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Administrative data

Description of key information

Acute oral toxicity (rats): LC50 >2000 mg/ kg bw


Acute inhalation toxicity (rats): LC50 >0.942 mg/L but <5.607 mg/L mg/ kg bw

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:
26 Jun 2017 - 25 July 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Batch: 09892701
- Purity: 99.9%
- Physical state/ Appearance: clear colourless liquid
- Expiry Date: 06 March 2018
- Storage Conditions: room temperature in the dark
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS (UK) Limited
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 - 12 weeks
- Fasting period before study:
- Housing: in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes
- Diet: ad libitum, with the exception of an overnight fast immediately before dosing and for approximately 3 to 4 hours after dosing
- Water: ad libitum, with the exception of an overnight fast immediately before dosing and for approximately 3 to 4 hours after dosing
- Acclimation period: at leat 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30- 70
- Air changes (per hr): at least 15
- Photoperiod: 12 hrs dark / 12 hrs light
Route of administration:
oral: gavage
Vehicle:
arachis oil
Remarks:
For the purpose of the study the 300 mg/kg dose level the test item was freshly prepared, as required, as a solution in arachis oil BP. For the purpose of the 2000 mg/kg dose level the test item was used as supplied
Details on oral exposure:
In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose.
In the absence of toxicity at a dose level of 300 mg/kg, an additional animal was treated at 2000 mg/kg.
In the absence of mortality at a dose level of 2000 mg/kg, an additional group of 4 animals was treated at 2000 mg/kg.
A total of five animals were therefore treated at a dose level of 2000 mg/kg in the study.
Doses:
300 and 2000 mg/kg
No. of animals per sex per dose:
1 in the 300 mg/kg dose
5 n the 2000 mg/kg dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of clinical observations were made 30 minutes, 1, 2, and 4 hours after dosing and then daily for 14 days.
- Frequency of individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
- Necropsy of survivors performed: yes . This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Preliminary study:
A sighting test has been conducted at dose levels of 300 mg/kg and 2000 mg/kg.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
other: Signs of systemic toxicity noted in animals treated at a dose level of 2000 mg/kg were ataxia, hunched posture and lethargy. There were no signs of systemic toxicity noted in the animal treated at a dose level of 300 mg/kg.
Gross pathology:
Abnormalities noted at necropsy of one animal treated at a dose level of 2000 mg/kg were ulcerated gastric mucosa, stomach adhered to the wall of the abdomen and thickened non-glandular epithelium of the stomach. No abnormalities were noted at necropsy
of the remaining animals that were killed at the end of the study.
Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
The acute oral median lethal dose (LD5o) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight.
Executive summary:

