Registration Dossier

Administrative data

Description of key information

The potential of acute toxicity of 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid was evaluated for the oral and dermal route.
An oral acute study on 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid showed 40% of mortalities in the rats treated with 5000 mg/kg. For the dermal route, a read-across is proposed with pentaerythritol ethoxylated esters with acrylic acid (CAS number 51728-26-8); in this study no mortality was observed at the dose of 2000 mg/kg in rats. To sum up, the oral and dermal LD50 were higher than 2000 mg/kg in rats.
No data is available by inhalation.

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:
28 July 1998 and 14 August 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study (OECD 401)
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan U.K. Ltd. Bicester, Oxon, England.
- Age at study initiation: 5-7 weeks old
- Weight at study initiation: 127 to 170 g
- Fasting period before study:
- Housing: in groups of up to five rats of the same sex in metal cages
- Diet (e.g. ad libitum): standard laboratory rodent diet , ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 15 days prior to the start of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ° C
- Humidity (%): 30-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12, artificial light (0700 - 1900 hours)
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Dose volume of 4.429 ml/kg bw.
The appropriate dose volume of the test substance was administered to each rat by oral gavage using a syringe and either a plastic cannula (18 g) or catheter (8 choke).
Doses:
5000 mg/kg
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
Cages of rats were checked at least twice daily for mortalities.
Animals were observed soon after dosing and at frequent intervals for the remainder of Day l. On subsequent days animals were observed on at least two occasions during the day (once in the morning and again at the end of the experimental day, with the exception of the day of study termination - morning only). The nature and severity of clinical signs and the time these were observed were recorded at each observation.
Animals surviving treatment were observed for 7 or 14 days respectively after dosing.
The bodyweight of each rat was recorded Days 1 (prior to dosing) 8 and 15 (or at death).
All surviving animals in the main study were killed by carbon dioxide asphyxiation at study termination (Day 15).
All animals were subjected to a macroscopic examination which consisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.


Statistics:
no
Preliminary study:
In the absence of precise toxicological information, a preliminary study comprising of two rats (one male and one female) dosed at 3200 mg/kg bodyweight was conducted to help define the toxic potential of the test substance and aid in selection of a suitable dosage for the main study.
There were no deaths. Clinical signs comprised piloerection, hunched posture, increased salivation, abnormal faeces and ungroomed appearance seen in both rats with lethargy and pallid extremities seen in the female only. Bodyweight gain for both rats were considered satisfactory for a study of this nature.
There were no macroscopic abnormalities noted in either animal at the terminal necropsy on Day 8.

Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 40% of mortality was observed at this dose
Mortality:
Two males and two females died (Day 2) during the study.
Clinical signs:
Piloerection was observed in all rats within two minutes of dosing. This sign persisted and was accompanied in rats later on Day 1 and/or at later intervals during the study by abnormal faeces and ungroomed appearance seen in all rats, with hunched posture, waddling/unsteady gait, lethargy, pallid extremities, increased salivation and thin appearance less commonly observed. Recovery of surviving rats, as judged by external appearance and behaviour, was complete in all animals by Day 15.
Body weight:
All surviving rats were considered to have achieved satisfactory bodyweight gains during the study.
Gross pathology:
Macroscopic examination of decedent animals revealed congestive changes (characterised by dark tissue/prominent blood vessels) in the heart, liver, spleen, stomach and along the alimentary tract. Gaseous distension and fluid contents were also noted in the stomach and along the alimentary tract. No macroscopic abnormalities were observed for surviving animals killed at study termination on Day 15.
Other findings:
no
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under these experimental conditions, the acute median lethal oral dose (LD50) to rats of SR-494 was indicated to be slightly greater than 5000 mg/kg bodyweight.
Executive summary:

A group of ten fasted rats (five males and five females) received a single oral gavage dose of the test substance administered. as supplied, at a dosage of 5000 mg/kg bodyweight. Two males and two females died during the study. All remaining animais were killed as scheduled at study termination (Day 15) and subjected to a macroscopic examination.

Clinical signs of reaction to treatment characterised by piloerection, abnormal faeces and ungroomed appearance were seen in all rats, with hunched posture, waddling/unsteady gait, lethargy, pallid extremities, increased salivation and thin appearance less commonly observed. There were no other signs of reaction to treatment and recovery was complete in all surviving rats by Day 15. All surviving rats were considered to have achieved satisfactory bodyweight gains throughout the study. Macroscopic examination of the decedents revealed congestive changes to the majority of tissues and organs with gaseous distension and fluid contents in the stomach and along the alimentary tract. No macroscopic abnormalities were observed for surviving animais killed at study termination on Day 15.

On the basis of 40% mortality at a dosage of 5000 mg/kg bodyweight, the acute median lethal oral dose (LD50) to rats of SR-494 was indicated to be slightly greater than 5000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
Value:
5 000 mg/kg bw
Quality of whole database:
The oral acute toxicity study is reliable with a klimisch score of 1.

Acute toxicity: via inhalation route

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
May-June 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study has been conducted according to OECD guideline no. 402 and under GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc.
- Age at study initiation: young adults
- Weight at study initiation: 200-260 g
- Fasting period before study: not applicable
- Housing: individually caging
- Diet (e.g. ad libitum): ssnif SM>RM-z+H complete diet ad libitum
- Water (e.g. ad libitum): tap water from the municipal supply
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-3
- Humidity (%):30-70%
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6:00 am to 6:00 pm

IN-LIFE DATES: From: 3 May 2012 To: 17 May 2012
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
The back of each animal was shaved (app. 10% area of the total body surfce) app. 24 hours prior to treatment. The test item was applied as a single dose as suplied to the shaved skin and remained ni contact with the skin for the 24-hour exposure period. Sterile gauze pads were placed on the skin of rats to cover the test item. These gauze pads were kept in contact with the skin by a patch with adhesive hypoallergenic plaster. The entire trunk of the animal was then crapped with semi occlusive plastic wrap for 24 hours.

