(1'R,2R)-2-Methyl-4-(2',2',3'-tri-nal and methylcyclopent-3'-en-1'-yl)-4-pent-enal

Endpoint summary

Description of key information

Oral: measured LD50 > 2000 mg/kg bw and the estimated LD50 cut-off is considered to be > 5000 mg/kg bw, male/female rat, OECD TG 420, 1995

Inhalation: No data

Dermal: measured LD50 > 2000 mg/kg bw and the estimated LD50 cut-off value was considered to be > 5000 mg/kg bw, male/female rat, OECD TG 402, 2001

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:

29-11-1994 to 13-01-1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study performed under GLP. All relevant validity criteria were met.

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

inspected: October 1992 ; signature: December 1992

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl: CD (SD) BR strain (VAF plus)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Recognised supplier
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 4 - 6 weeks.
- Weight at study initiation: 95-119 g (500 mg/kg and/or 2000 mg/kg bw range-finding test; sentinels); Main study: Male: 100-109 g and/or Female: 105 – 111 g (2000 mg/kg). Applicant assessment indicates: the weight variation did not exceed ±20% of the mean weight in the definitive test.
- Fasting period before study: Overnight before dosing and three to four hours after dosing.
- Housing: Group housed in groups of up to five by sex ; in suspended grid-bottomed cages above carboard lined excreta trays.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum (except for fasting period).
- Water (e.g. ad libitum): ad libitum (except for fasting period)
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24
- Humidity (%): 40 - 66%
- Air changes (per hr): Not reported, however reported as air conditioned
- Photoperiod: 12 h light / 12 h dark

IN-LIFE DATES: From: 29-11-1994 To: 21-12-1994

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5%

Details on oral exposure:

VEHICLE
- Concentration in vehicle: For the purpose of the range finding study: at 500 mg/kg and 2000 mg/kg bw dose levels the test item was freshly prepared, as required, as a solution in 0.5% CMC at 25 and 100 mg/mL to achieve the required does levels by bodyweight. For the main test: at 2000 mg/kg bw dose level the test item was freshly prepared, as required, as a solution in 0.5% CMC at 100 mg/mL to achieve the required does level by bodyweight.
- Amount of vehicle (if gavage): Test Item dose volume was 20 mL/kg (of bodyweight) in 0.5% CMC in both the range finding study: at 500 mg/kg and 2000 mg/kg bw and the main test: at 2000 mg/kg bw
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed.
- Lot/batch no. (if required): See full study report.
- Purity: See full study report.

MAXIMUM DOSE VOLUME APPLIED: 500 mg/kg bw dose level: 20 mL/kg of test item in vehicle (0.5% CMC) ; 2000 mg/kg bw dose level: 20 mL/kg of test item in vehicle (0.5% CMC).

DOSAGE PREPARATION (if unusual): Not applicable. The test item was prepared in the vehicle.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: In the absence of data regarding the toxicity of the test item, 500 mg/kg was chosen as the starting dose based on guideline recommendations within the range-finding test in one female before dosing at 2000 mg/kg bw a further single female. The starting dose of the main test was based on the observations from the range-finding test (lack of mortality, no clinical signs of toxicity, expected gains in bodyweight up to day 7).

Doses:

500 mg/kg bw and 2000 mg/kg bw (range finding test)
2000 mg/kg bw (main study)

No. of animals per sex per dose:

500 mg/kg bw in 0.5% CMC vehicle (starting dose) : 1 female (range finding study)
2000 mg/kg bw in 0.5% CMC vehicle (follow up dose) : 1 female (range finding study).
2000 mg/kg bw: 5 males and 5 females (main study) as applicable; total 5 per sex per dose level

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made 0.5, 1, 2, and 4 hours after dosing and then daily for fourteen days. Individual body weights were recorded on Day 0 (the day of dosing) and on Days 8 and 15.
- Necropsy of survivors performed: yes

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

500 mg/kg bw (range finding test): No mortality
2000 mg/kg bw (range finding test and definitive test): No mortality

Clinical signs:

other: 500 mg/kg bw (range finding test): No signs of systemic toxicity were noted. 2000 mg/kg bw (range finding test and definitive test): No signs of systemic toxicity were noted.

