(octahydro-4,7-methano-1H-indenediyl)bis(methylene) diacrylate

Endpoint summary

Description of key information

Acute studies are available by oral and dermal route and showed no death at the maximal dose of 2000 mg/kg.
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 January 2014 -- 26 March 2014

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)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

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: 209 g (range: 194 g to 234 g)
- Fasting period before study: yes, during the night before treatment
- Housing: polycarbonate cages
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 days before the beginning of the study

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: 24 February 2014 to 26 March 2014

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Justification for choice of vehicle: following recommendation from the Sponsor, the solubility assay first started at the concentration of 200 mg/mL, and following indication on the test article description, the choice vehicle was corn oil.

- Maximum dose-volume applied: 10 mL/kg

DOSAGE PREPARATION (if unusual): fresh dose formulations were prepared by the CiToxLAB France Pharmacy on the day of each administration and kept at room temperature and protected from light prior to administration.



CLASS METHOD (if applicable):
- Rationale for the selection of the starting dose: ----

Doses:

300 and 2000 mg/kg

No. of animals per sex per dose:

Three nulliparous and non-pregnant female rats

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

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: No clinical signs were observed in any animals.

Gross pathology:

There were no test item-related macroscopic post-mortem findings.
The few gross abnormalities were considered to be part of the normal background in untreated rats of these strain and age.

Other findings:

no

 Table 1

Sex	Female
Group	CiToxLAB France historical control data	1	2	3
Dose-level (mg/kg)	0	300	2000	2000
Body weight (mean (± SD))
. Day 1	198 (± 6.6)	201 (± 6.2)	224 (± 13.2)	201 (± 5.3)
. Day 8	239 (± 8.6)	246 (± 10.0)	273 (± 13.7)	242 (± 9.5)
. Day 15	258 (± 8.6)	262 (± 8.7)	285 (± 14.0)	261 (± 20.0)
Body weight change (mean (± SD))
. Days 1-8	+41 (± 7.2)	+45 (± 6.1)	+48 (± 0.6)	+41 (± 4.7)
. Days 8-15	+20 (± 6.7)	+16 (± 2.5)	+12 (± 4.7)	+19 (± 11.5)
. Days 1-15	+60 (± 6.0)	+61 (± 4.4)	+61 (± 4.0)	+60 (± 14.7)

SD: standard deviations.

 

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of this study, the oral LD0 of the test item, was higher than 2000 mg/kg in rats.
Therefore, the test item should not be classified as harmful or toxic by oral route according to the criteria of the CLP Regulation.

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.

This study was conducted in compliance with OECD Guideline No. 423 and the principles of Good Laboratory Practices.

 

Methods

 

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

Since no relevant toxicity data were available for the estimation of a lethal dose-level and any existing data have been taken into account by the Sponsor, the starting dose-level was 300 mg/kg for ethical reasons. After the first assay, the next higher dose-level of 2000 mg/kg was tested. Then, as no toxicity was observed at this higher dose-level, the results were confirmed in other three 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 report as no microscopic examination was performed.

 

Results

 

No unscheduled deaths occurred during the study and no clinical signs were observed in any animals.

When compared to the historical control data, a lower body weight gain was noted in 2/6 females given 2000 mg/kg (+7 gvs.+20 g ± 6.7 g in control data base) between Day 8 and Day 15. A higher body weight gain was observed in 1/6 females (+30 g vs.+20 g ± 6.7 g in control data base) given 2000 mg/kg over the same period.

Nevertheless, compared to the historical control data, the body weight of the animals was considered to be unaffected by the test item treatment.

No test item-related macroscopic post-mortem findings were noted.

 

Conclusion

 

Under the experimental conditions of this study, the oral LD0 of the test item, was higher than 2000 mg/kg in rats.

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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD0

Value:

2 000 mg/kg bw

Quality of whole database:

The acute oral study is considered to be reliable.

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:

22 January 2014 -- 21 March 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

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: 348 g (range: 341 g to 361 g) for the males and 235 g (219 g to 254 g) for the females
- 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: at least 5 days before the beginning of the study

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: 04 March 2014 to 21 March 2014

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume: no

Duration of exposure:

24 hr

Doses:

2000 mg/kg

No. of animals per sex per dose:

Ten rats (five males and five nulliparous and non pregnant females)

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

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

No unscheduled deaths occurred during the study.

Clinical signs:

other: No clinical signs indicative of systemic toxicity were observed in any animals. A very slight to moderate-to-severe erythema was noted in all males and a very slight to well defined erythema was recorded in all females from Day 2 until Day 6 at the latest

Gross pathology:

The spleen was enlarged in 4/5 males given the test item at 2000 mg/kg. In the absence of macroscopic findings in females given the same dose-level, this finding was considered to be incidental and unrelated to the test item administration.

