Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
April to June 1980
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail, test method comparable to guideline.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
Qualifier:
equivalent or similar to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
not specified
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
TNO/W 74
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Recognised animal supplier.
- Age at study initiation: Not reported.
- Weight at study initiation: 150 - 200 g
- Fasting period before study: Not reported
- Housing: Makrolon type III or II cages.
- Diet: Altromin-R maintenance diet for rats and mice, ad libitum.
- Water: ad libitum
- Acclimation period: Not reported.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not reported.
- Humidity (%): Not reported.
- Air changes (per hr): Not reported.
- Photoperiod (hrs dark / hrs light): Not reported.
Route of administration:
oral: gavage
Vehicle:
poloxamer
Remarks:
given by its alternative trade name "Lutrol" in study report.
Details on oral exposure:
Administered once via ,,Schlundsonde'' ("Gullet-tube"), i.e. oral gavage.
Doses:
100, 500, 750, 1000, 1500, 2000 and 2500 mg/kg bw (M); 100, 250, 500, 600, 750, 1000, 1250, 1750 and 2000 mg/kg bw (F).
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: At least once daily for 14 days.
- Necropsy of survivors performed: Yes.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
1 258 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
988 mg/kg bw
Based on:
test mat.
Mortality:
Mortalities occurred.
Clinical signs:
Poisoning symptoms occured about 5 minutes after treatment, including disturbances of general behaviour (apathy), laboured breathing, convulsions, tremors, and lying in prone/lateral positions. The symptoms persisted in surviving animals for up to 24 hours and disturbances in general condition for up to 6 days after treatment. (Translated from German).
Body weight:
No data
Gross pathology:
Post-mortem examinations of mortalities indicated pale, spotted livers, spleen and kidneys. Empysematous lung-changes were also noticeable. No pathalogical features were found in surviving animals upon euthanisation at the end of the study period. (Translated from German).

Table 1: Acute oral toxicity in "soberly-handled" rats (translated from German)

 Dose [mg/kg bw]  Toxicology Result [Dead / With Symptoms / Total Used]  Time of Death following Treatment  LD50 (14 -days) [mg/kg bw]
Male Rats
 100  0/0/10*  -

1258 (1044 - 1502)

b = 5.92**

 500  0/10/10  -
 750  1/10/10  1h 13'
 1000  3/10/10  2h 32'
 1500  7/10/10  1h 30' - 4h 20'
 2000  8/10/10  0h 15' - 24h 0'
 2500  10/10/10  0h 50' - 4h 20'
Female Rats
 100  0/10/10*  -

988 (841 - 1164)

b = 5.63**

 250  0/10/10  -
 500  0/10/10  -
 600  2/10/10  1h 40'
 750  3/10/10  2h 15' - 24h 0'
 1000  4/10/10  1h 5' - 2h 10'
 1250  7/10/10  0h 32' - 2h 47'
 1750  9/10/10  0h 20' - 4h 20'
 2000  10/10/10

 0h 30' - 24h 0'

* Maximum dose without negative effects

** Regression coefficient

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
EU criteria met
Conclusions:
Under the conditions of this study the LD50 was determined to be 1258 mg/kg bw in the male Wistar rat and 988 mg/kg bw in the female Wistar rat.
Executive summary:

The study was performed following a method equivalent or similar to OECD TG 401 to assess the acute oral toxicity potential of the test substance to male and female Wistar rats. The test item was administered as a single dose via oral gavage to groups of 10 male and 10 female rats per dose-level orally. Under the conditions of this study the LD50 was determined to be 1258 mg/kg bw for male Wistar rats and 988 mg/kg bw for female Wistar rats.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
test procedure in accordance with guideline (OECD 401)
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
not specified
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Remarks:
Crj: CD(SD)IGS
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Recognised laboratory supplier.
- Age at study initiation: 5 weeks.
- Weight at study initiation: 169.1 - 189.1 g (males), 125.0 - 147.5 g (females).
- Fasting period before study: 18 - 20 hours.
- Housing: 2 - 3 animals per cage in polycarbonate cages from a recognised laboratory supplier, with "white flakes" as floor bedding.
- Diet: solid feed (supplier detailed in study report), ad libitum.
- Water: drinking water with 2ppm added sodium hypochlorite, ad libitum.
- Acclimation period: 7 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2 ° C.
- Humidity (%): 55 ± 10 %.
- Air changes (per hr): 13 - 15.
- Photoperiod (hrs dark / hrs light): Not reported.
Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
10 mL/kg dose volume, calculated based on bodyweight on day of administration.
Details on oral exposure:
Single administration via oral gavage. The dose volume was 10mL/kg, calculated based upon the bodyweight on the day of administration.
Doses:
The dose was set based on the results of a preliminary study, which found that a single dose of 2000 mg / kg of the test substance caused death in 1/3 of each male and female group. The chosen dosing scheme was therefore 0(vehicle), 690, 980, 1400, and 2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
yes
Remarks:
One group of animals was given the vehicle with no test item.
Details on study design:
- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: Up to 6 hours after administration, followed by at least once daily for 14 days.
- Necropsy of survivors performed: Yes.
Statistics:
The mean and standard deviation were calculated for each group. No test was performed to determine statistical significance.
Key result
Sex:
male
Dose descriptor:
LDLo
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LDLo
Effect level:
1 400 mg/kg bw
Based on:
test mat.
Mortality:
Mortalities occurred.
Clinical signs:
In all males and females of the test substance group, respiratory distress, decreased locomotor activity, tremor and prone position were observed 5 minutes after administration, and slow respiration was observed 15 minutes after administration. Salivation was scattered 30 to 45 minutes after administration in the 980 mg / kg group, and recumbency was observed in the 1400 mg / kg group from 15 minutes to 2 hours after administration. In the case of death, in addition to the above findings, convulsions or cyanosis were observed immediately before death. In the survivors, respiratory distress was 15 minutes after administration, salivation was 1 hour after administration, prone and recumbent positions, and tremor was 3 hours after administration. Decreased locomotor activity and slow breathing disappeared by the day after administration. (translated from Japanese)
Body weight:
Males in the 1400 mg / kg (and above) groups showed decreased weight-gain. No abnormalities were observed in other test substance administration groups (translated from Japanese).
Gross pathology:
In the fatal cases, dark red patches in the lung were observed in one male and one male in the 2000 mg / kg group, and another male in the same group had a dark red spot in the thymus. No changes were found in the survivors.

Histologically, edema in the lungs and hemorrhage in the thymus were observed corresponding to macroscopic dark red spots in the lungs and dark red spots in the thymus.

(translated from Japanese)

Table 1: Acute oral toxicity in rats

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
EU criteria met
Conclusions:
Under the conditions of this study the lowest lethal dose (LDLo) was determined to be 2000 mg/kg bw in the male rat and 1400 mg/kg bw in the female rat.
Executive summary:

The study was performed according to OECD TG 401 to assess the acute oral toxicity potential of the test substance to male and female rats. The test item was administered as a single dose via oral gavage to groups of 5 male and 5 female rats per dose-level orally. Under the conditions of this study the lowest lethal dose (LDLo) was determined to be 2000 mg/kg bw for male rats and 1400 mg/kg bw for female rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
988 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:
April to June 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not specified
Qualifier:
equivalent or similar to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
not specified
GLP compliance:
not specified
Test type:
traditional method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
TNO/W 74
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Age at study initiation: not specified
- Weight at study initiation: 150-200g
- Fasting period before study: 16h
- Housing: Makrolon cages (type III/II)
- Diet (e.g. ad libitum): Altromin-R rat and mouse maintenance diet, provided ad libitum (except for exposure period)
- Water (e.g. ad libitum): water, ad libitum (except for exposure period)
- Acclimation period: not specified; study reports state that animals were "soberly handled" (implies handled carefully/gently)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

