Reaction mass of methyl 2-[[(E)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and methyl 2-[[(Z)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and oxydipropanol

Endpoint summary

Description of key information

Weight of Evidence: Substance Oral: LD50 = > 5000 mg/kg bw, 2017

Read-Across - methyl-2-[[(2,4-dimethyl-3-cyclohexen-1-yl)methylene]amino]benzoate: Oral: LD50= > 5000 mg/kg bw, female rat, eq. sim. to OECD TG 401, 1985

Read-Across - oxydipropanol: Oral: LD50= > 5000 mg/kg bw, female rat, US EPA OPP 81-1, 1995

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:

1995

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

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 similar physico-chemical, toxicological properties and because of common breakdown products and therefore potential mechanisms of action. Specifically, this source substance is a constituent of the source and target. With no indications of adverse effects. The read-across is assessed as part of a weight of evidence approach. 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 composition. Further information is included in attachment to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
The source substance is source substance is a constituent of the source and target. The read-across in weight of evidence indicates despite a common potential mode-of-action between source and target, no adverse effects are seen in several studies. When the information is taken together by expert judgement the weight of evidence indicates that there is an absence of adverse effects associated with the target.

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

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes

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: Recognised supplier
- Age at study initiation: males, 8 weeks of age; females, 10 weeks of age
- Weight at study initiation: males, 254 to 259 grams; females, 201 to 216 grams
- Fasting period before study: 18 hours, water was available at all times
- Housing: individually housed in wire cages under laboratory conditions.
- Diet (e.g. ad libitum): NIH-31M rodent diet, ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23
- Humidity (%): 35-65
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hour dark / 12 hours light

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

5010 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: First 5 hours post dose and then from 24 hours at twice daily intervals for 14 days
- Frequency of observations and weighing: All animals were examined shortly before and after dosing. On the day of dosing all animals were weighed and on day 15.
- Necropsy of survivors performed: Yes. Any animal found dead during the study would have undergone necropsy immediately.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality.

Clinical signs:

other: At one hour after dosing two males showed decreased locomotor activity and the remaninder of the group (3 male, 5 female) were ataxic. Similar signs persisted at three hours. At five hours following dosing several rats (4 male, 1 female) also showed yello

Gross pathology:

No significant findings.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study, the LD50 (male/female) was determined to be > 5000 mg/kg bw

Executive summary:

The study was performed according to EPA OPPTS 870.1100 (Acute Oral Toxicity) in accordance with GLP to assess the acute oral toxicity potential of the test substance to Sprague Dawley male/female rats. Following an acclimatisation period and overnight fasting, the test material was administered as a single oral dose to a group of five male and five female rats by oral gavage at a dose level of 5000 mg/kg bodyweight. All animals were observed for a fourteen day period for any signs of toxicity or other effects of treatment, after which they were subjected to gross necropsy. There was no significant effects observed during the study. All animals gained body weight. No abnormalities were observed during gross necropsy. Applicant assessment indicates that under the conditions of this study the LD50 male/female rats should be considered to be > 5000 mg/kg bw.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study follows protocols equivalent or similar to a recognised guideline and under GLP.

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 similar physico-chemical, toxicological properties and because of common breakdown products and therefore potential mechanisms of action. The read-across is assessed as part of a weight of evidence approach. 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 composition. Further information is included in attachment to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
The source substance is a common degradant of the target substance and with common degradants to the target under physiological conditions. The read-across in weight of evidence indicates despite a common potential mode-of-action between source and target, no adverse effects are in studies. When the information is taken together by expert judgement the weight of evidence indicates that there is an absence of adverse effects associated with the target.

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)

Deviations:

no

GLP compliance:

yes

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: Recognised Supplier
- Age at study initiation: Young adult (specific ages not reported).
- Weight at study initiation: males 239 - 257g; females 204 - 224g
- Fasting period before study: fasted overnight prior to dosing.
- Housing: Animals were housed in single sex groups of five in grid bottomed polypropylene cages.
- Diet: pelleted rodent diet ad libitum
- Water: mains drinking water ad libitum except during the pre-dose overnight.
- Acclimation period: at least 5 days (on receipt)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 24
- Humidity (%): 49 - 58
- Photoperiod: 12 hours light / 12 hours dark

Route of administration:

oral: gavage

Vehicle:

other: 0.25% aqueous gum tragacanth

Details on oral exposure:

Animals were dosed with the prepared test material by peroral injection using a rubber catheter attached to a syringe of suitable capacity. After dosing animals were returned to their cages and permitted access to food.