Other findings:

no

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of this study, the dermal LD0 of the test item, was higher than 2000 mg/kg in rats.
Therefore, the test item should not be classified as acutely toxic by dermal route according to the criteria of the CLP Regulation.

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 was conducted in compliance with OECD Guideline No. 402 and the principles of Good Laboratory Practices.

 

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 occurred during the study.

No clinical signs indicative of systemic toxicity were observed in any animals.

A very slight to moderate-to-severe erythema was noted in all males and a very slight to well-defined erythema was recorded in all females from Day 2 until Day 6. This was associated with very slight to moderate dryness from Day 4 or 5 until Day 13 in all animals. Scabs were observed in 2/5 males from Day 7 to Day 11.

When compared to CiToxLAB France historical control data, a higher body weight gain was observed in 1/5 males (+57 g vs. +39 ± 11.5 g in control data base) between Days 1 and 8 whereas a lower body weight gain was noted in 2/5 males (+35 g and +33 g, respectively, vs. +50 ± 12.0 g in control data base) between Day 8 and Day 15.

A lower body weight gain was observed in 2/5 females (+13 g and +14 g, respectively, vs. +25 ± 10.0 g in control data base) between Days 1 and 8. This was followed by a body weight loss of 2 g in one of them over the second part of the observation period.

Nevertheless and in absence of marked body weight effect, body weight of animals was considered unaffected by the test item treatment in both sexes when compared to CiToxLAB France historical control data.

At the end of the observation period, there were no macroscopic findings at necropsy attributable to the test item administration.

 

Conclusion

 

Under the experimental conditions of this study, the dermal LD0 of the test item, was higher than 2000 mg/kg in rats.

 

Therefore, the test item should not be classified as acutely toxic by dermal route according to the criteria of the CLP Regulation.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD0

Value:

2 000 mg/kg bw

Quality of whole database:

The acute dermal study is considered to be reliable.

Additional information

Acute oral study (Papineau 2014)

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 guideline 423). The test item, was administered once by oral route (gavage) to three groups of three fasted female Sprague-Dawley rats under a dosage-volume of 10 mL/kg. The test item was prepared in corn oil.

Since no relevant toxicity data were available for the estimation of a lethal dose-level and any existing data have been taken into account by the Sponsor, the starting dose-level was 300 mg/kg for ethical reasons. After the first assay, the next higher dose-level of 2000 mg/kg was tested. Then, as no toxicity was observed at this higher dose-level, the results were confirmed in other three 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.

No unscheduled deaths occurred during the study and no clinical signs were observed in any animals.

When compared to the historical control data, a lower body weight gain was noted in 2/6 females given 2000 mg/kg (+7 g vs.+20 g ± 6.7 g in control data base) between Day 8 and Day 15. A higher body weight gain was observed in 1/6 females (+30 g vs.+20 g ± 6.7 g in control data base) given 2000 mg/kg over the same period.

Nevertheless,compared to the historical control data, the body weight of the animals was considered to be unaffected by the test item treatment.

No test item-related macroscopic post-mortem findings were noted.

Under the experimental conditions of this study, the oral LD0 of the test item, was higher than 2000 mg/kg in rats.

 

Acute dermal study (Papineau 2014)

The objective of this study was to evaluate the potential toxicity of the test item, following a single dermal application to rats (OECD guideline 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 occurred during the study. No clinical signs indicative of systemic toxicity were observed in any animals. A very slight to moderate-to-severe erythema was noted in all males and a very slight to well-defined erythema was recorded in all females from Day 2 until Day 6. This was associated with very slight to moderate dryness from Day 4 or 5 until Day 13 in all animals. Scabs were observed in 2/5 males from Day 7 to Day 11.

When compared to historical control data, a higher body weight gain was observed in 1/5 males (+57 g vs.+39 ± 11.5 g in control data base) between Days 1 and 8 whereas a lower body weight gain was noted in 2/5 males (+35 g and +33 g, respectively,vs.+50 ± 12.0 g in control data base) between Day 8 and Day 15. A lower body weight gain was observed in 2/5 females (+13 g and +14 g, respectively,vs.+25 ± 10.0 g in control data base) between Days 1 and 8. This was followed by a body weight loss of 2 g in one of them over the second part of the observation period.

Nevertheless and in absence of marked body weight effect,body weight of animals was considered unaffected by the test item treatment in both sexes when compared to historical control data.

At the end of the observation period, there were no macroscopic findings at necropsy attributable to the test item administration.

Under the experimental conditions of this study, the dermal LD0 of the test item, was higher than 2000 mg/kg in rats.

 

Justification for classification or non-classification

Based on the available data, Tricyclodecane dimethanol diacrylate is not classified in the acute toxicity endpoint according to the Regulation EC no.1272/2008.