Reaction mass of (9E)-9-Undecenal and (9Z)-9-Undecenal and undec-10-enal

Endpoint summary

Description of key information

Acute Oral Toxicity (weight of evidence): LD50 > 5000 mg/kg bw, 2018

1. Acute Oral (Read-Across: undec-10-enal): LD50 > 5000 mg/kg bw, eq. or similar to OECD TG 401, 1971

2. Acute Oral (Read-Across: undec-9-enal): LD50 > 5000 mg/kg bw, eq. or similar to OECD TG 401, 1977

 

Acute Inhalation toxicity: measured LC50 > 1 mg/L and ≤ 5.mg/L (mean achieved concentration), male/female rat, OECD TG 403, 2019

 

Acute Dermal Toxicity (weight of evidence): LD50 > 5000 mg/kg bw, 2018

1. Acute Dermal Toxicity (Read-Across: undec-9-enal): LD50 > 5000 mg/kg bw, eq. or similar to OECD TG 402, 1977

2. Absence of systemic toxicity in other oral and dermal toxicity studies meeting GHS/EU criteria

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

1971

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Pre-GLP study following a method similar to a recognised guideline. The source and target substances must have an aldehyde group at the 1-carbon position and either a terminal (10-position) or an internal alkene (9-position or 8-position; with the terminal alkyl group no larger than an ethyl group and/or should not multiply substituted). The substance alkyl chain length of the substance should be more than 6 carbons in length and less than 14 carbons in length and fulfil the mono-alkene definition. The substance should not have any branched akyl groups or side chains. The target and source share common structural elements in the same relative positions. The source and target have very similar physico-chemical properties and thus have similar expected toxicokinetic behaviour. The substances have similar in silico chemical reactivity predictions. This is observed within available in vivo toxicology testing where low level local and systemic toxicity is demonstrated and comparable between target and source. The substances therefore demonstrate chemical similarity.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included in attachment to IUCLID section 13.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across is based on the hypothesis that the source and target substances have common structural features in the same relative positions. The source and target have similar physico-chemical, toxicological properties and because of common metabolism they share common or have similar breakdown products and therefore potential mechanisms of action. Further information is included in attachment to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source and target chemicals have comparable chemical similarity. Further information is included in attachment to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
The source substance is a chemically similar substance with common metabolism and common or similar degradants of the target substance. Further information is included in attachment to IUCLID section 13

4. DATA MATRIX
Further information is included in attachment to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

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
- Weight at study initiation: 150 - 300 g

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50%
- Amount of vehicle (if gavage): 5mL

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: derived from the initial screening study.

Doses:

5000 mg/kg

No. of animals per sex per dose:

screening study: 2main test: 8

Control animals:

no

Details on study design:

Initially two rats (fasted overnight) were used for screening purposes. They were given a single dose of 5 ml. or 5000 mg/kg of body weight by gastric intubation. Following the dosing, the toxic signs and mortality were recorded at one and four hours and once daily thereafter for a total of 14 days. Where the results indicated the test compound to be relatively nontoxic. (i.e., no deaths occurred), a group of eight additional rats was given the same dose via the same route. Following the above primary screening studies, the LD50 value was determined if one or two animals died within 48 hours in the initial screening (i.e., the first pair of animals) or if the incidence of death was greater than two of the total of 10 rats within the 14-day observation period. The LD50 value was determined using six groups of rats (five rats per group fasted overnight) by giving graded dosage levels of the test compounds via the same route. Toxic signs and mortality were recorded immediately following dosing and once daily thereafter for 14 days. The LD50 value was calculated according to Horn's method. A gross necropsy was performed on any animal that died during the study and on survivors which were killed by cervical dislocation at termination.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

no mortality was observed

Clinical signs:

other: diarrhoea, depression, salivation

Gross pathology:

no gross findings

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

For the target substance: the acute oral LD50 is > 5000 mg/kg.

Executive summary:

The study was performed on a source substance to assess the acute oral toxicity of the test material in the Sprague Dawley strain of rat. The study was performed pre-GLP and followed a method equivalent to OECD guideline 401. The test material was administered orally, once only by gavage. A screening study was performed with 2 test animals to determine the dose used in the main test. In the main test, 8 test animals were dosed at 5000 mg/kg body weight. Mortality and clinical signs were monitored during the study. All animals were subjected to gross necropsy after an observation period of 14 days. There were no deaths but clinical effects observed were diarrhoea, depression and salivation. The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat was estimated to be greater than 5000 mg/kg bodyweight.

