Acetophenone

Endpoint summary

Description of key information

oral LD50 rat: 2,081 mg/kg bw (key study: Worstmann, 1981)
dermal LD50 rat: 3,300 mg/kg bw (key study: Marzin, 1978)

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Gassner, Sulzfeld, Germany
- Weight at study initiation: males 110-135 g, females 100-120 g
- Fasting period before study: 16 hrs before substance application until 4 hrs post application
- Housing: 5 per cage
- Diet: ad libitum before and after treatment
- Water: ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 1 °C
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

1.0, 1.6, 2.5, 4.0 mL/kg corresponding to dosages of 1030, 1648, 2575, 4120 mg/kg bw

No. of animals per sex per dose:

5 males, 5 females

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical symptoms repeatedly on day of application, thereafter once daily; body weight on the day of application and on study day 7 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 081 mg/kg bw

95% CL:

1 597 - 2 730

Mortality:

Details of time course of death at the different tested doses are presented in Table 1
Except for 1 female rat of the highest dose group, all mortalities occurred within 24 hrs post application.
The LD50 was calculated at 2.02 mL/kg corresponding to 2,081 mg/kg with a 95% confidence interval of 1.55-2.65 mL/kg (1,597-2,730 mg/kg).

Clinical signs:

other: Immediately after application all rats showed piloerection and bending Further dose-related effects: 1030 mg/kg: decreased motility 10/10, staggering gait 10/10; 1648 mg/kg: decreased motility 1/5 m, 1/5 f; staggering gait 1/5 m, 3/5 f; most a

Gross pathology:

Deceased animals: slight to severe hyperemia of the liver
Animals sacrificed at the end of the study: no pathological findings

Table 1: Time course of mortality findings

Time point	Controls		1030 mg/kg		1648 mg/kg		2575 mg/kg		4120 mg/kg
	m	f	m	f	m	f	m	f	m	f
up to 6 hrs	0/5	0/5	1/5	1/5	2/5	0/5	1/5	3/5	3/5	2/5
6 - 24 hrs	0/5	0/5	0/5	0/5	0/5	1/5	1/5	1/5	2/5	2/5
24 - 48 hrs	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5
3 - 7 d	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	1/5
7 - 14 d	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5	0/5
Total mortality	0/5	0/5	1/5	1/5	2/5	1/5	2/5	4/5	5/5	5/5

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The oral LD50 in rats was 2,081 mg/kg bw. Death occurred within 24 hrs after application with unspecific clinical signs. Livers of deceased animals showed hyperemia.

Executive summary:

The acute toxicity was investigated in groups of 5 male and 5 female Sprague-Dawley rats by gavage application of undiluted acetophenone. The oral LD50 in rats was 2081 mg/kg bw. Death occurred within 24 hrs after application with unspecific clinical signs. Livers of deceased animals showed hyperemia.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 081 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Remarks:

source: PubChem, CheIDplus

Principles of method if other than guideline:

no data

GLP compliance:

no

Species:

rat

Route of administration:

inhalation

Duration of exposure:

8 h

Concentrations:

210 ppm

Sex:

not specified

Dose descriptor:

LC0

Effect level:

>= 210 ppm

Based on:

test mat.

Exp. duration:

8 h

Remarks on result:

other: ca. 1040 mg/m3 at 20°C

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Remarks:

source: PubChem, ChemIDplus

Principles of method if other than guideline:

no data

GLP compliance:

not specified

Test type:

other: no data

Species:

other: mammal (species unspecified)

Route of administration:

inhalation

Concentrations:

1200 mg/m3

No. of animals per sex per dose:

no data

Sex:

not specified

Dose descriptor:

LC50

Effect level:

1 200 mg/m³ air

Based on:

test mat.

