Registration Dossier

Administrative data

Description of key information

Acute Toxicity: Oral: LD50 = > 2,000 mg/kg bw; OECD 420; Blair Yasso., 2017

Acute Toxicity: Inhalation: Waiver

Acute Toxicity: Dermal: LD50 = > 2,000 mg/kg bw; OECD 402; A Sanders., 2018

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:
10 Oct 2016 - 02 Feb 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
The study was conducted in accordance with international guidelines and in accordance with GLP. All relevant validity criteria were met.
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
Used for data analysis where dosing performed in the study is below 5000 mg/kg
Deviations:
yes
Remarks:
The pre-test body weight of Animal 4 exceeded + 20% of the mean pre-test body weights of the previously dosed animals. No impact on the study.
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
yes
Remarks:
The pre-test body weight of Animal 4 exceeded + 20% of the mean pre-test body weights of the previously dosed animals. No impact on the study.
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
The pre-test body weight of Animal 4 exceeded + 20% of the mean pre-test body weights of the previously dosed animals. No impact on the study.
GLP compliance:
yes (incl. certificate)
Test type:
up-and-down procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Raleigh NC and Stone Ridge NY
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: body weight variation did not exceed ±20% of the mean body weight at the start of treatment
- Fasting period before study: yes
- Housing: Animals were individually housed in suspended wire-bottom cages that conform to the size recommendations in the Guide for the Care and Use of Laboratory Animals (National Research Council). Absorbent paper bedding, placed beneath the cage, changed at least three times per week.
- Diet (e.g. ad libitum): Fresh PMI Rat Chow (Diet #5012) will be available ad libitum except for 16 to 20 hours prior to dosing.
- Water (e.g. ad libitum): free access to mains drinking water
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Exact temperature was not indicated but both temperature and humidity was continuously recorded using automated recording device.
- Humidity (%): Exact temperature was not indicated but both temperature and humidity was continuously recorded using automated recording device.
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 : 12
IN-LIFE DATES: Not clarified in the study report
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
The test article was administered orally by syringe and a dosing needle on an mg/kg basis.
Initially, a single female Sprague Dawley rat was dosed orally with TX16352 at a dose level of 2000 mg/kg. Since the animal survived, four additional females were dosed at 2000 mg/kg.
Doses:
2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Each animal was given single dose of 2.0 mL - 2.5 mL dose volume of 2000 mg/kg of the test item (i.e. animal 1&2: 20.mL, animal 3&5 : 2.2 mL and animal 4 received 2.5 mL)
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 0.25, 1, 2 and 4 hours after dosing then daily thereafter for 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs and body weight
Statistics:
not required
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
No deaths reported
Clinical signs:
Piloerection, partially chewed food, chromorhinorrhea, few feces, and localized hair loss (side of neck) were observed.
Body weight:
all animals showed expected weight gain.
Gross pathology:
No abnormalities noted at necropsy.

Table 1:   Number of animals dead (and with evident toxicity)

 

Dose

(mg/kg bw

 

 

Mortality

(# dead / total)

 

Time range of deaths

(hours)

 

 

Number with evident toxicity

(# / total)

 

Male

Female

Combined

Male

Female

Combined

 

-

0/5

0/5

n/a

-

0/5

0/5

Table 2. Systemic Observation

Dose

2000 mg/kg

Animal ID/sex

1F

2F

3F

4F

5F

Time period

 

 

 

 

 

15 minutes

 

S

 

 

 

Hour 1

 

F,S

 

F

 

Hour 2

 

R

 

F

F

Hour 4

 

F

1

 

 

Day 1

F

F,S,X

1

 

 

Day 2

 

F,S,X

1

 

 

Day 3

 

 

1

 

 

Day 4

 

 

1

 

 

Day 5

 

 

 

2

 

Day 6

 

 

 

2

 

Day 7

 

 

 

 

 

Day 8

 

 

 

 

 

Day 9

 

 

 

 

 

Day 10

2

 

 

 

 

Day 11

 

 

 

 

 

Day 12

 

 

 

 

 

Day 13

2

 

 

 

 

Day 14

 

 

 

 

 

No entry indicates animal appeared normal at that observation period.
1 = Hair loss: left side of the neck 2 = Partially chewed food on pan liner F = Piloerection S = Chromorhinorrhea X = Few feces

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral median lethal dose (LD50) 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 Unclassified).
Executive summary:

OECD 425 (2017) - In an acute oral toxicity study, a group of fasted, 8-12 week old female Wistar rats were given a single oral dose of TX16352 at a single dose rate of 2000 mg/kg bw (limit test) and observed for 14 days.

In the absence of mortality during the observation period, the oral LD50 was estimated to be greater than 2000 mg/kg bw.

In addition, there were no treatment related clinical signs, necropsy findings or changes in body weight observed in any of the individuals.