The target substance is expected to have and acute oral LD50 of > 5000 mg/kg.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1971

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Pre-GLP study following a method similar to a recognised guideline. The source and target substances must have an aldehyde group at the 1-carbon position and either a terminal (10-position) or an internal alkene (9-position or 8-position; with the terminal alkyl group no larger than an ethyl group and/or should not multiply substituted). The substance alkyl chain length of the substance should be more than 6 carbons in length and less than 14 carbons in length and fulfil the mono-alkene definition. The substance should not have any branched akyl groups or side chains. The target and source share common structural elements in the same relative positions. The source and target have very similar physico-chemical properties and thus have similar expected toxicokinetic behaviour. The substances have similar in silico chemical reactivity predictions. This is observed within available in vivo toxicology testing where low level local and systemic toxicity is demonstrated and comparable between target and source. The substances therefore demonstrate chemical similarity.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

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
- Weight at study initiation: 150 - 300 g

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50%
- Amount of vehicle (if gavage): 5mL

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: derived from the initial screening study.

Doses:

5000 mg/kg

No. of animals per sex per dose:

screening study: 2main test: 8

Control animals:

no

Details on study design:

Initially two rats (fasted overnight) were used for screening purposes. They were given a single dose of 5 ml. or 5000 mg/kg of body weight by gastric intubation. Following the dosing, the toxic signs and mortality were recorded at one and four hours and once daily thereafter for a total of 14 days. Where the results indicated the test compound to be relatively nontoxic. (i.e., no deaths occurred), a group of eight additional rats was given the same dose via the same route. Following the above primary screening studies, the LD50 value was determined if one or two animals died within 48 hours in the initial screening (i.e., the first pair of animals) or if the incidence of death was greater than two of the total of 10 rats within the 14-day observation period. The LD50 value was determined using six groups of rats (five rats per group fasted overnight) by giving graded dosage levels of the test compounds via the same route. Toxic signs and mortality were recorded immediately following dosing and once daily thereafter for 14 days. The LD50 value was calculated according to Horn's method. A gross necropsy was performed on any animal that died during the study and on survivors which were killed by cervical dislocation at termination.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

no mortality was observed

Clinical signs:

other: diarrhoea, depression, salivation

Gross pathology:

no gross findings

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the study the acute oral LD50 of the test item is > 5000 mg/kg.

Executive summary:

The study was performed to assess the acute oral toxicity of the test material in the Sprague Dawley strain of rat. The study was performed pre-GLP and followed a method equivalent to OECD guideline 401. The test material was administered orally, once only by gavage. A screening study was performed with 2 test animals to determine the dose used in the main test. In the main test, 8 test animals were dosed at 5000 mg/kg body weight. Mortality and clinical signs were monitored during the study. All animals were subjected to gross necropsy after an observation period of 14 days. There were no deaths but clinical effects observed were diarrhoea, depression and salivation. The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat was estimated to be greater than 5000 mg/kg bodyweight.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

1977

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Pre-GLP Study following a method equivalent to a recognised guideline at a limit does, with some deviations not expected to affect the reliability of the study. The source and target substances must have an aldehyde group at the 1-carbon position and either a terminal (10-position) or an internal alkene (9-position or 8-position; with the terminal alkyl group no larger than an ethyl group and/or should not multiply substituted). The substance alkyl chain length of the substance should be more than 6 carbons in length and less than 14 carbons in length and fulfil the mono-alkene definition. The substance should not have any branched akyl groups or side chains. The target and source share common structural elements in the same relative positions. The source and target have very similar physico-chemical properties and thus have similar expected toxicokinetic behaviour. The substances have similar in silico chemical reactivity predictions. This is observed within available in vivo toxicology testing where low level local and systemic toxicity is demonstrated and comparable between target and source. The substances therefore demonstrate chemical similarity.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included in attachment to IUCLID section 13.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across is based on the hypothesis that the source and target substances have common structural features in the same relative positions. The source and target have similar physico-chemical, toxicological properties and because of common metabolism they share common or have similar breakdown products and therefore potential mechanisms of action. Further information is included in attachment to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source and target chemicals have comparable chemical similarity. Further information is included in attachment to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
The source substance is a chemically similar substance with common metabolism and common or similar degradants of the target substance. Further information is included in attachment to IUCLID section 13

4. DATA MATRIX
Further information is included in attachment to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Doses:

5 g/kg

No. of animals per sex per dose:

10 rabbits

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Dermal reactions appear to be scored at 24 hours by the Draize scoring system. The rats were observed daily for 14 days for signs of toxicity, pharmacological effects and mortality. Body weights were recorded pretest and in survivors at 14 days.
- Necropsy of survivors performed: Yes.