Doses:

The test material was suspended in 0.25% aqueous gum tragacanth to give a dose volume of 10 ml/kg at a dose level of 5.0 g/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All animals were examined frequently after dosing and then daily for fourteen consecutive days. Any signs of toxicity or other effects were noted along with the time of onset and duration. Animals were weighed at weekly intervals.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality observed.

Clinical signs:

other: No effects observed due to treatment were reported in the study.

Gross pathology:

No significant effects or abnormalities observed.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study the LD50 (male/female) was determined to be > 5000 mg/kg bw

Executive summary:

The study was performed in a method equivalent or similar to OECD TG 401 under GLP to assess the acute oral toxicity potential of the test substance to Sprague Dawley male/female rats. Following an acclimatisation period and overnight fasting, the test material was administered as a single oral dose to a group of five male and five female rats, by peroral injection, at a dose level of 5000 mg/kg bodyweight at a dose volume of 10 ml/kg in 0.25% aqueous gum tragacanth vehicle. All animals were observed for a fourteen day period for any signs of toxicity or other effects of treatment, after which they were subjected to gross necropsy. There was no significant effects observed during the study. All animals gained body weight. No abnormalities were observed during gross necropsy. Applicant assessment indicates that under the conditions of this study the LD50 male/female rats should be considered to be > 5000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

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

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Read-Across - methyl-2-[[(2,4-dimethyl-3-cyclohexen-1-yl)methylene]amino]benzoate: eq. similar to OECD TG 401 (1985): The study was performed in a method equivalent or similar to OECD TG 401 under GLP to assess the acute oral toxicity potential of the test substance to Sprague Dawley male/female rats. Following an acclimatisation period and overnight fasting, the test material was administered as a single oral dose to a group of five male and five female rats, by peroral injection, at a dose level of 5000 mg/kg bodyweight at a dose volume of 10 ml/kg in 0.25% aqueous gum tragacanth vehicle. All animals were observed for a fourteen day period for any signs of toxicity or other effects of treatment, after which they were subjected to gross necropsy. There was no significant effects observed during the study. All animals gained body weight. No abnormalities were observed during gross necropsy. Applicant assessment indicates that under the conditions of this study the LD50 male/female rats should be considered to be > 5000 mg/kg bw.

 

Read-Across - oxydipropanol: US EPA OPP 81-1 (1995): The study was performed according to EPA OPPTS 870.1100 (Acute Oral Toxicity) in accordance with GLP to assess the acute oral toxicity potential of the test substance to Sprague Dawley male/female rats. Following an acclimatisation period and overnight fasting, the test material was administered as a single oral dose to a group of five male and five female rats by oral gavage at a dose level of 5000 mg/kg bodyweight. All animals were observed for a fourteen day period for any signs of toxicity or other effects of treatment, after which they were subjected to gross necropsy. There was no significant effects observed during the study. All animals gained body weight. No abnormalities were observed during gross necropsy. Applicant assessment indicates that under the conditions of this study the LD50 male/female rats should be considered to be > 5000 mg/kg bw.

 

The applicant assesses this study by expert judgement and indicates that the weight of evidence by read-across to relevant data on both a common breakdown product (expected in physiological conditions) and/or main constituent that there is no evidence of significant toxicity at greater than acute oral toxicity: GHS category 4 levels. There is no evidence of significant clinical signs, body weight loss or abnormal signs in necropsy when tested at 5000 mg/kg bw limit dose in the male/female rat. The weight of evidence indicates that the substance should not produce significant acute toxicity as to produce are requirement to classify and label for acute oral toxicity in accordance with Regulation (EC) 1272/2008.

Justification for selection of acute toxicity – oral endpoint

Two in vivo studies available: 1. OECD 425: Klimisch 4 under GLP and; 2. eq. to OECD 401 under GLP: Klimisch 4 via read-across used within a weight of evidence approach to the endpoint.

Justification for classification or non-classification

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

The substance does not meet classification criteria under Regulation (EC) No 1272/2008: for Specific Target Organ Toxicity - Single Exposure.

Evaluation of available in vivo studies only; the selected studies support the conclusion that the substance does not meet the criteria for STO – SE under Regulation (EC) 1272/2008. Necropsy did not indicate abnormalities at guidance levels. In all relevant studies body weight gains were observed. Clinical signs were transient and fully reversible and not supporting of any category of classification.