IN-LIFE DATES: April - June 1980.
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: vapour-enriched clean air
Remark on MMAD/GSD:
No specific mention of MMAD/GSD in study report; 200 L/h air was supplied with 150 g heated (melted), dynamically-evaporated test-item.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The test item was heated to 55-57 °C, in order to melt it. The melted test item was then "dynamically evaporated" into a 200 L/hour flow of moisture-enriched, clean air.
- Exposure chamber volume: 10 L PVC box for whole-body exposure.
- Method of holding animals in test chamber: Not applicable; animals were in chamber for whole-body exposure.
- Source and rate of air: Unspecified source; 200L/h flow-rate.
- Method of conditioning air: moisture-enrichment.
- System of generating particulates/aerosols: Not specified; some sort of atomiser/nebuliser is implied by the test ("dynamic evaporation").
- Method of particle size determination: Not reported.
- Treatment of exhaust air: Not reported.
- Temperature, humidity, in air chamber: Not reported.

TEST ATMOSPHERE
- Brief description of analytical method used: Not reported; total exposure is calculated or inferred from the quantity of test item vapourised into the air stream entering the test chamber.
- Samples taken from breathing zone: Not reported.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Not reported.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Not reported.
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
7 h
Concentrations:
200 L/h air was supplied with ~150g test item, indicating a concentration of ~0.11 g/L test item.
No. of animals per sex per dose:
5 per sex per dose.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality, daily. Clinical signs during exposure and over the course of day one, followed by daily. Any evidence of mortality or overt toxicity was recorded at each observation. Individual body weights were recorded prior to treatment on the day of exposure and once weekly thereafter.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, and any other relevant toxicological effects were reported.
Statistics:
Where necessary, lethal dose calculations (mean) and confidence intervals were calculated with "Probit-Analyse" (Fink & Hund, Arzneimittelforschung 15, 624, 1965).
Sex:
male/female
Dose descriptor:
LCLo
Effect level:
> 110 mg/L air
Based on:
test mat.
Exp. duration:
7 h
Remarks on result:
not determinable
Remarks:
All animals survived for 14 days after a 7h exposure to approximately 0.11g/L (110mg/L) of the test item.
Mortality:
No mortalities occurred during the study period.
Clinical signs:
other: During exposure, excited states were observed for all animals, accompanied by slight irritation of the nasal mucous membranes. No other clinical signs were seen for the animals.
Body weight:
All animals showed expected gains in bodyweight.
Gross pathology:
At autopsy, 2/5 male and 1/5 female rats had "lung-changes" (dark red or grey discolouration with "bloomed" areas). The other rats "appeared normal".
Other findings:
- Organ weights: Not reported.
- Histopathology: Not reported.
- Potential target organs: Not applicable.
- Other observations: Not applicable.

Additional comments regarding test atmosphere generation:

Due to the solid state of the test item at standard temperature and pressure, the test item had a tendency to condense on the walls of the delivery tubing and test chamber. Solidified test-item had to be periodically re-evaporated by pouring warm water over the affected areas of tubing or test-chamber wall.

 

Table 1. Mortality data summary:

Group Number

Estimated Atmosphere Concentration (mg/L)

Mortalities

 

 

Female

Male

Total

1

110

0/5

0/5

0/10

 

 

 

 

 

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, the inhalation 7h-LC50 (male/female) was considered to be >110 mg/L within the TNO/W 74 Wistar rat.
Executive summary:

The study was performed historically according to a method similar to OECD TG 403 and EU Method B.2, to assess the acute inhalation toxicity of the test item. A single group of ten Wistar: TNO/W 74 strain rats (five males and five females) were exposed to an aerosol atmosphere of the test item. The groups were exposed for seven hours using a full-body exposure system, followed by a fourteen day observation period. The estimated mean atmosphere concentration was 110 mg/L. Mean Mass Median Diameter (particle size) and geometric Standard Deviation were not reported. There were no mortalities in the estimated 110 mg/L achieved atmosphere concentration. Some nasal mucous membrane irritation and "excited states" in the rats were observed. After exposure, no clinical signs were observed for any animals, and the study authors remark that following exposure they all appeared to "meet the physiological norm" and show expected gains in bodyweight. 2/5 male and 1/5 female rats showed lung abnormalities at macroscopic post-mortem examination (dark red or grey discolouration with "bloomed" areas). No abnormalities were found at macroscopic post-mortem examination in the other rats. Under the conditions of this study, the inhalation 7h-LC50 (male/female) could not be determined, and was therefore considered to be >110 mg/L within the Wistar: TNO/W 74 rat.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
110 mg/m³