Introduction
The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat.
Methods
Following a sighting test at dose levels of 300 mg/kg and 2000 mg/kg, a further group of four fasted females was given a single oral dose of test item at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.
Results
Mortality. There were no deaths.
Clinical Observations. Signs of systemic toxicity noted in animals treated at a dose level of 2000 mg/kg were ataxia, hunched posture and lethargy. There were no signs of systemic toxicity noted in the animal treated at a dose level of 300 mg/kg.
Body Weight. Animals showed expected gains in body weight except for one animal treated at a dose level of 2000 mg/kg which showed body weight loss during the first week with expected gain in body weight during the second week.
Necropsy. Abnormalities noted at necropsy of one animal treated at a dose level of
2000 mg/kg were ulcerated gastric mucosa, stomach adhered to the wall of the abdomen and thickened non-glandular epithelium of the stomach. No abnormalities were noted at necropsy of the remaining animals that were killed at the end of the study.
Conclusion
The acute oral median lethal dose (LDso) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Category 5).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
25 February 2020 - 31 March 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 433 (Acute Inhalation Toxicity: Fixed Concentration Procedure)
Version / remarks:
2018
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Appearance: Colorless liquid
- Storage conditions: Room temperature and protected from light
- Lot number: 09892803
- Purity: 98.8% (excludes optical isomer)
- Expiration date: 15 February 2023
Species:
rat
Strain:
other: [Crl:CD (SD)IGS Rats
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories; Raleigh, North Carolina 27610
- Rationale for use of males: OECD 433 guideline
- Age at study initiation: 9 to 10 weeks
- Weight at study initiation: 256 to 295 grams
- Housing: Polycarbonate cages with a stainless steel mesh lid.
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light):12 hour light/dark cycle
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Remark on MMAD/GSD:
Group MMAD (µm) Range
1 2.7 1.75 – 1.82
2 3.6 1.92 – 1.94
Details on inhalation exposure:
Restraint was required for nose only exposure. Animals were restrained (individual plastic exposure tube) during the exposure administration procedures (4 hours = 240 minutes). Animals were also restrained in tubes for up to 10 minutes each before and after exposure, during which time each animal was loaded into and out of the cones. The total time of restraint was expected to be up to a maximum of 260 minutes including the exposure time. The animals were habituated to the method of restraint once for 30 to 60 minutes preceding their test article exposure.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
ca. 4 h
Concentrations:
Nominal: 1.0 and 5.0 mg/L
Measured: 0.942 and 5.607 mg/L
Mean achieved gravimetric concentration was below target by 6% for Group 1.
Mean achieved gravimetric concentration was above target by 12% for Group 2.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: hourly during exposure, upon return to cage and hourly up to 2 hours after test article administration, then twice daily
- Frequency of weighing: once pretest and again on Days 1 (prior to exposure), 4, 8 and 15
- Observations involved: general condition, skin and fur, eyes, nose, oral cavity, abdomen and external genitalia as well as evaluations of respiration
- Necropsy of survivors performed: yes
- Other examinations performed: Special attention was paid to the lungs and respiratory tract for signs of irritancy and local toxicity

Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
> 0.942 - < 5.607 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
Five unscheduled deaths occurred. All 5 animals in the 5.0 mg/L exposure group were euthanized for welfare reasons on Days 1 or 2 of the exposure period due to MEDOL-10-related marked breathing impairment. Relevant macroscopic findings included gaseous distension of the gastrointestinal tract (stomach, small intestine and/or large intestine) and were considered to be secondary to aerophagia.
Clinical signs:
salivation
Body weight:
The animals exposed to 1.0 mg/L of test article showed normal weight gains during the 14 days after exposure.
The animals exposed to 5.0 mg/L of test article did not have body weights measured after exposure
Gross pathology:
Macroscopic changes at 1.0 mg/L were limited to red discoloration of the thymus in 1 male. The finding was considered incidental and not related to MEDOL-10 exposure.
Other findings:
Clinical Observations
The animals exposed to 1.0 mg/L of test article showed no test article-related clinical signs during or after exposure.
The animals exposed to 5.0 mg/L of test article showed no test article-related clinical signs during the exposure but showed excessive salivation, decreased activity and wet rales soon after the exposure. As a result of worsening conditions, 4 of 5 animals were euthanized on the day of exposure and the 5th animal was euthanized on the morning after exposure.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The lethal concentration in 50 percent of the animals (LC50) would be estimated to be >0.942 mg/L but <5.607 mg/L.
Executive summary:
Introduction-

The purpose of this study was to investigate the acute inhalation toxicity of MEDOL-10 and, if appropriate, allow the use of serial steps of Fixed Concentration Procedure (FCP) to provide a ranking of test article toxicity. Data from this study was primarily used to
classify and label the test article in accordance with the United Nations (UN) Globally Harmonized System of Classification and Labelling of Chemicals (GHS).


Results-

Five unscheduled deaths occurred. All 5 animals in the 5.0 mg/L exposure group were euthanized for welfare reasons on Days 1 or 2 of the exposure period due to MEDOL-10-related marked breathing impairment. Relevant macroscopic findings included gaseous distension of the gastrointestinal tract (stomach, small intestine and/or large intestine) and were considered to be secondary to aerophagia.


Conclusion-

Thus, the lethal concentration in 50 percent of the animals (LC50) would be estimated to be >0.942 mg/L but <5.607 mg/L which would categorize the test article as GHS Category 4.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
> 0.942 - < 5.607 mg/L air
Physical form:
inhalation: dust / mist

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:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

An acute oral toxicity study was conducted (Envigo Research Limited, 2017, Study CY02SF) to assess the toxicity of MEDOL-10 following a single oral administration. The study was conducted in accordance with EC Method B1 bis and OECD test guideline 420, and in compliance with GLP.


