4,4'-bis(diethylamino)benzophenone

Endpoint summary

Description of key information

The acute oral toxicity of the substance was investigated in a relaible in vivo study in which the substance was given by oral gavage at a single dose of 2000 mg/kg bw to female Wistar rats. The oral LD50 value of the substance in Wistar rats was established to exceed 2000 mg/kg body weight.

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:

19 February 2018 - 20 March 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

December 2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

May 2008

Deviations:

no

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

December 2002

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

Appearance: White to pale yellow green powder
Batch: 171116
Test item storage: At room temperature protected from light
Stable under storage conditions until: 16 November 2019 (expiry date)

Species:

rat

Strain:

Wistar

Remarks:

Crl: WI(Han)

Sex:

female

Details on test animals or test system and environmental conditions:

6 Females (nulliparous and non-pregnant).
Young adult animals (approximately 9-10 weeks old).

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed for general health/mortality and moribundity twice daily; postdose observations were performed at periodic intervals on the day of dosing (at least three times) and once daily thereafter; weighed individually on Day 1 (predose), 8 and 15.
- Necropsy of survivors performed: yes/no
- Other examinations performed: subjected to necropsy and descriptions of all internal macroscopic abnormalities were recorded.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture, piloerection, uncoordinated movements, pale skin and/or pale appearance were noted for the animals between Days 1 and 13.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of the substance in Wistar rats was established to exceed 2000 mg/kg body weight.

Executive summary:

The potential toxicity of the substance, when given by oral gavage at a single dose of 2000 mg/kg bw to female Wistar rats was determined in an in vivo according to OECD No.423 (2001) "Acute Oral Toxicity, Acute Toxic Class Method". No mortality occurred. Hunched posture, piloerection, uncoordinated movements, pale skin and/or pale appearance were noted for the animals between Days 1 and 13. Body weight loss was noted for three animals on Day 8; these animals regained weight during the second week. The body weight gain shown by the other three animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals. The oral LD50 value of the substance in Wistar rats was established to exceed 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Sufficient to address requirements.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 September 2017 - 26 September 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

Appearance: White to off-white crystalline powder
Batch: 20161118
Purity/Composition: 99.74%
Test item storage: At room temperature protected from light
Stable under storage conditions until: 17 November 2017 (expiry date)

Species:

rat

Strain:

Wistar

Remarks:

Crl: WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Females were nulliparous and non-pregnant.
Age at the Initiation of Dosing: Young adult animals (approximately 11 weeks old) were selected.
Weight at the Initiation of Dosing: Males: 295 to 320 g. Females: 186 to 197 g.
Acclimitisation: 5 days.
Housing: Polycarbonate cages.
Actual daily mean temperature: 21 to 22°C
Actual daily mean relative humidity: 46 to 60%.
A 12 hour light/12 hour dark cycle was maintained.
Ten or greater air changes per hour with 100% fresh air (no air recirculation).
Food and water: Ad libitum.

Type of coverage:

occlusive

Vehicle:

propylene glycol

Details on dermal exposure:

TEST SITE
- Area of exposure: back of the animals
- % coverage: 10% i.e. approximately 25 cm² for males and 18 cm² for females
- Type of wrap if used: Surgical gauze patch successively covered with aluminum foil and Coban elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water or an appropriate vehicle
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg body weight

Duration of exposure:

24 hours.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5/sex/dose

Control animals:

no

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Scales and/or erythema maculate were noted for two females between Days 3 and 10. General erythema, erythema maculate, scales and/or scabs were seen in the treated skin-area of three females during the observation period.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 value of the substance in Wistar rats was established to exceed 2000 mg/kg body weight.

Executive summary:

The potential toxicity of the substance was determined, when given by a single dermal dose. The study was conducted according to OECD No. 402 (1987) ''Acute Dermal Toxicity''. The substance was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight for 24 hours.  No mortality occurred. Scales and/or erythema maculate were noted for two females between Days 3 and 10. General erythema, erythema maculate, scales and/or scabs were seen in the treated skin-area of three females during the observation period. The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals. The dermal LD50 value of the substance in Wistar rats was established to exceed 2000 mg/kg body weight.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The following functional groups are common across the target and source substance: aryl groups and carbonyl groups. It is the scientific hypothesis of this read-across justification that the presence of these functional groups dictates the toxicological potential of the target substance. The target and sources substances both pass Lipinski’s rule of five and are therefore considered to have the potential to be absorbed into the body via the oral route. The breakdown products within the body are likely to be similar, or the same, as shown in the table below.
Breakdown products:
Source substance - Benzophenone, Toluene, Hippuric acid or ortho-Cresol
Target substance - Benzophenone, Diethylamine (x2)

The target and source substance are expected to degrade in a similar way within the body and are expected to generate similar if not the same major metabolites. The molecular weight of the target and source substance are similar and are both below 500 daltons. The water solubility and partition coefficients of the target and source substances are comparable. Both the target and source substances pass Lipinski’s rule of five indicating that they may be orally absorbed and therefore are available within the body and may act in a similar toxic way.


2. SOURCE AND TARGET CHEMICAL
The source and target substances are composed of the same functional groups bound together in similar ways. The molecular weight of the target and source substances are similar and they are expected to be absorbed in the body in similar ways. The breakdown products of the substance are expected to be the same or very similar and are expected to have the same potential for acute toxicity.
The target and source substance contains very low levels of unidentified impurities. These impurities are considered not to affect the classification and labelling of the substance due to the very low levels at which they occur. No information on impurities present in the source test materials was available in the literature sources.
The impact of “impurities” is therefore considered not to affect the reliability of the read-across prediction.


3. ANALOGUE APPROACH JUSTIFICATION
Due to the similarities of the source and target substance with regards to physico-chemical properties, Lipinski’s rule of 5, and the fact that the target substance is expected to breakdown into structurally similar molecules in the body, the target substance is expected to behave in a substantially similar manner to the source substance. The target substance is therefore predicted LD50 >2000 mg/kg bw in the OECD 402 study when conducted in the rat. By extension, the target substance is considered not to fulfil the criteria for acute toxicity under the Classification, Labelling, and Packaging (CLP) regulation (1272/2008).

4. DATA MATRIX
See appended full justification document.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Deviations:

no

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

1

Justification for classification or non-classification

Based on the findings of a reliable acute oral toxicity study conducted on the substance, classification of the substance is not justified.