REMOVAL OF TEST SUBSTANCE
At the end of the exposure period, the area of skin treated with the test item was washed with water of body temperature.
Duration of exposure:
The test was applied as supplied, as a single dermal 24-hour exposure followed by a 14-day observation period.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 animals/sex
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no details
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology
Statistics:
no data
Preliminary study:
not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: (No mortality occurred)
Mortality:
No mortality occurred.
Clinical signs:
No systemic clinical signs were observed after the treatment with the test substance or during the 14-day observation period. No local signs were observed immediately after treatment or during the 14-day observation period.
Body weight:
The body weight and the body weight gain of the treated animals did not show any effects related to the test substance.
Gross pathology:
There was no evidence of test substance-related observations at a dose level of 2000 mg/kg bw at necropsy.
Other findings:
no
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The caute dermal median lethal dose (LD50) of the test substance was found to be higher than 2000 mg/kg bw in male and female Wistar rats.
Executive summary:

An acute dermal toxicity study was performed with Pentaerythritol, ethoxylated, esters with acrylic acid in CRL:(WI)Wistar rats, in compliance with OECD Guideline No.402. A limit test was carried out at 2000 mg/kg bw in both sexes (5 rats/sex). The test item was applied as supplied, as a single dermal 24 -hour exposure following by a 14 -day observation period. Clinical observations were performed on all animals at 1 and 5 hours after dosing and daily for 14 days thereafter. Bodyweight was measured prior to dosing on Day 0 and on Day 7 and 14. Rats were euthanized and a gross macroscopic examination performed at the end of the 2 -week observation period (Day 14).

No mortality occurred and no clinical signs were observed after the treatment with the test item during the 14 -day observation period. After treatment with the test item no local signs were observed or during the 14 -day observation period. The body weight and body weight gain of the treated animals did not show any test item-related effect. There was no evidence of the test item-related observations at a dose level of 2000 mg/kg at necropsy.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The dermal acute toxicity study is reliable with a klimisch score of 1.

Additional information

Oral acute toxicity

In the key study, a group of ten fasted rats (five males and five females) received a single oral gavage dose of the test substance administered as supplied, at a dosage of 5000 mg/kg bodyweight. Two males and two females died during the study. All remaining animals were killed as scheduled at study termination (Day 15) and subjected to a macroscopic examination.

Clinical signs of reaction to treatment characterised by piloerection, abnormal faeces and ungroomed appearance were seen in all rats, with hunched posture, waddling/unsteady gait, lethargy, pallid extremities, increased salivation and thin appearance less commonly observed. There were no other signs of reaction to treatment and recovery was complete in all surviving rats by Day 15. All surviving rats were considered to have achieved satisfactory bodyweight gains throughout the study. Macroscopic examination of the decedents revealed congestive changes to the majority of tissues and organs with gaseous distension and fluid contents in the stomach and along the alimentary tract. No macroscopic abnormalities were observed for surviving animals killed at study termination on Day 15. On the basis of 40% mortality at a dosage of 5000 mg/kg bodyweight, the acute median lethal oral dose (LD50) to rats of 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid was indicated to be slightly greater than 5000 mg/kg bodyweight.

In the supporting study, a group of ten fasted rats (five males and five females) received a single oral gavage dose of the test substance, administered as supplied at a dose level of 2000 mg/kg bodyweight. No mortalities was observed in this study. Clinical signs of reaction to treatment included piloerection, hunched posture, wadding/unsteady gait, lethargy, pallid extremities, soft to liquid faeces, increased salivation, walking on toes and ungroomed appearance all seen in all rats. There were no other signs of reaction to treatment and recovery was complete in all animals by Day 6. All rats were considered to have achieved satisfactory bodyweight gains throughout the study. Macroscopic examination of animals killed on Day 15 revealed no abnormalities. The discriminating dose to rats of 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid was demonstrated to be 2000 mg/kg bw

Dermal acute toxicity

An acute dermal toxicity study was performed with Pentaerythritol, ethoxylated, esters with acrylic acid acid (an analoguous substance of 2,2-bis(hydroxymethyl) -1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid) in CRL:(WI)Wistar rats, in compliance with OECD Guideline No.402. A limit test was carried out at 2000 mg/kg bw in both sexes (5 rats/sex). The test item was applied as supplied, as a single dermal 24 -hour exposure following by a 14 -day observation period. Clinical observations were performed on all animals at 1 and 5 hours after dosing and daily for 14 days thereafter. Bodyweight was measured prior to dosing on Day 0 and on Day 7 and 14. Rats were euthanized and a gross macroscopic examination performed at the end of the 2 -week observation period (Day 14).

No mortality occurred and no clinical signs were observed after the treatment with the test item during the 14 -day observation period. After treatment with the test item no local signs were observed or during the 14 -day observation period. The body weight and body weight gain of the treated animals did not show any test item-related effect. There was no evidence of the test item-related observations at a dose level of 2000 mg/kg at necropsy.

The discriminating dose to rats of Pentaerythritol, ethoxylated, esters with acrylic acid was demonstrated to be 2000 mg/kg bw.


Justification for selection of acute toxicity – oral endpoint
Two studies are available for this endpoint. The selected study was performed on the same composition of the registered substance.

Justification for selection of acute toxicity – dermal endpoint
Only one study is available for this endpoint.

Justification for classification or non-classification

Toxicity by oral or dermal route is very low (LD50> 5000 mg/kg), no classification is expected for this endpoint according to the Regulation EC n°1272/2008 and to the Directive 67/548/EEC.