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: n = 10

Mortality:

No mortalities.

Clinical signs:

other: Diarrhea was observed

Gross pathology:

In rat #3 of 10 - dark kidney. No other significant findings reported.

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

For the target substance: the acute oral LD50 is > 5000 mg/kg.

Executive summary:

The study was performed on a source substance to assess the acute oral toxicity of the test material in the rat. The study was performed pre-GLP and followed a method equivalent to OECD guideline 401. The test material was administered orally. In the test, 10 test animals were dosed at 5000 mg/kg body weight. Mortality and clinical signs were monitored during the study. All animals were subjected to gross necropsy after an observation period of 14 days. There were no mortalities but clinical effects observed were diarrhoea only. The acute oral median lethal dose (LD50) of the test material in the rat was estimated to be greater than 5000 mg/kg bodyweight.

The target substance is expected to have and acute oral LD50 of > 5000 mg/kg.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1977

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Pre-GLP Study following a method equivalent to a recognised guideline at a limit does, with some deviations not expected to affect the reliability of the study. The source and target substances must have an aldehyde group at the 1-carbon position and either a terminal (10-position) or an internal alkene (9-position or 8-position; with the terminal alkyl group no larger than an ethyl group and/or should not multiply substituted). The substance alkyl chain length of the substance should be more than 6 carbons in length and less than 14 carbons in length and fulfil the mono-alkene definition. The substance should not have any branched akyl groups or side chains. The target and source share common structural elements in the same relative positions. The source and target have very similar physico-chemical properties and thus have similar expected toxicokinetic behaviour. The substances have similar in silico chemical reactivity predictions. This is observed within available in vivo toxicology testing where low level local and systemic toxicity is demonstrated and comparable between target and source. The substances therefore demonstrate chemical similarity.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Doses:

5 g/kg

No. of animals per sex per dose:

10 rabbits

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Dermal reactions appear to be scored at 24 hours by the Draize scoring system. The rats were observed daily for 14 days for signs of toxicity, pharmacological effects and mortality. Body weights were recorded pretest and in survivors at 14 days.
- Necropsy of survivors performed: Yes.

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: n = 10

Mortality:

No mortalities.

Clinical signs:

other: Diarrhea was observed

Gross pathology:

In rat #3 of 10 - dark kidney. No other significant findings reported.

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the study the acute oral LD50 of the test item is > 5000 mg/kg.

Executive summary:

The study was performed to assess the acute oral toxicity of the test material in the rat. The study was performed pre-GLP and followed a method equivalent to OECD guideline 401. The test material was administered orally. In the test, 10 test animals were dosed at 5000 mg/kg body weight. Mortality and clinical signs were monitored during the study. All animals were subjected to gross necropsy after an observation period of 14 days. There were no mortalities but clinical effects observed were diarrhoea only. The acute oral median lethal dose (LD50) of the test material in the rat was estimated to be greater than 5000 mg/kg bodyweight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 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

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11-04-2019 to 22-05-2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

Information as to the availability of the in vivo study is provided in 'attached justification'.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No 8147, April 2011

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

inspected: December 2017 ; signature: January 2018

Test type:

traditional method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Recognised supplier
- Age at study initiation: 9 - 10 weeks
- Weight at study initiation: Approximately the same age and body weight variation did not exceed +/- 20% of the sex mean. Females: 177-223 g and Males: 270 – 330 g
- Fasting period before study: None.
- Housing: Group housing of five animals per sex per cage in labelled polycarbonate Makrolon cages (type IV), containing sterilised sawdust bedding and paper cage enrichment.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum (except for exposure period period)
- Water (e.g. ad libitum): mains drinking water, ad libitum (except for exposure period period)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24
- Humidity (%): 40 to 70 (actual 47 to 62%)
- Air changes (per hr): at least 10 (no recirculation)
- Photoperiod (hrs dark / hrs light): 12 h light / 12 h dark

IN-LIFE DATES: From: 11-04-2019 To: 22-05-2019

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Mass median aerodynamic diameter (MMAD):

>= 2.9 - <= 3.3 µm

Geometric standard deviation (GSD):

>= 2 - <= 2.1

Remark on MMAD/GSD:

MMAD/GSD relates to:
5 mg/L (7.8 mg/L nominal), 5.1 ± 0.1 mg/L (mean achieved concentration) dose : MMAD = 3.2 GSD = 2.1 and MMAD = 3.3 GSD = 2.0
1 mg/L (2.9 mg/L nominal), 1.1 ± 0.1 mg/L (mean achieved concentration) dose : MMAD = 2.9 GSD = 2.0 and MMAD = 3.1 GSD = 2.1