Remarks on result:

other: unknown exposure duration

Reference 3

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Remarks:

Exposure to substantially saturated vapor atmosphere with unknown substance concentration, compilation of data with insufficient documentation of test conditions and test results; data acceptable for assessment in a weight of evidence approach.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method: Generation of satured vapour atmosphere by passing a flowing stream of air through a fritted disc bubbler at room temperature
- Principle of test: 6 male rats are exposed during 8 hours
- Parameters analysed / observed: mortality

GLP compliance:

no

Test type:

fixed concentration procedure

Limit test:

yes

Species:

rat

Strain:

not specified

Remarks:

albino

Sex:

male

Route of administration:

inhalation: vapour

Type of inhalation exposure:

not specified

Vehicle:

not specified

Details on inhalation exposure:

Generation of satured vapour atmosphere by passing a flowing stream of air through a fritted disc bubbler at room temperature

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

ca. 8 h

Concentrations:

not measured: substantially saturated vapor atmosphere at room temperature

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: no data
- Clinical signs including body weight: no data

Sex:

male

Dose descriptor:

LC0

Effect level:

>= 2 130 mg/m³ air

Based on:

test mat.

Remarks:

430 ppm

Exp. duration:

8 h

Remarks on result:

other: According to Patty (1981), the maximum vapour concentration at 20°C is 430 ppm, equivalent to about 2130 mg/m3.

Mortality:

no deaths observed

Interpretation of results:

GHS criteria not met

Conclusions:

8h LC0 in rat is higher that the saturated vapour concentration (ca. 430 ppm ou 2130 mg/m3)

Executive summary:

Rats, subjected to the inhalation of normal atmosphere saturated with acetophenone vapors for an 8 hour exposure period, exhibited 100% survival.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Study with test protocol similar to OECD guideline 402 with acceptable deviations: less detailed documentation of testing procedure, no microscopic examination, confidence interval not specified; sufficient documentation of test results; study acceptable for assessment

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:

(less detailed documentation of testing procedure, no microscopic examination, confidence interval not specified)

Principles of method if other than guideline:

5 doses of acetophenone covering a dose range of 1.82-5.2 g/kg were dermally applied with occclusion to groups of 5 male and 5 female rats. Mortality, clinical symptoms and weight development were observed for up to 15 days. All animals found dead and survivors sacrificed on day 15 p.a. were subjected to an autopsy with macroscopic examination of the principal viscera in abdomen and thorax.

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: IFFA CREDO
- Weight at study initiation: 130-150 g
- Fasting period before study: no data

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 6 x 6 cm
- % coverage: not specified
- Type of wrap if used: aluminium foil and sparadrap

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with soap water
- Time after start of exposure: 24 hrs

Duration of exposure:

24 hrs

Doses:

1,82, 2,36, 3, 4, 5,2 g/kg

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days post application
- Frequency of observations and weighing: clinical signs daily, body weight on day 0, 5, 10 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic examination of viscera in abdomen and thorax

Statistics:

Statistically significant difference of body weight development with p<0.05, p<0.01 (statistical method not specified)
LD50 calculated by method of Dragstedt and Lang

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 300 mg/kg bw

Based on:

test mat.

Mortality:

3 g/kg: 3/10; 4 and 5.2 g/kg: all rats died (for details see Table 1)

Clinical signs:

other: see Table 1

Gross pathology:

Jejunum and ileum identified as target after dermal application

Table 1: Findings after acute dermal application of acetophenone to rats

Dose group (g/kg)	Mortality		Clinical symptoms		Autopsy	Body weight (g)
	Incidence	Time to death p.a.	Timepoint p.a.	Symptoms		Day 0	Day 5	Day 10	Day 15
0	0/10			-		140.5 ±5	167.2±8.7	184.2±17	221±22.9
1.82	0/10		1-2 hrs in 5/10, 1-24 hrs in 5/10 From 6 hrs	Reduced spontaneous activity Prostration (1/10) and palpebral ptosis (10/10)	No macroscopic findings
2.36	0/10		Up to 48 hrs Up to 72 hrs	Reduced spontaneous activity with staggering gait, lacrimation palpebral ptosis (10/10)	9/10: congestion of mucous layer of jejunum; yellowish liquid in a part of the jejunum	137.3±4.2	155.5±8.4*	175±15	212.5±22.4
3	3/10	6 hrs – 6 d	Up to 5 d 2 hrs – 2 d 6 hrs – 5 d	Reduced spontaneous activity staggering gait, prostration, tremor; lacrimation, palpebral ptosis Flat and halting breath 1/10 loss of weight and cyanosis on day 5, death on day 6	6/7 survivors: mucous intestinal congestion, 2/7 thinning of the abdominal lining in the region of jejunum and ileum, yellowish liquid present
4	10/10	6-48 hrs	From start of exposure	Staggering gait, prostration and inhibition of turn-around reflex, piloerection, lacrimation, palpebral ptosis, flat breath	No macroscopic findings
5.2	10/10	2-24 hrs	0 min up to death	Same as 4 g/kg	No macroscopic findings

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

With a LD50 of 3.300 mg/kg in rats, acetophenone showed only very slight toxicity after dermal exposure. Clinical symptoms were typical of effects on the nervous symptoms and on the eyes with a LOAEL of 1820 mg/kg. Autopsy revealed the intestinal tract (jejunum and ileum) to be a target of the adverse action of acetophenone with a LOAEL of 2360 mg/kg.

