Registration Dossier

Administrative data

Description of key information

Oral: measured LD50 > 2000 and < 5000 mg/kg bw and the estimated LD50 cut-off was considered to be 2500 mg/kg bw, female rat, OECD TG 423, 2000

Inhalation: No data

Dermal: measured LD50 > 2000 mg/kg bw and the estimated LD50 cut-off value was considered to be > 5000 mg/kg bw, male/female rat, OECD TG 402, 2001

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:
08-09-2011 to 07-10-2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. All relevant validity criteria were met.
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
inspected: September 1999 ; signature: December 1999
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Remarks:
ICO: OFA-SD (lOPS Caw)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Recognised animal supplier
- Age at study initiation: ca. 6 weeks (nulliparous and non-pregnant)
- Weight at study initiation: females: 170 ±7 g and males: 141 ±2 g
- Fasting period before study: Overnight (ca. 18 hours) and fasting ceased ca. 4 hours after administration of the test item.
- Housing: Group housing 3 same sex animals per polycarbonate cages ( 48 cm x 27 cm x 20 cm) containing sterilized sawdust as bedding material as cage-enrichment.
- Diet: certified rat diet ad libitum
- Water: filtered certified water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ±2
- Humidity (%): 30 - 70
- Air changes (per hr): ca. 12 cycles/hr
- Photoperiod: 12 hours light / 12 hours dark

IN-LIFE DATES: From: 11-04-2000 To: 10-05-2000
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Identity: Corn Oil (batch number: reported in the full study report)
- Concentration in vehicle: The concentration of the test item in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION (if unusual): Not applicable. The test item was prepared in the vehicle. It was administered to the animals under a volume of 10 mL/kg. The volume administer was adjusted according to bodyweight on day of treatment.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: In the absence of data suggesting the test material was toxic, 200 mg/kg was chosen as the starting dose. The toxicity of the test item was assessed by stepwise treatment of groups of 3 males (initially) then 3 females, as appropriate. The first group was treated at a dose level of 200 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step 2000 mg/kg bw. Then a further test was conducted on three females at the highest dose level. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups..
Doses:
Initial: 200 mg/lg and final: 2000 mg/kg
No. of animals per sex per dose:
3 at the highest employed dose (3 males and 3 females)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality/Viability: Clinical signs and mortality: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The signs were graded according to fixed scales and the time of onset, degree and duration were recorded ; Bodyweights: Days 1 (pre-administration), 8 and 15
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 - < 5 000 mg/kg bw
Based on:
test mat.
Mortality:
2000 mg/kg bw: there was 1/3 female mortalities and 0/3 male mortalities. Mortality occurred on day 1 within 30 minutes of treatment.
200 mg/kg bw: there was no male mortalities.
Clinical signs:
2000 mg/kg bw: In the female mortality which occurred within 30 minutes of treatment, no clinical signs were observed. Females gave no clinical signs within the observation period. In males, no mortality occurred. Hypoactivity, piloerection, stiff gait and dyspnoea were noted in all males for 24 and 48 hours. All signs had reversed by day 3.
300 mg/kg bw: No significant clinical signs.
Body weight:
All survivors showed bodyweight gains over the study period. The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain and consistent with laboratory controls.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination.
Other findings:
- Organ weights: Not reported.
- Histopathology: Not reported. No macropathological abnormalities.
- Potential target organs: Not applicable.
- Other observations: Not applicable.

Applicant assessment indicates: the single female mortality at 2000 mg/kg bw/day may not be test item administration related, as there is no corresponding clinical signs and abnormal macro pathological findings in other females at the same dose level. All females gained body weight during the study. Additionally, the abnormal male clinical signs were not significant and were transient - ceasing within 72 hours. Expert judgement may associate these signs with the treatment procedure. It is considered that the single female mortality is not conclusively treatment related. This is given the absence of corresponding findings and additionally given the proximity of mortality to the oral gavage treatment procedure. The LD50 cut off value of 2500 mg/kg bw has been assigned. This may increased if additional evidence becomes available conclusively indicating the single female mortality is not test item related, on the weight of evidence.

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study the oral LD50 established to be > 2000 and < 5000 mg/kg bw in female Wistar rats.
Executive summary:

The study was performed according to OECD TG 423 and EU Method B1 tris guidelines in accordance with GLP to assess the acute oral toxicity of the test item following a single oral administration in the female Sprague-Dawley ICO: OFA-SD (lOPS Caw) strain male/female rat by the acute class method. The test item was administered by oral gavage in a corn oil vehicle to two sequential groups of three male rats at 200 mg/kg bw and/or three male and then three females at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). There was no mortality, clinical signs or abnormalities in necropsy and all animals gained weight at 200 mg/kg bw. There was a single female mortality in the second group at 2000 mg/kg bw within 30 minutes of treatment. No clinical signs was observed in females. In males no mortality occurred. Hypoactivity, piloerection, stiff gait and dyspnoea were clinical signs noted in all males on days 1 and/or day 2. Recovery was complete on day 3. The body weight gain shown by survivors over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals at any dose level. The oral LD50 value of the test item in Sprague-Dawley rats was established to be > 2000 and < 5000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
The available information as a whole meets the tonnage driven information requirements of REACH.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Regulation (EC) No. 1907/2006 Annex VII, column 2 section 8.5 (as amended by Commission Regulation (EU) 2016/863) the acute inhalation toxicity (OECD TG 436/433 or OECD TG 403) study does not need to be conducted based on available data for at least one additional route. There is an acute oral toxicity and an acute dermal toxicity study available. Toxicity via the inhalation route is not envisaged and the test item is not a skin corrosive. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.4, July 2017) the study does not need to be conducted.
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:
05-09-2001 to 25-10-2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. All relevant validity criteria were met.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
inspected: February 2000 ; signature: April 2000
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl: CD (SD) IGS BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Females (if applicable) nulliparous and non-pregnant: Yes.
- Age at study initiation: ca. 8 weeks age (nulliparous and non-pregnant)
- Weight at study initiation: > 200 g (actual: 212 – 238 g males and 207 – 224 g females)
- Fasting period before study: Not applicable
- Housing: during acclimation: group housed by sex; during study: individually housed in polypropylene cages furnished with softwood bedding.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C (or 22 ± 3 °C)
- Humidity (%): 30 - 70%
- Air changes (per hr): > 15 air changes per hour
- Photoperiod: 12 h light / 12 h dark

IN-LIFE DATES: From: To: 05-09-2001 to 19-09-2001
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: the day before treatment the back and flanks were clipped free of hair. Dorsal area application.
- % coverage: Approximately 10% of total body surface
- 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 and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test item.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg (or dose volume 2.19 mL/kg)
- Concentration (if solution): See below.
- Constant volume or concentration used: 2.19 mL volume ; at a dose level of 2000 mg/kg bw test item.
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 per sex per dose (5 male/5 female)
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, and 4 hours and subsequently once daily for days 2 to 15. Local effects were examined once daily days 2 to 15 after the completion of the 24-hour exposure period. Full details on the scoring and criteria (appears consistent with Draize for Erythema) are given in the full study report. Individual bodyweights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
Statistics:
No statistical analyses were performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
- Clinical observations: No signs of systemic toxicity were noted during the observation period.
- Dermal reactions: All sites indicated no irritation (score = 0) from day 1 to day 14. There was evidence of crust formation on days 4 to 5 in female-1. This observation ceased on day 6.
Body weight:
It was considered there was no toxicologically significant effects on bodyweight. All males/females gained bodyweight during the study.
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 2000 mg/kg bw in male/female Sprague-Dawley rat. Under the conditions of this study and under the Globally Harmonized Classification System of Classification and Labelling of Chemicals (GHS), the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight.
Executive summary:

The study was performed according to OECD TG 402 and EU Method B.3 Acute Toxicity (Dermal) and in accordance with GLP to assess the acute dermal toxicity of the test item in the Sprague-Dawley Crl: CD (SD) IGS BR strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin 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. There was no mortality during the study. There were no signs of system toxicity or abnormalities on necropsy. It was considered there was no toxicologically significant effects on bodyweight. All males/females gained bodyweight during the study. No signs of dermal irritation were noted (score 0) up to day 14 in all males/females. Crust formation was observed in days 4 and 5 on one female application site only which reversed at day 6. The dermal LD50 was established to exceed 2000 mg/kg bw in male/female Sprague-Dawley Crl: CD (SD) IGS BR rat. 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:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
The available information as a whole meets the tonnage driven information requirements of REACH.

Additional information

ORAL: Key study : OECD TG 420, 2000: The study was performed according to OECD TG 423 and EU Method B1 tris guidelines in accordance with GLP to assess the acute oral toxicity of the test item following a single oral administration in the female Sprague-Dawley ICO: OFA-SD (lOPS Caw) strain male/female rat by the acute class method. The test item was administered by oral gavage in a corn oil vehicle to two sequential groups of three male rats at 200 mg/kg bw and/or three male and then three females at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). There was no mortality, clinical signs or abnormalities in necropsy and all animals gained weight at 200 mg/kg bw. There was a single female mortality in the second group at 2000 mg/kg bw within 30 minutes of treatment. No clinical signs was observed in females. In males no mortality occurred. Hypoactivity, piloerection, stiff gait and dyspnoea were clinical signs noted in all males on days 1 and/or day 2. Recovery was complete on day 3. The body weight gain shown by survivors over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals at any dose level. The oral LD50 value of the test item in Sprague-Dawley rats was established to be > 2000 and < 5000 mg/kg body weight.

 

INHALATION: No data.

DERMAL: Key study : OECD TG 402, 2001: The study was performed according to OECD TG 402 and EU Method B.3 Acute Toxicity (Dermal) and in accordance with GLP to assess the acute dermal toxicity of the test item in the Sprague-Dawley Crl: CD (SD) IGS BR strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin 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. There was no mortality during the study. There were no signs of system toxicity or abnormalities on necropsy. It was considered there was no toxicologically significant effects on bodyweight. All males/females gained bodyweight during the study. No signs of dermal irritation were noted (score 0) up to day 14 in all males/females. Crust formation was observed in days 4 and 5 on one female application site only which reversed at day 6. The dermal LD50 was established to exceed 2000 mg/kg bw in male/female Sprague-Dawley Crl: CD (SD) IGS BR rat. 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.

Justification for classification or non-classification

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for acute toxicity: oral

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for acute toxicity: inhalation

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for acute toxicity: dermal