Registration Dossier

Administrative data

Description of key information

An oral limit test was performed on the BPA 2PO with 2/5 deaths in female and 0/5 males observed. Clinical signs were seen widely in the treated animals, but all surviving animals appeared normal at the end of the observation period with no histological findings. The animals that died showed effects to GI tract, lungs, liver and kidneys. A read-across study on BPA 2PO and a supporting study on BPA 5PO both gave an LD50>2,000 mg/kg bw.

It was not considered appropriate to attempt an inhalation toxicity study as the substance is a viscous liquid with negligible vapour pressure.

Acute dermal toxicity on BPA 5PO showed no clinical signs. There was a slight reduction in weight / weight gain in some animals and one rat showed transient slight irritation. The acute dermal LD50was >2000 mg/kg bw.

Read across considered valid and further animal testing not justified.

Justification for selection of acute toxicity – oral endpoint

The key study was conducted in a GLP accredited laboratory according to OECD Testing Guideline 401.

Justification for selection of acute toxicity – inhalation endpoint

REACH Guidance Document R.7.a, Chapter. 7.4 Acute toxicity, indicates that in principle no inhalation studies are needed when vapour pressure < 0.1 Pa at 20°C or particle size > 100 µm. The substance is a viscous liquid with a very negligible vapour pressure at 20°C. The use of the substance is limited to industrial and professional users and does not involve the forming of aerosols, particles or droplets of an inhalable size. Exposure to humans via the inhalation route is considered unlikely to occur.

Justification for selection of acute toxicity – dermal endpoint

The study was conducted in a GLP accredited laboratory according to OECD Testing Guideline 402.

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
DMSO
Details on oral exposure:
Exposure period of 14 days.
Doses:
2000 mg/kg bodyweight.
No. of animals per sex per dose:
5
Control animals:
not specified
Preliminary study:
A range-finding study was conducted using 1 female and 1 male rat to establish the dosing regime. The dose level was 2000 mg/kg, the concentration was 200 mg/ml and the dose volume was 10 ml/kg. Overt signs of toxicity or death were observed 30 minutes, 1, 2 and 4 hours after dosing, and then once daily for 5 days. The range-finding test found no deaths or clinical signs of toxicity. As a result, a dose of 2000 mg/kg bodyweight was selected for the main study.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Two females died one or two days after dosing.
Clinical signs:
Common signs of systemic toxicity noted were ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration with isolated incidents of hypothermia and loss of fighting reflex.
Body weight:
Surviving animals showed expected bodyweight gain during the study.
Gross pathology:
Abnormalities noted for the two females that died were haemorrhagic lungs, dark liver, dark kidneys, slight haemorrhage of the gastric mucosa and/or haemorrhage of the small and large intestines. No abnormalities were noted of the animals that were killed at the end of the study.

See the attached background material for tables providing information on individual clinical observations and mortality data in the range finding study, individual clinical observations and mortality data in the main study, individual bodyweights and weekly bodyweight gain in the main study, and individual necropsy findings in the main study.

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley strain of rat was found to be greater than 2000 mg/kg bodyweight.
Executive summary:

The oral acute toxicity of the test substance was determined in accordance with the OECD Guideline for Testing of Chemicals 401. Male and female rats were exposed to 2,000 mg/kg bw of the test substance. The LD50 was found to be > 2,000 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline available
Principles of method if other than guideline:
The test was carried out by means of stomach intubation in rats that had been fasted. Food was given after the dose was received.
GLP compliance:
no
Test type:
other: tested by means of stomach intubation
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
other: intubation
Vehicle:
propylene glycol
Doses:
5.00, 3.98, 3.16, 3.51 and 1.99 g BPA/kg
No. of animals per sex per dose:
5
Control animals:
not specified
Preliminary study:
No information given.
Sex:
male
Dose descriptor:
LD50
Effect level:
3.65 other: g/kg bodyweight
Based on:
not specified
Remarks on result:
other: Using method of Weil 1952
Sex:
male
Dose descriptor:
LD50
Effect level:
3.42 other: g/kg bodyweight
Based on:
not specified
Remarks on result:
other: Using method of Litchfield and Wilcoxon 1949
Sex:
female
Dose descriptor:
LD50
Effect level:
2.81 other: g/kg bodyweight
Based on:
not specified
Remarks on result:
other: Using method of Weil 1952
Sex:
female
Dose descriptor:
LD50
Effect level:
3.03 other: g/kg bodyweight
Based on:
not specified
Remarks on result:
other: Using method of Litchfield and Wilcoxon 1949
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3.27 other: g/kg bodyweight
Based on:
not specified
Remarks on result:
other: Using method of Weil 1952
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3.23 other: g/kg bodyweight
Based on:
not specified
Remarks on result:
other: Using method of Litchfield and Wilcoxon 1949
Mortality:
Male:

5.00 g/kg = 1/5 (24 hrs); 5/5 (48 hrs); 5/5 (14 days)
3.98 g/kg = 0/5 (24 hrs); 3/5 (48 hrs); 3/5 (14 days)
3.16 g/kg = 0/5 (24 hrs); 1/5 (48 hrs); 1/5 (14 days)
3.51 g/kg = 0/5 (24 hrs); 1/5 (48 hrs); 1/5 (14 days)
1.99 g/kg = 1/5 (24 hrs); 1/5 (48 hrs); 1/5 (14 days)

Female:


5.00 g/kg = 0/5 (24 hrs); 5/5 (48 hrs); 5/5 (14 days)
3.98 g/kg = 1/5 (24 hrs); 3/5 (48 hrs); 3/5 (14 days)
3.16 g/kg = 0/5 (24 hrs); 3/5 (48 hrs); 4/5 (14 days)
3.51 g/kg = 0/5 (24 hrs); 2/5 (48 hrs); 2/5 (14 days)
1.99 g/kg = 0/5 (24 hrs); 0/5 (48 hrs); 0/5 (14 days)
Clinical signs:
Depression, ataxia, hematuria and lacrimation.
Gross pathology:
Gross examination of rats that died showed pathological changes in the GI tract, liver, kidneys and lungs. In most cases changes were also seen in thymus, spleen, adrenals, bladder, pituitary and brain.

The signs of intoxication, chiefly depression and ataxia, produced by a single oral dose of the test substance were evident for the most part during the first 24 hours post dose. Most of the rats that died were dead by 48 hours after dosing; surviving rats all appeared normal at 72 hours.

Interpretation of results:
GHS criteria not met
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 of the test substance to male and female rats was found to be 2,810 mg/kg bw.
Executive summary:

The oral acute toxicity of the test substance was determined by exposing male and female rats to 5.00, 3.98, 3.16, 3.51 and 1.99 g/kg bw of the test substance by means of stomach intubation. The LD50 was found to be 2,810 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals and environmental conditions:
Test animals
Source: Charles River Japan
Age at study initiation: 9 weeks
Weight at study initiation: 229-246 g
Fasting period before study: 16-17 hr
Housing: 3/cage
Diet: MR(pellet), Nosan Corporation, Japan, ad libitum
Water: tap water (filtered and UV sterilized), ad libitum
Acclimation period: 5 days

Environmental condition
Temperature (℃): 23.6-24.6
Humidity (%): 51-60
Air changes (per hr): >10/hr
Photoperiod (hrs dark/hrs light): 12hr/12hr
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
Concentration in vehicle: 20.0 w/v% (200 mg/mL)
Amount of vehicle (if gavage): 10 mL/kg body weight
Doses:
2000 mg/kg
No. of animals per sex per dose:
3 females/dose
Control animals:
no
Details on study design:
Duration of observation period following administration: 14 days
Frequency of observation and weighing: 1, 4, 8 and 15 day
Necropsy of survivors performed: yes
Other examinations performed: clinical signs
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
not specified
Mortality:
No deaths observed during exposure period
Clinical signs:
3 of 3 (Step 1) and 2 of 3 (Step 2) animals showed restlessness soon after dose.
3 of 3 animals (both Step 1 and 2) showed decrease in locomotive activity after dose.
1 of 3 animals of Step 1 showed salivation soon after dose.
1 of 3 animals (both Step 1 and 2) showed diarrhea 2-4 hr after dose.
3 of 3 animals (both Step 1 and 2) showed soiled fur on 1 day after dose.
Body weight:
Gained normally
Gross pathology:
No abnormalities detected at necropsy.
Interpretation of results:
GHS criteria not met
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 of the test substance was >2,000 mg/kg bw.
Executive summary:

The oral acute toxicity of the test substance was determined in accordance with the OECD Guideline for Testing of Chemicals 423. Female rats were exposed to 2,000 mg/kg bw of the test substance. The LD50 was found to be >2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The key study conducted on BPA 2PO and the two supporting studies (conducted on BPA 2PO and BPA 5PO) agree that the LD50 of the test substance is >2000 mg/kg bw. The substance is not classified as an acute oral toxin according to EU CLP.

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
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:
2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
other: Limit test
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
One day prior to treatment, hair was removed from the dorso-lumbar region of each rat with electric clippers taking care to avoid damaging the skin, exposing an area equivalent to approximately 10% of the total body surface area. The test substance was applied by spreading it evenly over the prepared skin. The treatment area (approximately 50 mm x 50 mm) was covered with porous gauze held in place with a non-irritating dressing, and further covered by a waterproof dressing encircled firmly around the trunk of the animal. Treatment in this manner was performed on Day 1 (day of dosing) of the study only. At the end of the 24 hours exposure period the dressing was carefully removed and the treated area of skin was washed with warm water (30 - 40°C), to remove any residual test substance. The treated area was blotted dry with absorbent paper. A record of the weight of the test substance dispensed and the amount remaining after dosing was made. The balance of these two weights was compared with the predicted usage as a check that the doses had been administered correctly.
Duration of exposure:
24 hours.
Doses:
A group of ten rats (five males and five females) was treated at 2000 mg/kg bodyweight.
No. of animals per sex per dose:
5.
Control animals:
no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths or signs of adverse effects
Clinical signs:
Very slight irritation in one animal Day 2; resolved by Day 3
Body weight:
Slight reduction or reduced gain in body weight in some animals. Significance not clear.
Gross pathology:
No histological findings

There were no deaths and no systemic response to treatment in any animal. Very slight erythema was seen in one animal on Day 2. This reaction had resolved by Day 3. A loss of bodyweight was noted in one male, and a low or no bodyweight gain was noted for three females between Days 1 and 8. A low bodyweight gain was also noted for one female between Days 8 and 15. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study. No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15. See attached background material for tables summarising information on dermal reactions, individual and group mean bodyweights, individual bodyweight changes, and macroscopic findings.

Interpretation of results:
GHS criteria not met
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 of the test substance to rats was found to be >2,000 mg/kg bw.
Executive summary:

The acute dermal toxicity of the test substance was determined in accordance with the OECD Guideline for Testing of Chemicals 402. A group of 10 rats (5 males and 5 females) received a single topical application of the test substance, as supplied, at a dose level of 2000 mg/kg bodyweight, for a duration of 24 hours. There were no deaths and no systemic response to treatment in any animal. Very slight erythema was seen in one animal on Day 2. This reaction had resolved by Day 3. A loss of bodyweight was noted in one male, and a low or no bodyweight gain was noted for three females between Days 1 and 8. A low bodyweight gain was also noted for one female between Days 8 and 15. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study. No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15. The acute dermal LD50 of the test substance to rats was found to be >2000 mg/kg bw.

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

Additional information

Justification for classification or non-classification

Oral and dermal LD50 were found to be > 2,000 mg/kg bw, therefore the registered substance does not need to be classified for acute toxicity according to the EU CLP (EC No 1272/2008) regulation. No data is available regarding acute inhalation toxicity and in view of lack of exposures no studies are indicated. The registered substance is not a pure aliphatic, alicyclic and aromatic hydrocarbons and has a relatively high viscosity (visually checked) and so does not indicate an immediate concern for aspiration hazard.