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: An aerosol was generated by nebulization of the test substance by means of a nebulizer and pressurized air. The primary aerosol was diluted with pressurized air before it entered the exposure chamber
- Exposure chamber volume: Not reported. Was consistent with Am. Ind. Hyg Assoc. J. 44(12): 923-928, 1983.
- Method of holding animals in test chamber: Restraining tubes.
- Source and rate of air: filtered air
- Method of conditioning air: Compressed air was supplied by means of an oil free compressor and passed through a water trap and respiratory quality filters before it was introduced to the nebulizer.
- System of generating particulates/aerosols: nebulizer; the chamber mean total flow rate was maintained at 23 L/min (5 mg/L exposure level) and 42 L/min (1 mg/L exposure level).
- Method of particle size determination: Particle size was determined using a cascade impactor. The device consisted of eight impactors stages containing fiber glass filters.
- Treatment of exhaust air: From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.
- Temperature, humidity, in air chamber: The temperature and relative humidity inside the exposure chamber were measured by an electronic thermometer/humidity meter: 20.7-21.2°C, 8-17% humidity.

TEST ATMOSPHERE
- Brief description of analytical method used: Actual concentration was determined (n= 19 and 14 at 5 and 1 mg/L respectively) multiple times during the exposure period. Samples were drawn from the test atmosphere through a tube mounted in one of the free animal ports of the middle section of the exposure chamber. The collected amount of the test substance in the air sample was measured gravimetrically. Sample volumes were measured by means of a dry gas meter. The time-weighted mean concentration with the standard deviation was calculated. Full details of the analytical method are provided in the full study report.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): Not applicable.
- Concentration of test material in vehicle (if applicable): Not applicable.
- Justification of choice of vehicle: Not applicable.
- Lot/batch no. (if required): Not applicable.
- Purity: Not applicable.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: The particle size of the generated atmosphere inside the exposure chamber was determined two times during each exposure period using a cascade impactor. The particle size distribution for each group is reported in table 1.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The Mass Median Aerodynamic Diameter (MMAD) was determined and is reported for each group in table 1.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: Not applicable.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

- 5.0 mg/L (7.8 mg/L nominal), 5.1 mg/L (mean achieved concentration) with a generation efficiency of 65%.
- 1.0 mg/L (2.9 mg/L nominal), 1.1 mg/L (mean achieved concentration) with a generation efficiency of 39%.

No. of animals per sex per dose:

5 per sex per dose. Full details are provided in table 2.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality, twice daily. Clinical signs three times during exposure and on day one at one and three hours and then once daily. Any evidence of mortality or overt toxicity was recorded at each observation. Individual body weights were recorded on arrival, prior to treatment on the day of exposure and on Days 1, 4, 8 and 14 or after mortality.
- Necropsy of survivors performed: yes (and in the event of any mortalities)
- Other examinations performed: clinical signs, body weight, organ weights, and any other relevant toxicological effects were reported.

Statistics:

No statistical analysis was performed.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1 - <= 5 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

At 5 mg/L : all animals were found dead or humanely terminated in moribund condition within 3 hours after the 4-hours exposure.
At 1 mg/L : one male was found dead on Day 4, and one male and two females were humanely terminated in moribund condition on Day 7. No further mortality occurred.

Clinical signs:

other:

Body weight:

At 1 mg/L : body weight loss was noted for all animals, which continued until Day 4, 7 or 8 for the majority of animals which regained weight during the second week. One male showed weight loss until the end of the observation period.

Gross pathology:

At 5 mg/L : macroscopic post mortem examination revealed abnormalities of the lungs (reddish discolouration), esophagus (grey-white foamy contents) and/or thymus (many/isolated dark red or reddish foci) for eight out of ten animals that died or were humanely terminated during the study.
At 1 mg/L : macroscopic post mortem examination of the males that died or were humanely terminated during the study revealed abnormalities of the lungs (reddish discolouration), thymus (many dark red foci) or testis (reduced size left side). Macroscopic examination of the females that were terminated during the study revealed no abnormalities. Macroscopic examination of the survivors revealed lungs that were not collapsed and/or several/many reddish foci of the thymus for two males and one female. No further abnormalities were noted. Applicant assessment indicates: reduced sized of testes was seen in Male #15 only and may not be test item exposure related as was only observed in 1/5 males during the study.

Other findings:

- Other observations: The respiratory tract was subjected to a detailed macroscopic examination for signs of irritancy or local toxicity during necropsy.

