Reaction products of ((5E)-5-ethylidenebicyclo[2.2.1]hept-2-ene and (5Z)-5-ethylidenebicyclo[2.2.1]hept-2-ene) and 2-methyl-1,3-butadiene, epoxidized

Endpoint summary

Description of key information

Oral: LD50(rat, male) = 3100 mg/kg bw rat, equiv. or sim. to OECD 401, 1979

Dermal: LD50(rabbit, female) = > 2000 mg/kg bw, equiv. or sim. to OECD TG 402, 1979

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:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Pre-GLP study following a method equivalent to a recognised guideline. Minor deviations not deemed to impact the reliability of the study.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

The principles of the method were in accordance with the US 16 CFR 1500.3 definitions.

Deviations:

yes

Remarks:

Absence of gross pathology and/or assessment in the other sex - not deemed to impact reliability of the study.

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Recognised animal supplier
- Age at study initiation: 8 weeks
- Weight at study initiation: 189 - 282g
- Fasting period before study: not reported
- Housing: The animals were housed 5/cage in suspended wire mesh cages· (20" x 10" x 7").
- Diet: rat chow ad libitum
- Water: ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 21
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The test material was given orally by syringe and 13 gauge blunt end needle. Doses were selected at log intervals. Ten male rats were dosed at each level. For liquid materials, the dose was based on the sample weight as calculated from the specific gravity.

Doses:

1.73, 2.47, 3.51 and 5.0 g/kg

No. of animals per sex per dose:

10 males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed 3-4 hours after dosing and once daily for 14 days.
- Necropsy of survivors performed: no

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Sex:

male

Dose descriptor:

LD50

Effect level:

3 100 mg/kg bw

Based on:

test mat.

95% CL:

> 2 600 - < 3 700

Mortality:

One animal died on day 1 at 1.73 g/kg bw.
Two animals died on day 1 at 2.47 g/kg bw.
Seven animals died on day 1 at 3.51 g/kg bw.

Clinical signs:

other: At 1.73 g/kg bw: Isolated instances of ptosis, chromorhinorrhea , chromodacryorrhea and piloerection were noted on the day of dosing and on days one and two. All animals appeared normal from Days 3 through 14 At 2.47 g/kg bw: Isolated instances of chromor

Gross pathology:

Not examined

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

EU criteria not met

Conclusions:

Under the conditions of this study the LD50 was determined to be 3100 mg/kg bw in male wistar rats.

Executive summary:

The pre-GLP study was performed following a method similar to OECD 401 to assess the acute oral toxicity potential of the test substance to male Wistar rats. The test material was administered as a single oral dose to groups of 10 male rats orally, at dose levels of 1.73, 2.47, 3.51 and 5.0 g/kg bodyweight. All animals were observed for a fourteen day period for any signs of toxicity or other effects of treatment. Animals were not examined for gross pathology. Deaths occurred at all dose levels. Significant signs noted included ptosis, piloerection, chromorhinorrhea, chromodacryorrhea, diarrhea, lethargy, flaccid muscle tone, dyspnea and sensitivity to manipulation. The surviving animals appeared generally healthy during the second week of observation. Under the conditions of this study the LD50 was determined to be 3100 (C.I. 2600 - 3700) mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 100 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 an available for at least one additional route. There is an acute oral toxicity and an dermal toxicity study available indicating that the EU criteria has not been met. Toxicity via the inhalation route is not envisaged and the test item is not a skin corrosive or irritant. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.2, 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:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Pre-GLP study following a method equivalent to a recognised guideline. Minor deviations not deemed to impact the reliability of the study.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Limit test of 2000 mg/kg bw on clipped-abraded skin and occlusive dressing.

Qualifier:

according to guideline

Guideline:

other: 16 CFR 1500.40

Version / remarks:

The principles of the method were in accordance with the US 16 CFR 1500.3 definitions.

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Recognised animal supplier
- Age at study initiation: Approximately 8 weeks of age.
- Weight at study initiation: Between 1.8 and 2.5 kg
- Housing: The animals were housed in compliance with US 9 CFR Part 3; group housed two per cage in suspended wire mesh cage.
- Diet: rabbit chow ad libitum
- Water: ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 21
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Clipped area was 200 square cm ; abrasions were completed in at least 50% of the exposure sites extending the length of the exposure site. Abrasion was scratching of the stratum corneum but which did not reach derma or produce bleeding.
- % coverage: approximately 10%
- Type of wrap if used: covered with large gauze patches and an impervious material was wrapped snugly around the trunk of each animal. The dressings were removed after twenty-four hours and any excess material was removed and the approximate amount remaining was noted.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the exposure site was wiped, but not washed, to remove excess material as per US 16 CFR 1500.40.
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg based on specific gravity of the test item.
- Constant volume or concentration used: No (volume); Yes (concentration) – test item was tested neat, without vehicle.

