3	20.0
MEAN		168.4	185.5	200.7	221.5	8.2	19.4
SD		1.41	2.33	2.33	2.29	0.10	0.43
4	Female	162.6	188.3	209.6	230.2	11.3	22.3
5	Female	159.2	186.5	207.4	228.6	11.2	22.6
6	Female	159.0	182.1	203.2	224.8	11.6	23.4
MEAN		160.2	185.6	206.7	227.9	11.4	22.8
SD		1.63	2.60	2.65	2.26	0.16	0.51
7	Female	151.3	198.6	218.8	239.6	10.2	20.6
8	Female	146.2	186.4	206.6	227.4	10.8	22.0
9	Female	159.8	184.0	204.2	225.0	11.0	22.3
MEAN		152.4	189.7	209.9	230.7	10.7	21.6
SD		5.61	6.39	6.39	6.39	0.35	0.71
10	Female	165.7	171.6	192.2	213.0	12.0	24.1
11	Female	158.6	165.8	186.4	207.6	12.4	25.2
12	Female	156.4	158.4	179.6	200.8	13.4	26.8
MEAN		160.2	165.3	186.1	207.1	12.6	25.4
SD		3.97	5.40	5.15	4.99	0.58	1.08

MACROSCOPIC FINDINGS

Dose	Step	Animal Number	Sex	Mode of death	Macroscopic findings
300  mg/Kg body weight	I	01	Female	Terminal Sacrifice	No Abnormality Detected
		02	Female	Terminal Sacrifice	No Abnormality Detected
		03	Female	Terminal Sacrifice	No Abnormality Detected
	II	04	Female	Terminal Sacrifice	No Abnormality Detected
		05	Female	Terminal Sacrifice	No Abnormality Detected
		06	Female	Terminal Sacrifice	No Abnormality Detected
2000  mg/Kg body weight	III	07	Female	Terminal Sacrifice	No Abnormality Detected
		08	Female	Terminal Sacrifice	No Abnormality Detected
		09	Female	Terminal Sacrifice	No Abnormality Detected
	IV	10	Female	Terminal Sacrifice	No Abnormality Detected
		11	Female	Terminal Sacrifice	No Abnormality Detected
		12	Female	Terminal Sacrifice	No Abnormality Detected

 

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results, the median lethal dose (LD50) of FAT 40879/B after single oral administration to female rats, observed over a period of 14 days is LD50 cut-off value of 5000 mg/Kg body weight and the estimated acute toxicity is between 2000 < ATE ≤ 5000.

Executive summary:

In a GLP-compliant study conducted according to OECD guideline 423, FAT 40879/B was administered to Wistar rats by oral gavage at a dose level of 300 mg/Kg body weight and 2000 mg/kg body weight to 2 dose groups in 4 steps. The first two steps (Step I & II) represents the dose group of 300 mg/kg bodyweight and the next two steps (Step III & IV) represents the dose group of 2000 mg/Kg bodyweight. Three animals were allocated at each step. The test item was formulated in vehicle (distilled water) at a concentration of 30 mg/mL for Step I and Step II and 200 mg/mL for Step III and Step IV, administered at a dose volume of 10 mL/kg body weight.

The animals were treated as follows:

Step I            3 females treated at 300 mg/kg       

Step II           3 females treated at 300 mg/kg      

Step III          3 females treated at 2000 mg/kg     

Step IV         3 females treated at 2000 mg/kg     

The animals were observed daily during the acclimatization period for mortality/viability and clinical signs and observations were recorded. All the animals were observed for clinical signs during first 30 minutes and at approximately 1, 2, 3 and 4 hours after administration of test item on test day 0 and once daily during test days 1‑14. Mortality/viability was recorded during first 30 minutes and at approximately 1, 2, 3 and 4 hours after administration of test item on test day 0 (in common with the clinical signs) and twice daily during days 1-14 (once on the day of receipt, on holidays and days of terminal sacrifice). Body weights were re­corded on test day 0 (prior to administration), and on day 7 and 14. All treated and surviving animals were necropsied and examined macroscopically at the end of observation period. All animals appeared normal throughout the acclimatization period. All animals of Step I (Animal No. 01, 02 and 03) and Step II (Animal No. 04, 05 and 06) treated at 300 mg/kg body weight and all the animals of Step III (Animal No. 07, 08 and 09) and Step IV (Animal No. 10, 11 and 12) treated at 2000 mg/kg body weight appeared normal at first 30 minutes, 1, 2, 3, and 4 hour observation on test day 0 after treatment and throughout the experiment period (up to day 14). The body weight of the animals was considered to be within the normal range of variability commonly recorded for this species, strain and age. There was body weight gain in all the animals by days 7 and 14 as compared to day 0. No gross pathological abnormalities were observed in any of the treated animals at terminal sacrifice, hence histopathology analysis was not necessary. Based on the results, the median lethal dose (LD50) of FAT 40879/B after single oral administration to female rats, observed over a period of 14 days is LD₅₀ cut-off value of 5000 mg/kg body weight and the estimated acute toxicity is between 2000 < ATE ≤ 5000.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