Table 1.0 : Characteristics of the achieved atmosphere

Group Number	Nominal Concentration (mg/L)	Time-weighted mean actual concentration (mg/L)	Mean Mass Median Aerodynamic Diameter (µm)	Geometric Standard Deviation	Comments
1 (1 mg/L)	2.9	1.1 ± 0.1	2.9 – 3.1	2.0 – 2.1	n=14 samples ; generation efficiency (ratio of actual and nominal concentration) of 39%
2 (5 mg/L)	7.8	5.1 ± 0.1	3.2 – 3.3	2.0 – 2.1	n=19 samples ; generation efficiency (ratio of actual and nominal concentration) of 65%

 

Table 2.0 : Mortality data

Group Number	Nominal Concentration (mg/L)	Time-weighted mean actual concentration (mg/L)	Mortalities
			Female	Male
1	2.9	1.1 ± 0.1	2/5	2/5
2	7.8	5.1 ± 0.1	5/5	5/5

Clinical signs:

At 5 mg/L : slow breathing, shallow breathing, difficult breathing and gasping was seen for during exposure. After exposure, lethargy, flat and/or hunched posture, laboured respiration and ptosis were seen for the animals prior to mortality.

At 1 mg/L : slow breathing was seen during exposure. After exposure, lethargy, hunched posture, slow breathing and/or laboured respiration, were seen for the animals on Days 1 and/or 2. There was reoccurrence of the signs in one female and one male humanely terminated on Day 7. For one surviving male and one surviving female from Day 7 onwards, in addition quick breathing, rales and/or piloerection were noted. The survivors had recovered from clinical signs by Day 13 or 14.

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the study, the inhalation 4h-LC50 (male/female) was considered to be > 1 and ≤ 5 mg/L within the Crl:WI(Han) rat.

Executive summary:

The study was performed according to OECD TG 403, EU Method B.2, US EPA OPPTS 870.1300 and Japanese JMAFF guidelines in accordance with GLP to assess the acute inhalation toxicity of the test item. A single group of ten Wistar: Crl:WI(Han) strain rats (five males and five females) were exposed to an aerosol atmosphere of the test item. The groups were exposed for four hours using a nose only exposure system, followed by a fourteen day observation period. The time-weighted mean achieved atmosphere concentrations were as follows: 5.1 ± 0.1 mg/L based on a nominal concentration of 7.8 mg/L and/or1.1 ± 0.1 mg/Lbased on a nominal concentration of 2.9 mg/L. The atmosphere generation efficiencies were 65% and 39%, respectively. The characteristics of the achieved atmosphere where Mean Mass Median Diameter (particle size): > 2.9 μm and < 3.3 μm with geometric Standard Deviation > 2.0 and < 2.1. At 5 mg/L, all animals were found dead or humanely terminated in moribund condition within 3 hours after the 4-hours exposure. At 1 mg/L, one male was found dead on Day 4, and one male and two females were sacrificed in moribund condition on Day 7. No further mortality occurred. At 5 mg/L, slow breathing, shallow breathing, difficult breathing and gasping was seen during exposure. After exposure, lethargy, flat and/or hunched posture, laboured respiration and ptosis were seen prior to mortality. At 1 mg/L, slow breathing was seen for all males/females during exposure. After exposure, lethargy, hunched posture, slow breathing and/or laboured respiration, were seen on Days 1 and/or 2. There was reoccurrence of the signs in one female and one male humanely terminated on Day 7. For one surviving male and one surviving female from Day 7 onwards, in addition quick breathing, rales and/or piloerection were noted. The survivors had recovered from the clinical signs by Day 13 or 14. Body weight loss was noted for all males/females, at 1 mg/L, which continued until Day 4, 7 or 8 for the majority which regained weight during the second week. One male showed weight loss until the end of the observation period. At 5 mg/L, macroscopic post mortem examination revealed abnormalities of the lungs (reddish discolouration), esophagus (grey-white foamy contents) and/or thymus (many/isolated dark red or reddish foci) for eight out of ten male/females in mortality or were humanely terminated in moribund condition during the study. At 1 mg/L, macroscopic post mortem examination of the males in mortality or were humanely terminated during the study revealed abnormalities of the lungs (reddish discolouration), thymus (many dark red foci) or testis (reduced size left side, isolated to one male). Macroscopic examination of the females that were sacrificed in moribund condition during the study revealed no abnormalities. Macroscopic examination of the surviving animals revealed not collapsed lungs and/or several/many reddish foci of the thymus for two males and one female. No further abnormalities were noted. Under the conditions of this study, the inhalation 4h-LC50 (male/female) was considered to be > 1 and ≤ 5 mg/L within the Wistar: Crl:WI(Han) rat.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