In conclusion, the test item, TX16352 did not meet the criteria for classification according to Regulation (EC) No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixture.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
The endpoint is concluded based on a single key study with a Klimisch rating of 1. No effects were observed up to the limit dose of 2000 mg/kg bw/day

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
The vapour pressure of the substance was determined to be < 3.2 x 10-3 Pa , which renders inhalation exposure to this substance negligible, negating the need for an acute toxicity study via the inhalation route. This waiver is in accordance with REACH Annex VIII, Section 8.5.2, Column 2 and ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R7.a.
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:
10 May 2018 - 06 November 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Guideline study performed under GLP. All relevant validity criteria were met.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
24 February 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Oxon, UK
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: body weight variation did not exceed ±20% of the mean body weight at the start of treatment
- Fasting period before study: not specified
- Housing: individually housed in suspended solid floor polypropylene cages furnished with softwood flake bedding.
- Diet (e.g. ad libitum): free access to food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK)
- Water (e.g. ad libitum): free access to mains drinking water
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25 ºC
- Humidity (%): 30 - 70 %
- Air changes (per hr): minimum of 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 : 12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: back and flanks of each animal were clipped free of hair.
- % coverage: Approximately 10% of total body surface
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi‑occluded with a piece of self‑adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- The treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP and distillled water to remove any residual test item.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 2000 mg/kg bw
- Constant volume or concentration used: Undiluted
Duration of exposure:
24h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and mortality checks were conducted at approximately 0.5, 1, 2, 4, hours and subsequently once daily for 14 days. Full details on the scoring and criteria (consistent with Draize) are given in the full study report. Individual bodyweight were recorded prior to application of the test item on Day -1 (before dosing) and on Days 0, 1 and 14.
- Necropsy of survivors performed: yes
Statistics:
n/a
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Mortality:
There were no deaths.
Clinical signs:
There were no signs of systemic toxicity.
Body weight:
All animals showed expected gains in body weight.
Gross pathology:
No abnormalities were noted at necropsy.

Table 1.  Clinical Observations and Mortality Data

 

Dose

(mg/kg bw

 

 

Mortality

(# dead / total)

 

Time range of deaths

(hours)

 

 

Number with evident toxicity

(# / total)

 

Male

Female

Combined

Male

Female

Combined

 2000

0/5

0/5

0/10

n/a

0/5

0/5

0/5

Table 2.  Dermal effects Noted After Initiation of Exposure

 

Days after exposure

 

 Erythema(#/ total)

 Edema(# / total)

Other(# / total)

Male

Female

Male

Female

Male

Female

1

0/5

0/5

0/5

0/5

5/5 (BrBl)

5/5 (Bl)

2

0/5

0/5

0/5

0/5

5/5 (Br)

0/5

3

0/5

0/5

0/5

0/5

5/5 (Br)

0/5

4

0/5

0/5

0/5

0/5

5/5 (Br)

0/5

5

0/5

0/5

0/5

0/5

5/5 (Br)

0/5

6-14

0/5

0/5

0/5

0/5

0/5

0/5

0 =       No reactions

 Bl=       Blanching of the skin

 Br=       Light brown discoloration of the epidermis

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study the dermal LD50 was established to exceed 2000 mg/kg bw in male & female Wistar (RccHan:WIST) strain rat. Applicant assessment indicates, under the conditions of this study, and according to the GHS criteria, the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight.
Executive summary:

A study was performed according to OECD TG 402; Acute Toxicity (Dermal) and in accordance with GLP to assess the acute dermal toxicity of the test substance in the Wistar (RccHan:WIST)  strain rat.  A group of ten animals (five males and five females) were given a single, 24 hour, semi‑occluded dermal application of the test item to intact skin at a dose level of 2000 mg/kg body weight  for a duration of 24 hour under semi-occluded condition and sequent observation for 14 days.

There was no mortality during the study. There were no signs of system toxicity or abnormalities on necropsy. All animals showed expected gains in body weight during the study. Very slight erythema, blanching of the skin and light brown discoloration of the epidermis were noted during the observation period. Treated skin sites of female animals appeared normal two days after treatment and of male animals six days after treatment.

Under the conditions of this study the dermal LD50 was established to exceed 2000 mg/kg bw in Wistar (RccHan:WIST) strain rat. Applicant assessment indicates, under the conditions of this study, and according to the GHS criteria, the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
The endpoint is concluded based on a single key study with a Klimisch rating of 1. No effects were observed up to the limit dose of 2000 mg/kg bw/day

Additional information

Acute Toxicity: Oral

OECD 420 (2017) - In an acute oral toxicity study (OECD 420) conducted on the registered substance, groups of fasted, 8-9 week old, female Wistar rats were given a single oral dose of the substance at doses 2000 mg/kg bw and observed for 14 days.  Oral LD50 Females = >2000 mg/kg bw.  According to the UN GHS classification, the test item does not meet the classified with respect to acute oral toxicity.

Acute Toxicity: Inhalation

The vapour pressure of the substance was determined to be < 3.2 x 10-3 Pa , which renders inhalation exposure to this substance negligible, negating the need for an acute toxicity study via the inhalation route.  This waiver is in accordance with REACH Annex VIII, Section 8.5.2, Column 2 and ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R7.a.

Acute Toxicity: Dermal

OECD 402 (2018) - In an acute dermal toxicity study (OECD 402) conducted on the registered substance, groups of five, 8 - 12 week old, male/female Wistar (RccHan:WIST) rats were given a single dose of undiluted test item salts at doses 2000 mg/kg bw and observed for 14 days.  Oral LD50 Females = >2000 mg/kg bw.  According to the UN GHS classification, the test item does not meet the classified with respect to acute dermal toxicity.

Justification for classification or non-classification

According to the UN GHS classification, the test item does not meet the classification with respect to acute toxicity.