Duration of exposure:

24h

Doses:

2000 mg/kg

No. of animals per sex per 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: Observed daily for signs of toxicity, pharmacological effects and for mortalities. Bodyweights were recorded pre-exposure and at the end of the 14 day exposure period (or at mortality).
- Necropsy of survivors performed: yes/no
- Other examinations performed: clinical signs, body weight

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: n=10 (females); n=5 non-abraded and n=5 abraded

Mortality:

Non abraded skin (n=5): One (1) mortality on day 11. Pre-mortality clinical signs included lethargy, diarrhea, ptosis, adipsia and anorexia.
Abraded skin (n=5): Two (2) mortalities on day 6 and 13: There were no pre-mortality clinical signs for day 6 mortality. For the day 13 mortality lethargy, ptosis, diarrhea, yellow nasal discharge and emaciation, was observed.

Clinical signs:

other: There were isolated instances of diarrhoea, lethargy and ptosis noted up to day 14 in four survivors.

Gross pathology:

Not performed.

Other findings:

Other observations (such as local responses) were noted within the report.

Table 1. Local Reactions – day 1

Number	Erythema	Oedema
1	1	0
3 *	2	0
5	1	1
7	2	1
9	2	2
2# *	1	0
4# *	1	2
6#	2	3
8#	2	2
10#	1	2

# Abraded skin

* mortality

Note. Scoring consistent with Draize et al.

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria not met

Conclusions:

Under the conditions of this study the LD50 was determined to be > 2000 mg/kg in female rabbits.

Executive summary:

The pre-GLP study was performed following a method similar to OECD 402 to assess the dermal toxicity of the test substance to the New Zealand white rabbit. The test substance was evaluated in ten female rabbits. A dose of 2000 mg/kg test substance (undiluted), was applied to the back clipped intact and abraded skin sites of the rabbit under a occlusive dressing for 24 hours. After twenty-four hours and any excess material was removed and the approximate amount remaining was noted. The animals were observed for a 14 day period for signs of toxicity and for mortalities. There were three mortalities during the study. In the intact skin sites on mortality occurred at day 13 with pre-mortality clinical signs including lethargy, diarrhoea, ptosis, adipsia and anorexia. In the abraded sites, two mortalities occurred. There were no pre-mortality clinical signs for day 6 mortality. For the day 13 mortality lethargy, ptosis, diarrhoea, yellow nasal discharge and emaciation, was observed. In the intact sites three of four survivors gained weight during the study. In number 7 survivor there was a slight body weight decline (- 0.1 g) at day 14. In the abraded sites, in number 6 there was a slight body weight decline (- 0.1 g) at day 14. In number 8 survivor there was no weight gain. Isolated instances of diarrhoea, lethargy and ptosis were noted in four survivors although remained generally healthy throughout the observation period. Local effects were very slight to well defined erythema and very slight to moderate oedema. Applicant assessment indicates there was more significant local effects in abraded sites than in intact skin sites at 24 hours. Under the conditions of this study the LD50 was determined to be greater than 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

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

Acute Oral:

Eq. or similar to OECD TG 401, 1979: The pre-GLP study was performed following a method similar to OECD 401 to assess the acute oral toxicity potential of the test substance to male Wistar rats. The test material was administered as a single oral dose to groups of 10 male rats orally, at dose levels of 1.73, 2.47, 3.51 and 5.0 g/kg bodyweight. All animals were observed for a fourteen day period for any signs of toxicity or other effects of treatment. Animals were not examined for gross pathology. Deaths occurred at all dose levels. Significant signs noted included ptosis, piloerection, chromorhinorrhea, chromodacryorrhea, diarrhea, lethargy, flaccid muscle tone, dyspnea and sensitivity to manipulation. The surviving animals appeared generally healthy during the second week of observation. Under the conditions of this study the LD50 was determined to be 3100 (C.I. 2600 - 3700) mg/kg bw.

Acute Dermal:

Eq. or similar to OECD TG 402, 1979: The pre-GLP study was performed following a method similar to OECD 402 to assess the dermal toxicity of the test substance to the New Zealand white rabbit. The test substance was evaluated in ten female rabbits. A dose of 2000 mg/kg test substance (undiluted), was applied to the back clipped intact and abraded skin sites of the rabbit under a occlusive dressing for 24 hours. After twenty-four hours and any excess material was removed and the approximate amount remaining was noted. The animals were observed for a 14 day period for signs of toxicity and for mortalities. There were three mortalities during the study. In the intact skin sites on mortality occurred at day 13 with pre-mortality clinical signs including lethargy, diarrhoea, ptosis, adipsia and anorexia. In the abraded sites, two mortalities occurred. There were no pre-mortality clinical signs for day 6 mortality. For the day 13 mortality lethargy, ptosis, diarrhoea, yellow nasal discharge and emaciation, was observed. In the intact sites three of four survivors gained weight during the study. In number 7 survivor there was a slight body weight decline (- 0.1 g) at day 14. In the abraded sites, in number 6 there was a slight body weight decline (- 0.1 g) at day 14. In number 8 survivor there was no weight gain. Isolated instances of diarrhoea, lethargy and ptosis were noted in four survivors although remained generally healthy throughout the observation period. Local effects were very slight to well defined erythema and very slight to moderate oedema. Applicant assessment indicates there was more significant local effects in abraded sites than in intact skin sites at 24 hours. Under the conditions of this study the LD50 was determined to be greater than 2000 mg/kg bw.

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: dermal

 

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