1 000 mg/m³ air

Quality of whole database:

The available information as a whole meets the tonnage driven information requirements of REACH.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

1977

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Pre-GLP study following a method equivalent to a recognised guideline at a limit dose, with some deviations not expected to affect the reliability of the study. The source and target substances must have an aldehyde group at the 1-carbon position and either a terminal (10-position) or an internal alkene (9-position or 8-position; with the terminal alkyl group no larger than an ethyl group and/or should not multiply substituted). The substance alkyl chain length of the substance should be more than 6 carbons in length and less than 14 carbons in length and fulfil the mono-alkene definition. The substance should not have any branched akyl groups or side chains. The target and source share common structural elements in the same relative positions. The source and target have very similar physico-chemical properties and thus have similar expected toxicokinetic behaviour. The substances have similar in silico chemical reactivity predictions. This is observed within available in vivo toxicology testing where low level local and systemic toxicity is demonstrated and comparable between target and source. The substances therefore demonstrate chemical similarity.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included in attachment to IUCLID section 13.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across is based on the hypothesis that the source and target substances have common structural features in the same relative positions. The source and target have similar physico-chemical, toxicological properties and because of common metabolism they share common or have similar breakdown products and therefore potential mechanisms of action. Further information is included in attachment to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source and target chemicals have comparable chemical similarity. Further information is included in attachment to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
The source substance is a chemically similar substance with common metabolism and common or similar degradants of the target substance. Further information is included in attachment to IUCLID section 13

4. DATA MATRIX
Further information is included in attachment to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Limit dose of 5000mg/kg bw applied single dose; gross pathology completed.

Principles of method if other than guideline:

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

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Type of wrap if used: Not reported.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5000 mg/kg

Duration of exposure:

24h

Doses:

5000 mg/kg

No. of animals per sex per dose:

Not reported

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Dermal reactions appear to be scored at 24 hours by the Draize scoring system. The rabbits were observed daily for 14 days for signs of toxicity, pharmacological effects and mortality. Body weights were recorded pretest and in survivors at 14 days
.- Necropsy of survivors performed: Yes.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities at the 5000 mg/kg bw limit dose.

Clinical signs:

other: None reported. No regrowth of hair at application site during the course of the 14 day observation period.

Gross pathology:

White thin walled areas of intestines in 2/10 rabbits; white area in outer surface of liver in 2/10 rabbits. White nodules in liver 1/10 rabbits.

Other findings:

Redness: 2/10 rabbits = mild redness (Score = 1) ; 6/10 rabbits = moderate skin irritation (score = 3) ; 1/10 rabbits severe (score = 4)Edema: 10/10 rabbits = moderate (score = 3)

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

For the target substance: the dermal LD50 was determined to be > 5000 mg/kg. The substance is expected to produce positive local irritation responses at the dose level employed.

Executive summary:

The pre-GLP study was performed on a source substance following a method similar to OECD 402 to assess the dermal toxicity of the test material to the rabbit. The test substance was evaluated in 10 rabbits. A dose of 5000 mg/kg test substance (undiluted), was applied for 24 hours. Skin observations were made 24 hours after patch removal and then daily for 14 days for signs of toxicity, pharmacological effects and mortality. No mortalities were observed. Very slight to well defined erythema and moderate edema were noted at 24 hours in all animals. Under the conditions of this study the LD50 is considered to be greater than 5000 mg/kg.

The target substance is expected to have and acute dermal LD50 of > 5000 mg/kg.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1977

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Pre-GLP study following a method equivalent to a recognised guideline at a limit dose, with some deviations not expected to affect the reliability of the study. The source and target substances must have an aldehyde group at the 1-carbon position and either a terminal (10-position) or an internal alkene (9-position or 8-position; with the terminal alkyl group no larger than an ethyl group and/or should not multiply substituted). The substance alkyl chain length of the substance should be more than 6 carbons in length and less than 14 carbons in length and fulfil the mono-alkene definition. The substance should not have any branched akyl groups or side chains. The target and source share common structural elements in the same relative positions. The source and target have very similar physico-chemical properties and thus have similar expected toxicokinetic behaviour. The substances have similar in silico chemical reactivity predictions. This is observed within available in vivo toxicology testing where low level local and systemic toxicity is demonstrated and comparable between target and source. The substances therefore demonstrate chemical similarity.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Limit dose of 5000mg/kg bw applied single dose; gross pathology completed.

