Registration Dossier

Administrative data

Description of key information

Acute toxicity for OTNE:

- Oral (OECD TG 401): LD50 >5000 mg/kg bw

- Dermal (OECD TG 402): LD50 >5000 mg/kg bw

- Inhalation (route to route extrapolation from acute oral information): LD50 > 22360 mg/m3

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:
15 February 1980 - 29 February 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was conducted in compliance with the Code of GLP, Federal Register, 43, 247, Dec. 22, 1978 and the study can be compared to the deleted OECD 401 guideline for testing acute oral toxicity (OECD earlier version 401, 1981).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
1981
Deviations:
yes
Remarks:
10 male and 10 female rats, one dose tested
Principles of method if other than guideline:
Not relevant
GLP compliance:
yes
Remarks:
Code of GLP, Federal Register, 43, 247, Dec. 22, 1978.
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: TacN(SD)fBR (albino)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms (Germantown, N.Y.)
- Age at study initiation: no data
- Weight at study initiation: 180 to 280 grams
- Fasting period before study: yes, overnight
- Housing: singly in wire cages under standard laboratory conditions meeting the standards described in the 'Guide for the Care and Use of Laboratory Animals' (DHEW Publication No. (NIH) 78-23 Revised 1978).
- Diet: Purina Rodent Laboratory Chow 5001 ad libitum
- Water: ad libitum
- Acclimation period: seven days

ENVIRONMENTAL CONDITIONS: no data

IN-LIFE DATES: no data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 5.1 ml/kg bw.
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
10 males, 10 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality and pharmacotoxic signs at 1, 3, 5 and 24 hours following dosing and twice daily (once daily on weekends) for the remainder of the 14 day observation period. Weighing: pre-fast, dosing, and terminal.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, other: necropsy-tissues examined: lungs, heart, liver, spleen, kidney, adrenals, bladder, stomach, intestines. Other tissues examined grossly: the external carcass (fur, skin and orifices), peritoneal and pleural mucosa, internal mesentery.
Preliminary study:
In a preliminary range finding assay in which two fasted rats (one of each sex) were treated by gavage at 5000 mg/kg bw., there were no deaths during the 72 hour observation period.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: No mortality noted at this dose level.
Mortality:
There were no deaths in 10 males and 10 females dosed with the test article.
Clinical signs:
There were no clinical signs in any animal dosed at 5000 mg/kg bw. All the animals appeared normal in health and behavior throughout the 14 day observation period.
Body weight:
The animals all gained weight in a normal pattern.
Gross pathology:
There were no signs indicative of toxicity in any of the ten animals necropsied at term. No visible lesions in the tissues examined.
Interpretation of results:
other: criteria not met
Remarks:
according to EU CLP (EC 1272/2008 and its amendments)
Conclusions:
The LD50 for rats was in excess of 5000 mg/kg bw similar to OECD TG 401.
Executive summary:

The acute oral toxicity of the test substance was examined in a limit test equivalent to OECD TG 401. In a preliminary assay in which two rats were treated by gavage at 5000 mg/kg bw. Thereafter, ten male and ten female albino rats (TacN(SD)fBR) weighing between 180 and 280 grams were fasted overnight and were then dosed by gavage with 5000 mg/kg bw. of the test substance. In the preliminary assay no mortality occurred during the 72 h observation period. In the main test no mortality was seen, clinical signs and body weight gain were similar to controls.No other signs indicative of toxicity was seen. At necropsy, none of the animals had any signs indicative of systemic toxicity. The LD50 was in excess of 5000 mg/kg under the conditions of the current study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The acute oral toxicity result is of sufficient quality and adequate for this dossier.

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:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The derived acute inhalation toxicity result is of sufficient quality and sufficiently adequate for this dossier.

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:
18 March 1980 - 1 April 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed similar to the OECD TG 402 "Acute Dermal Toxicity", 1987, but was not performed under GLP. Report is well documented, and the design is considered scientifically accepted.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
8 male and 8 female rat, one dose tested
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Labs (Wilmington, Mass., USA)
- Age at study initiation: no data
- Weight at study initiation: 180 to 280 grams
- Housing: singly in wire cages under standard laboratory conditions meeting the standards described in the 'Guide for the Care and Use of Laboratory Animals' (DHEW Publication No. (NIH) 78-23 Revised 1978).
- Diet: Purina Rodent Laboratory Chow 5001 ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS: no data

IN-LIFE DATES: no data
Type of coverage:
open
Vehicle:
other: SDA39C (alcoholic solution)
Details on dermal exposure:
TEST SITE
- Area of exposure: area bounded by the nape of the neck, the mid dorsum between pectoral and pelvic girdles and the lateral aspects of the scapulae (the backs of the rats were clipped from the scapular region to the hips a day prior to treatment)
- % coverage: less than 30% of the body surface