Executive summary:

5 doses of acetophenone ranging from 1.82-5.2 g/kg were applied dermally with occclusion to groups of 5 male and 5 female rats. Mortality, clinical symptoms and weight development were observed for up to 15 days. All animals found dead and survivors sacrificed on day 15 p.a. were subjected to an autopsy with macroscopic examination of the principal viscera in abdomen and thorax. With a LD50 of 3.300 mg/kg in rats, acetophenone showed only very slight toxicity after dermal exposure. Clinical symptoms were typical of effects on the nervous symptoms and on the eyes with a LOAEL of 1820 mg/kg. Autopsy revealed the intestinal tract (jejunum and ileum) to be a target of the adverse action of acetophenone with a LOAEL of 2360 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 300 mg/kg bw

Additional information

Oral toxicity

Two acute oral toxicity studies with test protocols similar to OECD Guideline 401 are available for classification. Oral LD50 values in Sprague-Dawley rats were 2,081 mg/kg bw and 2,200 mg/kg (key study: Worstmann, 1981; supporting study: Marzin, 1978). Death occurred within 24 hrs after application. The LOAEL was 710 mg/kg bw for clinical signs as staggering gait, inhibition of turn-around reflex, watery eyes, palpebral ptosis, slowed down breath, flabby appearance and cyanotic extremities. For Osborne-Mendel rats a higher LD50 of 3,200 mg/kg bw was reported (Jenner et al., 1964; supporting study). Death appeared within 1 hr to 4 days and some rats showed coma within 5 min after application, which persisted for up to 24 hrs.

A lower LD50 was reported in an old, insufficiently documented study (Smyth and Carpenter, 1948), which is not comparable to the guideline conditions of the key studies and is not adequate for classification. The more recent studies leading to higher LD50 values are superseding the old study (quoted as reliability 3 according to Klimisch criteria) having lead to DSD Annex I classification as Xn R22.

 

Dermal toxicity

In a key study with a test protocol similar to OECD Guideline 402, with a LD50 of 3.300 mg/kg in rats, acetophenone showed only very slight toxicity after dermal exposure. Clinical symptoms were typical of effects on the nervous symptoms and on the eyes with a LOAEL of 1820 mg/kg. Autopsy revealed the intestinal tract (jejunum and ileum) to be a target of the adverse action of acetophenone with a LOAEL of 2360 mg/kg (Marzin, 1978).

 

Inhalation toxicity

No adequate information is available on acute inhalation toxicity. Based on physical properties exposure to acetophenone due to evaporation is expected to be low at room temperature and inhalation is not a relevant path of exposure. Additionally, the known low acute toxicity of acetophenone by the oral and dermal path, supports that an inhalation toxicity study is scientifically not justified.

Justification for selection of acute toxicity – oral endpoint
The selected study is comparable to guideline study and is sufficiently documented; study acceptable as key study.
Other studies with lowest LD50 values were not selected, because considered of low quality and not reliable for the hazard assessment.

Justification for selection of acute toxicity – dermal endpoint
The selected study was the only one considered as reliable, with a test protocol similar to OECD guideline 402 with acceptable deviations. The other data were not reliable as poorly documented and from secondary litterature.

Justification for classification or non-classification

Based on the reliable studies reporting oral LD50 values of > 2,000 mg/kg there is no classification of acetophenone for acute oral toxicity based on EU regulation 1272/2008. However as acetophenone is classified as Acute Tox 4 H302 in Annex VI of CLP Regulation, it shall be classified and labelled in accordance with this harmonised classification.

Based on the reliable study reporting a dermal LD50 value of > 2,000 mg/kg there is no classification of acetophenone for acute dermal toxicity based on EU regulation 1272/2008.