OECD guideline and GLP complaince study

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation)

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute Toxicity: Oral

In a GLP-compliant study conducted according to OECD guideline 423, FAT 40879/B was administered to Wistar rats by oral gavage at a dose level of 300 mg/Kg body weight and 2000 mg/Kg body weight to 2 dose groups in 4 steps. The first two steps (Step I & II) represents the dose group of 300 mg/kg bodyweight and the next two steps (Step III & IV) represents the dose group of 2000 mg/kg bodyweight. Three animals were allocated at each step. The test item was formulated in vehicle (distilled water) at a concentration of 30 mg/mL for Step I and Step II and 200 mg/mL for Step III and Step IV, administered at a dose volume of 10 mL/kg body weight. All the animals appeared normal throughout the study period. There were no mortality observed. No gross pathological abnormalities were observed in any of the treated animals at terminal sacrifice, hence histopathology analysis was not necessary. Based on the results, the median lethal dose (LD50) of FAT 40879/B after single oral administration to female rats, observed over a period of 14 days is LD50 cut-off value of 5000 mg/Kg body weight and the estimated acute toxicity is between 2000 < ATE ≤ 5000.

 

Acute Toxicity: Inhalation

Currently no study to assess acute inhalation toxicity of FAT 40879 is available. However, based on low vapour pressure (1.55 x 10^-35) and high melting point (>350 °C) the substance is considered to have low volatility. Synthesis and formulation of this chemical is performed in a closed process; the final product consists of liquid formulations only. Hence, the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalation route will be unlikely to occur. Based on column 2, ‘Specific rules for adaptation from column 1’ of the table given in REACH Annex VII, the study on acute inhalation toxicity only needs to be conducted if an exposure via inhalation is to be expected, based on the likelihood of an exposure to aerosols, particles or droplets. Referring to the expected low volatility of the substance, the fact that the substance is imported into the EU in a formulated form as a liquid formulation, the exposure via inhalation is unlikely. Further, FAT 40879 was found to be miscible in water (water solubility >519 g/L) and have low log partition coefficient (<-5.76), hence in the case of dust of the substance entering the respiratory tract, it will be trapped in the mucus and cleared, thereby further limiting the absorption. The chemical showed low toxicity potential (LD50 >2000 mg/kg bw) in the available acute oral toxicity study with no mortality or systemic toxicity, hence it does not need to be classified as STOT SE. Taking the above arguments into consideration, low toxicity potential is expected on acute exposure of FAT 40879 via inhalation routes and hence testing by the inhalation route was considered scientifically not necessary.

 

Acute Toxicity: Dermal

Currently no study to assess the acute dermal toxicity of FAT 40879 is available. However, the high molecular weight of the chemical >900g/mol is indicating it being too large for dermal absorption. It has water solubility of >519 g/L and n-octanol/water partition coefficient (log P) of <-5.76, indicating it being too hydrophilic to cross the lipid rich environment of the stratum corneum in the epidermis. Hence, the dermal uptake for the substance will be low. Synthesis and formulation of this chemical is performed in a closed process; the final product consists of liquid formulations only. In addition, the use of this substance will not result in aerosols, particles or droplets, so exposure to humans via the dermal route will be unlikely to occur. The chemical showed low toxicity potential in the available acute oral toxicity study, with no mortality or systemic toxicity (LD₅₀>2000 mg/kg bw), hence it does not need to be classified as STOT SE. Similarly, absence of local toxicity in in-vitro eye and skin irritation studies as well as absence of systemic toxicity in sensitization studies, further supports the conclusion that low toxicity is expected for the chemical via the dermal route. Taking the above arguments into account, low toxicity potential is expected on acute exposure of FAT 40879 via dermal route and hence testing by the dermal route was considered scientifically not necessary.

Justification for classification or non-classification

Based on the observed LD₅₀ of >2000 mg/kg bw in the acute oral toxicity study, the test substance does not considered to be classified according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.