Gross pathology:

500 mg/kg bw (range finding test): No abnormalties were noted at necropsy.
2000 mg/kg bw (range finding test and definitive test): No abnormalties were noted at necropsy in all females and 4/5 males. One male an enlarged spleen at necropsy.

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study, the oral LD50 was estimated to be greater than 2000 mg/kg bw in male/female rats. Under the conditions of this study and under the Globally Harmonized Classification System of Classification and Labelling of Chemicals (GHS), the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight.

Executive summary:

The study was performed according to OECD TG 420 and EU Method B.1 under GLP to assess the acute oral toxicity of the test item following a single oral administration in the male/female Crl: CD (SD) BR (VAF plus) strain rat by the fixed dose method. The test item was administered by oral gavage in an initial range finding test at 500 mg/kg bw in a solution of 0.5% CMC (carboxymethyl cellulose) to one female and following an absence of toxicity then at 2000 mg/kg bw in 0.5% CMC (carboxymethyl cellulose) to one female. There was an absence of toxicity up to day 7 in both females. Subsequently, in a main study further groups of five fasted males and females was given a single oral dose of test item, at a dose level of 2000 mg/kg body weight in 0.5% CMC (carboxymethyl cellulose). No mortalities were observed. No significant clinical signs were noted and all maintained a healthy appearance throughout the observation period terminated on day 15. All males and females gained bodyweight. There were no abnormalties noted at necropsy in all females and 4/5 males. One male an enlarged spleen at necropsy. Under the conditions of this study, the oral LD50 was estimated to be greater than 2000 mg/kg bw in the male/female Crl: CD (SD) BR rat. Applicant assessment indicates that the estimated LD50 cut-off is considered to be > 5000 mg/kg bw on the basis of absence of significant clinical toxicological effects and/or bodyweight increases in all males/females.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 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 available data for at least one additional route. There is an acute oral toxicity and an acute dermal toxicity study available. Toxicity via the inhalation route is not envisaged and the test item is not a skin corrosive. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.4, 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:

09-05-2001 to 23-05-2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study performed under GLP. All relevant validity criteria were met.

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)

Remarks:

inspected: February 2000 ; signature: April 2000

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl: CD (SD) IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Recognised supplier
- Females (if applicable) nulliparous and non-pregnant: Yes.
- Age at study initiation: ca. 8 weeks age (nulliparous and non-pregnant)
- Weight at study initiation: > 200 g (actual: 270 – 292 g males and 224 – 240 g females)
- Fasting period before study: Not applicable
- Housing: during acclimation and observation period: group housed by sex; during exposure: individually housed in polypropylene cages furnished with softwood bedding.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C (or 22 ± 3 °C)
- Humidity (%): 30 - 70%
- Air changes (per hr): > 15 air changes per hour
- Photoperiod: 12 h light / 12 h dark

IN-LIFE DATES: From: To: 09-05-2001 to 23-05-2001

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: the day before treatment the back and flanks were clipped free of hair. Dorsal area application.
- % coverage: Approximately 10% of total body surface
- Type of wrap if used: The area of application was covered by a semi-occlusive dressing and wrapped with a piece of elastic self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test item.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg (or dose volume 2.19 mL/kg)
- Concentration (if solution): See below.
- Constant volume or concentration used: 2.19 mL volume ; at a dose level of 2000 mg/kg bw test item.

Duration of exposure:

24 hours

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 per sex per dose (5 male/5 female)

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and mortality checks were conducted at approximately 0.5, 1, 2, and 4 hours and subsequently once daily for days 2 to 15. Local effects were examined once daily days 2 to 15 after the completion of the 24-hour exposure period. Full details on the scoring and criteria (appears consistent with Draize for Erythema) are given in the full study report. Individual bodyweights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes

Statistics:

No statistical analyses were performed.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed.