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiping with a clean cloth
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml/100 g bw
- Concentration (if solution): 5000 mg/kg bw
- Constant volume or concentration used: yes, constant concentration
Duration of exposure:
24 hours
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
8 males and 8 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality and pharmacotoxic signs: at 1, 3, 5 and 24 hours following dosing and twice daily (once daily on weekends) for the remainder of the 14 day observation period. Weighing: Pre-dose and Day 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, other: necropsy-tissues examined: lungs, heart, liver, spleen, kidney, adrenals, bladder, stomach, intestines. Other tissues examined grossly: the external carcass (fur, skin and orifices), peritoneal and pleural mucosa, internal mesentery.
Preliminary study:
In a preliminary range finding assay in which two rats (one of each sex) were treated at 5000 mg/kg bw., there were no deaths during the 72 hour observation period.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: No mortality noted at this dose level.
Mortality:
No mortality was seen in the 8 males and 8 females dosed with the test article.
Clinical signs:
There were no clinical signs of toxicity in any animal dosed at 5000 mg/kg bw. All the animals appeared normal in health and behavior throughout the 14 day observation period.
Body weight:
The animals all gained weight in a normal pattern (10 g or more).
Gross pathology:
There were no signs indicative of toxicity in any of the rats necropsied at term. No visible lesions in the tissues examined.
Interpretation of results:
other: criteria are not met
Remarks:
according to EU CLP (1272/2008 and its amendments)
Conclusions:
This study found no effects that related to acute dermal toxicity in rats after administrating a single dose of 5000 mg/kg bw. The LD50 was in excess of 5000 mg/kg.
Executive summary:

The dermal acute toxicity of the substance, a yellow liquid, was examined according to a similar to OECD TG 402, 1987, protocol. First a preliminary study was performed with x males and females. In the final study eight male and eight female albino rats (Sprague-Dawley CD strain) were used. The animals weighing between 180 and 280 grams, were clipped on the day prior to dosing and the test substance, prepared in the diluent supplied, was applied onto the skin at 5000 mg/kg bw. The volume of the solution administered was 0.5 ml/100 g bw.

In the preliminary study no mortality occurred in 72h. In the main study none of the test animals showed any clinical signs indicative of systemic toxicity. All of the animals remained healthy throughout the study and gained weight in a normal manner. At necropsy performed on the survivors at term, none of the animals had any signs indicative of systemic toxicity. The dermal LD50 was greater than 5000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The acute dermal toxicity result is of sufficient quality and adequate for this dossier.

Additional information

Acute oral toxicity

The acute oral toxicity of the test substance was examined in a limit test. In a preliminary assay in which two rats were treated by gavage at 5000 mg/kg bw, there were no deaths during the 72 hour observation period. Ten male and ten female albino rats (TacN(SD)fBR) weighing between 180 and 280 grams were fasted overnight and were then dosed by gavage with 5000 mg/kg bw of the test article. None of the animals showed any pharmacological effect or clinical sign indicative of toxicity. All of the animals appeared normal in health and behaviour throughout the study. There were no deaths. At necropsy, none of the animals had any signs indicative of systemic toxicity. The LD50 was in excess of 5000 mg/kg under the conditions of the current study and the compound was therefore assessed as practically non-toxic. Based on EU criteria the substance does not have to be classified as acute toxic (oral).

Acute inhalation toxicity

The acute inhalation toxicity for the substance can be derived using data on the acute oral toxicity using the following methodology:CLP guidance (2015 3.1.3.3.4. Example 8, page 255):using the extrapolation formula 1 mg/kg bw = 0.0052 mg/l/4h. 

The LD50 of the substance for acute oral toxicity is > 5000 mg/kg bw. This 5000 mg/kg bw can be converted to > 26 mg/l = 26 gram/m3. Taking into account the inhalation absorption as 100% and oral absorption 86%, the acute inhalation toxicity would become =>22360 mg/kg bw.

The saturated vapour pressure of the substance is: 48.5 mg/m3 (MW*VapPres/ (8.3*293). This means that the acute inhalation LC50 > 22360 mg/m3 cannot be reached because it exceeds the saturated vapour pressure by more than a factor of 400 (461).

Acute dermal toxicity

The dermal acute toxicity of the test substance, a yellow liquid, was examined (similar to OECD test guideline 402, 1987). In a preliminary assay in which two rats of each sex were dosed by application of a prepared alcoholic solution of the test substance to the skin at 5000 mg/kg bw, there were no deaths during the 72 hour observation period. Eight male and eight female albino rats (Sprague-Dawley CD strain), weighing between 180 and 280 grams, were clipped on the day prior to dosing and the test substance, prepared in the diluent supplied, was applied onto the skin at 5000 mg/kg bw. The volume of the solution administered was 0.5 ml/100 g bw.

None of the test animals showed any clinical signs indicative of systemic toxicity. All of the animals remained healthy throughout the study and gained weight in a normal manner. At necropsy performed on the survivors at term, none of the animals had any signs indicative of systemic toxicity. The dermal LD50 was greater than 5000 mg/kg bw.

Justification for classification or non-classification

Based on the available information in the dossier, the substance OTNE does not need to be classified for acute toxicity via the oral, dermal, and inhalation route when considering the criteria outlined in the EU CLP Regulation (EC 1272/2008 and its amendments).