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:
April to June 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail. Test procedure is comparable to guideline study with acceptable restrictions.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not specified
Qualifier:
equivalent or similar to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
not specified
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
TNO/W 74
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier.
- Females (if applicable) nulliparous and non-pregnant: Not specified.
- Age at study initiation: not specified.
- Weight at study initiation: 150 – 200 g.
- Fasting period before study: 16 h.
- Housing: during acclimation and observation period: Makrolon Type III/II cages.
- Diet (e.g. ad libitum): Altromin-R rat and mouse maintenance diet, ad libitum.
- Water (e.g. ad libitum): Water, ad libitum.
- Acclimation period: not specified; study reports that animals were handled "soberly" (implies carefully/gently).

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not specified.
- Humidity (%): Not specified.
- Air changes (per hr): Not specified.
- Photoperiod: Not specified.

IN-LIFE DATES: From: April 1980 To: June 1980.
Type of coverage:
semiocclusive
Vehicle:
poloxamer
Remarks:
reported under an alternative trade name ("Lutrol").
Details on dermal exposure:
TEST SITE
- Area of exposure: previously-clipped and undamaged back skin.
- % coverage: Not specified.
- Type of wrap if used: The area of application was covered by a semi-occlusive dressing and wrapped with a piece of elastic self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the 24-hour contact period the bandage was carefully removed and the treated skin flushed with water, soap and cotton wool.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5000 mg/kg bw
- Concentration (if solution): Not specified.
- Constant volume or concentration used: A solution of the test item in lutrol was used, in sufficient quantity to deliver a dose of 5000 mg/kg bw test-item.
Duration of exposure:
24 hours
Doses:
5000 mg/kg
No. of animals per sex per dose:
5 per sex per dose (5 male/5 female)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and mortality checks were conducted during the acclimatisation period, and throughout test day 1; Subsequent observations occured daily for days 2 to 15. Body weights were measured prior to testing, but not reported. Local effects were examined daily days 2 to 15 after the completion of the 24-hour exposure period. The study report does not disclose observations of erythema, however elsewhere in the report a separate skin-irritation/corrosion test is performed and documented.
- Necropsy of survivors performed: yes
Statistics:
Where necessary, LD50/LC50 calculations and confidence-interval calculations were performed using "Probit-Analyse" (Fink and Hund, Arzneimittelforschung 15, 624, 1965).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
- Clinical observations: None reported.
- Dermal reactions: Not reported; however a separate skin irritation/corrosion study elsewhere in the study report covers this.
Body weight:
No remarks were made regarding bodyweight; applicant assessment indicates that based on the rest of the study report (where bodyweights are reported), this implies that animals showed expected gains in bodyweight.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
- Organ weights: Not reported.
- Histopathology: Not reported. No macropathological abnormalities.
- Potential target organs: Not applicable.
- Other observations: Not applicable.
Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study the dermal LD50 was established to exceed 5000 mg/kg bw in male/female Wistar rats. 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 on the basis of absence of significant clinical toxicological effects and/or bodyweight increases in all males/females.
Executive summary:

The study was performed historically according to a method similar to OECD TG 402 and EU Method B.3 Acute Toxicity (Dermal), to assess the acute dermal toxicity of the test item in the TNO/W 74 strain rat. A group of ten animals (five males and five females) was given a single, 24 hour semi-occluded dermal application of the test item delivered in poloxamer to intact skin at a dose level of 5000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There was no mortality during the study. There were no signs of system toxicity or abnormalities on necropsy. Applicant assessment indicates there were no toxicologically significant effects on bodyweight. Signs of dermal irritation were not reported; however an additional study in the same report documents a skin-irritation/corrosion test. The dermal LD50 was established to exceed 5000 mg/kg bw in male/female TNO/W 74 rats. 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 on the basis of absence of significant clinical toxicological effects and/or bodyweight increases in all males/females.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Additional information

Justification for classification or non-classification