Principles of method if other than guideline:

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

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Type of wrap if used: Not reported.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5000 mg/kg

Duration of exposure:

24h

Doses:

5000 mg/kg

No. of animals per sex per dose:

Not reported

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Dermal reactions appear to be scored at 24 hours by the Draize scoring system. The rabbits were observed daily for 14 days for signs of toxicity, pharmacological effects and mortality. Body weights were recorded pretest and in survivors at 14 days.
- Necropsy of survivors performed: Yes.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities at the 5000 mg/kg bw limit dose.

Clinical signs:

other: None reported. No regrowth of hair at application site during the course of the 14 day observation period.

Gross pathology:

White thin walled areas of intestines in 2/10 rabbits; white area in outer surface of liver in 2/10 rabbits.
White nodules in liver 1/10 rabbits.

Other findings:

Redness: 2/10 rabbits = mild redness (Score = 1) ; 6/10 rabbits = moderate skin irritation (score = 3) ; 1/10 rabbits severe (score = 4)
Edema: 10/10 rabbits = moderate (score = 3)

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 determined to be > 5000 mg/kg. The test item is not considerd to be toxic to rabbits via the dermal route. The substance produced positive local irritation responses at the dose level employed.

Executive summary:

The pre-GLP study was performed following a method similar to OECD 402 to assess the dermal toxicity of the test material to the rabbit. The test substance was evaluated in 10 rabbits. A dose of 5000 mg/kg test substance (undiluted), was applied for 24 hours. Skin observations were made 24 hours after patch removal and then daily for 14 days for signs of toxicity, pharmacological effects and mortality. No mortalities were observed. Very slight to well defined erythema and moderate edema were noted at 24 hours in all animals. Under the conditions of this study the LD50 is considered to be greater than 5000 mg/kg.

Reference 3

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation)

the study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and, in the absence of an in vivo study by the oral route, no systemic effects after dermal exposure are predicted on the basis of non-testing approaches (e.g. read across, QSAR studies)

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 dermal toxicity (OECD TG 402) study does not need to be conducted based on an available for at least one additional route. In accordance with REACH Regulation (EC) No. 1907/2006 Annex XI: section 1.2 – weight of evidence, based on data on constituent substances (analogues). The available data via the oral route and its weight of evidence indicates that the acute oral toxicity LD50 > 5000 mg/kg bw. This is matched by available data on constituent substances (analogues) via the dermal route with an acute dermal toxicity LD50 > 5000 mg/kg bw. There is an absence of systemic toxicity in available Skin Sensitisation tests (OECD TG 429) and in acute dermal irritation tests (eq. or similar to OECD TG 404) on constituent substances. This indicates a clear weight of evidence that the EU criteria (Acute Toxicity and STOT-SE) will not been met. Toxicity via the dermal route is not envisaged. Further testing is not scientifically justified. 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 adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 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 Toxicity:

1. Eq. to OECD 401, 1971: Read-Across SOURCE (undec-10-enal): The study was performed to assess the acute oral toxicity of the test material in the Sprague Dawley strain of rat. The study was performed pre-GLP and followed a method equivalent to OECD guideline 401. The test material was administered orally, once only by gavage. A screening study was performed with 2 test animals to determine the dose used in the main test. In the main test, 8 test animals were dosed at 5000 mg/kg body weight. Mortality and clinical signs were monitored during the study. All animals were subjected to gross necropsy after an observation period of 14 days. There were no deaths but clinical effects observed were diarrhoea, depression and salivation. The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat was estimated to be greater than 5000 mg/kg bodyweight.

2. Eq. to OECD 401, 1977: Read-Across SOURCE (undec-9-enal): The study was performed to assess the acute oral toxicity of the test material in the rat. The study was performed pre-GLP and followed a method equivalent to OECD guideline 401. The test material was administered orally. In the test, 10 test animals were dosed at 5000 mg/kg body weight. Mortality and clinical signs were monitored during the study. All animals were subjected to gross necropsy after an observation period of 14 days. There were no mortalities but clinical effects observed were diarrhoea only. The acute oral median lethal dose (LD50) of the test material in the rat was estimated to be greater than 5000 mg/kg bodyweight.

