Propylidynetrimethanol, ethoxylated, esters with acrylic acid, reaction products with diethylamine

Endpoint summary

Description of key information

The potential of acute toxicity of Diethylamine modified ethoxylated trimethylolpropane triacrylate was evaluated in two studies, one by oral route and one by dermal route. No mortalities were showed in both studies; 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:

19 June 2012 - 18 July 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: breeder: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approximately 8 weeks old on the day of treatment
- Mean body weight at study initiation: 222 g (range: 212 g to 238 g)
- Fasting period before study: yes, during the night before treatment
- Housing: polycarbonate cages with stainless steel lids
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: the animals were acclimated to the study conditions for a period of 5 or 8 days before treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h.

IN-LIFE DATES: 26 June 2012 to 13 July 2012.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Justification for choice of vehicle:
The vehicle used in the study was selected from the results of solubility assays performed by CIToxLAB France prior to the preliminary assay.
The solubility assay first started with drinking water treated by reverse osmosis and 0.5% methylcellulose aqueous solution and was not satisfactory. However, a yellow suspension was obtained at 200 mg/mL with corn oil.
- Maximum dose-volume applied: 20 mL/kg.

DOSAGE PREPARATION (if unusual):
The test item was administered as a homogeneous suspension in the vehicle. The test item was mixed under magnetic agitation with the required quantity of vehicle.
Dose formulations preparations were prepared by the CiToxLAB France Pharmacy extemporaneously on the day of each administration.
The dose formulations were stored at room temperature and delivered to the study room in brown flasks.

CLASS METHOD (if applicable):
Rationale for dose-level selection
The starting dose-level was selected in agreement with the Sponsor, based on the following rationale:
- based on available test item toxicity data, no morbidity or mortality was expected to occur at the dose level of 2000 mg/kg. This was therefore chosen as the starting dose-level.

Doses:

2000 mg/kg.

No. of animals per sex per dose:

3 females per treatment step

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).

Statistics:

no

Key result

Sex:

female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No unscheduled deaths occurred during the study.

Clinical signs:

other: Piloerection was observed in 4/6 females within 4 hours after treatment. No clinical signs persisted from day 2.

Gross pathology:

The only macroscopic finding noted (red discoloration in the thymus in a single female) at the end of the observation period is commonly recorded in the Sprague-Dawley rat and was considered to be incidental and not to be related to the test item administration.

Other findings:

no

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD0 of the test item was higher than 2000 mg/kg in rats.

Executive summary:

The objective of this study was to evaluate the potential acute toxicity of the test item following a single oral administration (gavage) to rats,according to OECD No. 423 (2001) and EU Method B.1tris (2008) guidelines.

This study was conducted in compliance with the principles of Good Laboratory Practice.

 

Methods

The test item was administered once by oral route (gavage) to two groups of three fasted female Sprague-Dawley rats under a dosage-volume of 10 mL/kg. The test item was prepared in corn oil.

Based on available test item toxicity data, the starting dose-level of 2000 mg/kg was chosen. After the first assay, as no toxicity was observed, the results were confirmed in three other females.

Each animal was observed at least once a day for mortality and clinical signs for 15 days. Body weight was recorded on day 1 and then on days 8 and 15.

On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. Macroscopic lesions were preserved in buffered formalin then destroyed at the finalization of the study reportas no microscopic examination was performed.

Results

No unscheduled deaths occurred during the study.

Piloerection was observed in 4/6 females within 4 hours after treatment. No clinical signs persisted from day 2.

When compared to CiToxLAB France historical control data, a lower body weight gain was noted in 3/6 females between day 8 and day 15.

The test item administration did not induce any macroscopic changes.

Conclusion

The oral LD₅₀of the test item was higher than 2000 mg/kg in rats.

 Therefore, the test item is not classified as toxic or harmful by oral route according to the criteria of CLP Regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 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:

experimental study

Adequacy of study:

key study

Study period:

19 June 2012 - 08 August 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

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: breeder: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approximately 8 weeks old on the day of treatment
- Mean body weight at study initiation: the males had a mean body weight of 348 g (range: 340 g to 365 g) and the females had a mean body weight of 244 g (range: 231 g to 254 g)
- Fasting period before study: yes, during the night before treatment
- Housing: the animals were housed by five from the same sex and group in polycarbonate cages with stainless steel lids
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: the animals were acclimated to the study conditions for a period of 5 (females) or 8 (males) days before treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h.