 


In the absence of data regarding the toxicity of the test item, one fasted female Winsar strain rat was given a single oral dose of test item at a dose level of 300 mg/kg body weight. As no toxicity was observed an additional female was treated with a dose of 2000 mg/kg body weight. In the absence of mortality at this dose level, a group of four females was treated with a single oral dose of test item at a dose level of 2000 mg/kg. Sufficient time was allowed between each dose group to confirm the survival of the previously dosed animals. The animals were observed for 14 days.


 


Signs of systemic toxicity noted in female rats treated at a dose level of 2000 mg/kg included ataxia, hunched posture and lethargy. No signs of systemic toxicity noted in the female treated at a dose level of 300 mg/kg. Animals showed expected body weight gains except for one female treated at a dose level of 2000 mg/kg which showed body weight loss during the first week with expected gain in body weight during the second week. Abnormalities noted at necropsy of one female treated at a dose level of 2000 mg/kg were ulcerated gastric mucosa, stomach adhered to the wall of the abdomen and thickened non-glandular epithelium of the stomach. No abnormalities were noted at necropsy of the remaining animals that were sacrificed at the end of the study.


 


It was concluded that the acute median lethal dose in the female Wistar strain rat following single oral administration of MEDOL-10 was greater than 2000 mg/kg body weight.


 


 


 


An acute inhalation toxicity study was conducted (Covance Laboratories, 2020, Study MC11PM) to assess the toxicity of MEDOL-10 by liquid
aerosol via nose only inhalation for 4 hours at target exposures of 1.0 and 5.0 mg/L.


 


MEDOL-10 was exposed to rats at the target inhalation exposure levels of 1.0 and
5.0 mg/L for 4 hours (actual exposures of 0.942 and 5.607 mg/L, respectively, based on gravimetric results). The 1.0 mg/L exposure level was well-tolerated but the 5.0 mg/L exposure level resulted in 100% mortality within 1 day after exposure. Thus, the lethal concentration in 50 percent of the animals (LC50) would be estimated to be >0.942 mg/L but <5.607 mg/L which would categorize the test article as GHS Category 4.


 


 


According to paragraph 16 of the OECD guidance document 237 (1) dermal toxicity study may be waived if the test chemical has shown no adverse effects in an acute oral toxicity test up to 2000 mg/kg bw. As the LC50 of acute oral toxicity of MEDOL-10 was found to be greater than 2000 mg/kg bw, the acute dermal toxicity study was not conducted.


 


1. OECD (2017), Guidance Document on Considerations for Waiving or Bridging of Mammalian Acute Toxicity Tests, OECD Series on Testing and Assessment, No. 237, OECD Publishing, Paris,https://doi.org/10.1787/9789264274754-en

Justification for classification or non-classification

The acute oral LD50 of MEDOL-10 was determined to be greater than 2000 mg/kg. According to table 3.1.1 of CLP Regulation (Commission Regulation 1272/2008) MEDOL-10 is not classified for acute oral toxicity.


The acute inhalation lethal concentration in 50 percent of the animals (LC50) would be estimated to be >0.942 mg/L but <5.607 mg/L which would categorize the test article as GHS Category 4. According to the CLP Regulation (Commission Regulation 1272/2008) the cut off values for category 4 classification are as follows: 1.0 < ATE ≤ 5.0. Even though the estimated LC50 falls slightly outside of this range, the 1.0 mg/L exposure level was well-tolerated but the 5.0 mg/L
exposure level resulted in 100% mortality within 1 day after exposure, therefore category 4 classifcation(H332: Harmful if inhaled) is the most appropriate classification for Medol 10.


According to paragraph 16 of the OECD guidance document 237 (1) dermal toxicity study may be waived if the test chemical has shown no adverse effects in an acute oral toxicity test up to 2000 mg/kg bw. As the LC50 of acute oral toxicity of MEDOL-10 was found to be greater than 2000 mg/kg bw, the acute dermal toxicity study was not conducted and therefore it can be assumed that Medol 10 is not classified for acute dermal toxicity.