Acute Inhalation Toxicity:

Key study : OECD TG 403, 2019 : The study was performed according to OECD TG 403, EU Method B.2, US EPA OPPTS 870.1300 and Japanese JMAFF guidelines in accordance with GLP to assess the acute inhalation toxicity of the test item. A single group of ten Wistar: Crl:WI(Han) strain rats (five males and five females) were exposed to an aerosol atmosphere of the test item. The groups were exposed for four hours using a nose only exposure system, followed by a fourteen day observation period. The time-weighted mean achieved atmosphere concentrations were as follows: 5.1 ± 0.1 mg/L based on a nominal concentration of 7.8 mg/L and/or1.1 ± 0.1 mg/Lbased on a nominal concentration of 2.9 mg/L. The atmosphere generation efficiencies were 65% and 39%, respectively. The characteristics of the achieved atmosphere where Mean Mass Median Diameter (particle size): > 2.9 μm and < 3.3 μm with geometric Standard Deviation > 2.0 and < 2.1. At 5 mg/L, all animals were found dead or humanely terminated in moribund condition within 3 hours after the 4-hours exposure. At 1 mg/L, one male was found dead on Day 4, and one male and two females were sacrificed in moribund condition on Day 7. No further mortality occurred. At 5 mg/L, slow breathing, shallow breathing, difficult breathing and gasping was seen during exposure. After exposure, lethargy, flat and/or hunched posture, laboured respiration and ptosis were seen prior to mortality. At 1 mg/L, slow breathing was seen for all males/females during exposure. After exposure, lethargy, hunched posture, slow breathing and/or laboured respiration, were seen on Days 1 and/or 2. There was reoccurrence of the signs in one female and one male humanely terminated on Day 7. For one surviving male and one surviving female from Day 7 onwards, in addition quick breathing, rales and/or piloerection were noted. The survivors had recovered from the clinical signs by Day 13 or 14. Body weight loss was noted for all males/females, at 1 mg/L, which continued until Day 4, 7 or 8 for the majority which regained weight during the second week. One male showed weight loss until the end of the observation period. At 5 mg/L, macroscopic post mortem examination revealed abnormalities of the lungs (reddish discolouration), esophagus (grey-white foamy contents) and/or thymus (many/isolated dark red or reddish foci) for eight out of ten male/females in mortality or were humanely terminated in moribund condition during the study. At 1 mg/L, macroscopic post mortem examination of the males in mortality or were humanely terminated during the study revealed abnormalities of the lungs (reddish discolouration), thymus (many dark red foci) or testis (reduced size left side, isolated to one male). Macroscopic examination of the females that were sacrificed in moribund condition during the study revealed no abnormalities. Macroscopic examination of the surviving animals revealed not collapsed lungs and/or several/many reddish foci of the thymus for two males and one female. No further abnormalities were noted. Under the conditions of this study, the inhalation 4h-LC50 (male/female) was considered to be > 1 and ≤ 5 mg/L within the Wistar: Crl:WI(Han) rat.

Acute Dermal Toxicity:

1. Eq. to OECD 402, 1977: Read-Across SOURCE (undec-9-enal): The pre-GLP study was performed following a method similar to OECD 402 to assess the dermal toxicity of the test material to the rabbit. The test substance was evaluated in 10 rabbits. A dose of 5000 mg/kg test substance (undiluted), was applied for 24 hours. Skin observations were made 24 hours after patch removal and then daily for 14 days for signs of toxicity, pharmacological effects and mortality. No mortalities were observed. Very slight to well defined erythema and moderate edema were noted at 24 hours in all animals. Under the conditions of this study the LD50 is considered to be greater than 5000 mg/kg.

2. 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 dermal toxicity (OECD TG 402) study does not need to be conducted based on an available for at least one additional route. In accordance with REACH Regulation (EC) No. 1907/2006 Annex XI: section 1.2 – weight of evidence, based on data on constituent substances (analogues). The available data via the oral route and its weight of evidence indicates that the acute oral toxicity LD50 > 5000 mg/kg bw. This is matched by available data on constituent substances (analogues) via the dermal route with an acute dermal toxicity LD50 > 5000 mg/kg bw. There is an absence of systemic toxicity in available Skin Sensitisation tests (OECD TG 429) and in acute dermal irritation tests (eq. or similar to OECD TG 404) on constituent substances. This indicates a clear weight of evidence that the EU criteria (Acute Toxicity and STOT-SE) will not been met. Toxicity via the dermal route is not envisaged. Further testing is not scientifically justified. 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.

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 meets classification criteria under Regulation (EC) No 1272/2008 for acute toxicity: inhalation: category 4: H332

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

 

The weight of evidence based on read-across to constituent substances; via the oral and dermal routes indicates that the substance cannot be expected to produce acute toxicity sufficient for classification and labelling under the EU criteria. There is no evidence of significant systemic toxicity and no mortalities were observed. Therefore toxicity at category 4 acute toxicity is by expert judgement not supported.

 

The available acute inhalation study indicates that the substance will produce acute toxicity sufficient for classification and labelling under the EU criteria.

 

References:

1. OECD TG 403 (2009)

2. OECD 39 (2009)