IN-LIFE DATES: 26 June 2012 to 13 July 2012.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 10% of body surface, dorsal site
- Type of wrap if used: hydrophilic gauze pad + adhesive hypoallergenic aerated semi-occlusive dressing + restraining bandage

REMOVAL OF TEST SUBSTANCE
- Removal of dressing: 24h post-exposure
- Washing: at 24h post-exposure, with a moistened cotton pad

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 20 mL/kg
- Constant volume: no.

Duration of exposure:

24 hours

Doses:

2000 mg/kg.

No. of animals per sex per dose:

5 animals per group.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).

Statistics:

no

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No unscheduled deaths occurred during the study.

Clinical signs:

other: No clinical signs indicative of systemic toxicity were observed in any animals. Very slight or well-defined erythema was observed at application sites of 3/5 males on days 2 and 3 and all females from day 2 until day 6 (3/5 females), on day 7 (1/5 female

Gross pathology:

No macroscopic test item-related findings were observed.
The macroscopic findings correlated with common histological findings in control rats, and thus were considered to be incidental.

Other findings:

no

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD0 of the test item was higher than 2000 mg/kg in rats.

Executive summary:

The objective of this study was to evaluate the potential toxicity of the test item following a single dermal application to rats.

This study wasperformed according to the international guidelines (OECD No. 402 and Council Regulation No. 440/2008 of 30 May 2008, Part B.3) andin compliance with the principles of Good Laboratory Practice.

 

Methods

The test item was applied in its original form to the skin of five female then five male Sprague-Dawley rats at the dose-level of 2000 mg/kg. The application site was covered by a semi-occlusive dressing for 24 hours.

Each animal was observed at least once a day for mortality and clinical signs for 15 days. From day 2, any local reactions at the treatment site were also noted. Body weight was recorded on day 1 and then on days 8 and 15.

On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. Macroscopic lesions were preserved in buffered formal in then destroyed at the finalization of the study report as no microscopic examination was performed.

 

Results

No unscheduled deaths and no clinical signs indicative of systemic toxicity were observed in any animals.

Body weight was unaffected by the test item treatment.

Very slight or well-defined erythema was observed at application sites of males and females mostly on days 2 andsingle female presented with moderate to severe erythema on days 2 and 3 along with slight or moderate edema, and slight dryness from day 4 to day 7.

Scabs were noted at application site of 4/5 females and 2/5 males between days 3 and 13.

Very slight or slight dryness was also noted at application site of 2/5 males between days 4 and 8.

No macroscopic test item-related findings were observed.

Conclusion

The dermal LD₅₀of the test item was higher than 2000 mg/kg in rats.

Therefore, the test item is not classified as toxic or harmful by dermal route according to the criteria of CLP Regulation.

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

The objective of this study was to evaluate the potential acute toxicity of the test item following a single oral administration (gavage) to rats (OECD 423). The test item was administered once by oral route (gavage) to two groups of three fasted female Sprague-Dawley rats under a dosage-volume of 10 mL/kg. The test item was prepared in corn oil. No unscheduled deaths occurred during the study (14 -day of observation). Piloerection was observed in 4/6 females within 4 hours after treatment. No clinical signs persisted from day 2. When compared to historical control data, a lower body weight gain was noted in 3/6 females between day 8 and day 15. The test item administration did not induce any macroscopic changes.

The oral LD50 of Diethylamine modified ethoxylated trimethylolpropane triacrylate was higher than 2000 mg/kg in rats.

Dermal acute toxicity

The objective of this study was to evaluate the potential toxicity of the test item following a single dermal application to rats (OECD 402).

The test item was applied in its original form to the skin of five female then five male Sprague-Dawley rats at the dose-level of 2000 mg/kg. The application site was covered by a semi-occlusive dressing for 24 hours.

No unscheduled deaths and no clinical signs indicative of systemic toxicity were observed in any animals. Body weight was unaffected by the test item treatment. Very slight or well-defined erythema was observed at application sites of males and females mostly on days 2 and single female presented with moderate to severe erythema on days 2 and 3 along with slight or moderate edema, and slight dryness from day 4 to day 7.

Scabs were noted at application site of 4/5 females and 2/5 males between days 3 and 13. Very slight or slight dryness was also noted at application site of 2/5 males between days 4 and 8. No macroscopic test item-related findings were observed.

The dermal LD50 of Diethylamine modified ethoxylated trimethylolpropane triacrylate was higher than 2000 mg/kg in rats.

Justification for classification or non-classification

Toxicity by oral or dermal route is very low (LD0> 2000 mg/kg), no classification is expected for this endpoint according to the Regulation EC n°1272/2008.