Clinical signs:

other: - Clinical observations: No signs of systemic toxicity were noted during the observation period. - Dermal reactions: All sites indicated no irritation (score = 0) from day 1 to day 14.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

- Organ weights: Not reported.
- Histopathology: Not reported. No macropathological abnormalities.
- Potential target organs: Not applicable.
- Other observations: Not applicable.

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study the dermal LD50 was established to exceed 2000 mg/kg bw in male/female Sprague-Dawley rat. Applicant assessment indicates under the conditions of this study, and according to the GHS criteria, the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight on the basis of absence of significant clinical toxicological effects and/or bodyweight increases in all males/females.

Executive summary:

The study was performed according to OECD TG 402 and EU Method B.3 Acute Toxicity (Dermal) and in accordance with GLP to assess the acute dermal toxicity of the test item in the Sprague-Dawley Crl: CD (SD) IGS BR strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There was no mortality during the study. There were no signs of system toxicity or abnormalities on necropsy. It was considered there was no toxicologically significant effects on bodyweight. All males/females gained bodyweight during the study. No signs of dermal irritation were noted (score 0) up to day 14 in all males/females. The dermal LD50 was established to exceed 2000 mg/kg bw in male/female Sprague-Dawley Crl: CD (SD) IGS BR rat. Applicant assessment indicates under the conditions of this study, and according to the GHS criteria, the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight on the basis of absence of significant clinical toxicological effects and/or bodyweight increases in all males/females.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

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

ORAL: Key study : OECD TG 420, 1995 : The study was performed according to OECD TG 420 and EU Method B.1 under GLP to assess the acute oral toxicity of the test item following a single oral administration in the male/female Crl: CD (SD) BR (VAF plus) strain rat by the fixed dose method. The test item was administered by oral gavage in an initial range finding test at 500 mg/kg bw in a solution of 0.5% CMC (carboxymethyl cellulose) to one female and following an absence of toxicity then at 2000 mg/kg bw in 0.5% CMC (carboxymethyl cellulose) to one female. There was an absence of toxicity up to day 7 in both females. Subsequently, in a main study further groups of five fasted males and females was given a single oral dose of test item, at a dose level of 2000 mg/kg body weight in 0.5% CMC (carboxymethyl cellulose). No mortalities were observed. No significant clinical signs were noted and all maintained a healthy appearance throughout the observation period terminated on day 15. All males and females gained bodyweight. There were no abnormalties noted at necropsy in all females and 4/5 males. One male an enlarged spleen at necropsy. Under the conditions of this study, the oral LD50 was estimated to be greater than 2000 mg/kg bw in the male/female Crl: CD (SD) BR rat. Applicant assessment indicates that the estimated LD50 cut-off is considered to be > 5000 mg/kg bw on the basis of absence of significant clinical toxicological effects and/or bodyweight increases in all males/females.

 

INHALATION: No data.

DERMAL: Key study : OECD TG 402, 2001 : The study was performed according to OECD TG 402 and EU Method B.3 Acute Toxicity (Dermal) and in accordance with GLP to assess the acute dermal toxicity of the test item in the Sprague-Dawley Crl: CD (SD) IGS BR strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There was no mortality during the study. There were no signs of system toxicity or abnormalities on necropsy. It was considered there was no toxicologically significant effects on bodyweight. All males/females gained bodyweight during the study. No signs of dermal irritation were noted (score 0) up to day 14 in all males/females. The dermal LD50 was established to exceed 2000 mg/kg bw in male/female Sprague-Dawley Crl: CD (SD) IGS BR rat. Applicant assessment indicates under the conditions of this study, and according to the GHS criteria, the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight on the basis of absence of significant clinical toxicological effects and/or bodyweight increases in all males/females.

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: inhalation

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