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Administrative data

Description of key information

Oral (subchronic): NOEL = 578 mg/kg bw/day 4'-methylacetophenone (data derived from subchronic acetophenone study with systemic NOEL = 518 mg/kg bw/day)
Oral (subacute): NOAEL = 251 mg/kg bw/day 4'-methylacetophenone (data derived from subacute acetophenone study with systemic NOAEL = 225 mg/kg bw/day); LOAEL = 838 mg/kg bw/day 4'-methylacetophenone (data derived from subacute acetophenone study with systemic LOAEL = 750 mg/kg bw/day)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Pre-GLP, pre-OECD TG study with sufficient detail in documentation
Principles of method if other than guideline:
The study was conducted prior to the publication of OECD TGs. Rats received daily oral doses of the test substance dissolved in corn oil for a period of 17 weeks.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: not reported
- Age at study initiation: weanling
- Weight at study initiation: not reported
- Fasting period before study: not reported
- Housing: individually in wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- not reported
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
appropriate amounts of test substance were weighed and mixed in the diet
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Loss of acetophenone from laboratory animal diet during a 7-day period: 31 %
Percentage loss = 100-(100xday 7 recovery/day 0 recovery)
Duration of treatment / exposure:
17 weeks
Frequency of treatment:
Continuously
Remarks:
Doses / Concentrations:
0, 1000, 2500 and 10000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 75, 118, 750 mg/kg bw/day
Basis:
other: calculated from assumed body weight (400 g) and food consumption (30 mg/day/rat)
No. of animals per sex per dose:
10 males and 10 females
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: not reported
Positive control:
No
Observations and examinations performed and frequency:
Body weight, food intake and general conditions: every week
Haematology (white cell count, red cell count, haemoglobins, haematocrits): after three months
Gross pathology: at termination of study
Histopathology: at termination of study
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Not reported
Statistics:
Not reported
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
There was no effect on growth or haematology, and no macroscopic or microscopic change in the tissues.
Dose descriptor:
NOEL
Effect level:
100 000 ppm
Based on:
test mat.
Remarks:
acetophenone
Sex:
male/female
Basis for effect level:
other: No effect
Dose descriptor:
NOEL
Effect level:
518 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
acetophenone
Sex:
male/female
Basis for effect level:
other: No effect observed at the highest received dose = 750 mg/kg bw/day, but assuming 31 % loss of acetophenone from laboratory animal diet during a 7-day period
Dose descriptor:
NOEL
Effect level:
578 mg/kg bw/day (nominal)
Based on:
other: 4'-methylacetophenone
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
Oral repeated exposure of rats to acetophenone by feeding over a period of 17 weeks resulted no adverse effects up to 100000 ppm in the diet. Considering 31 % of acetophenone loss from laboratory animal diet during a 7-day period, the corrected NOEL is 518 mg/kg bw/day.
Executive summary:

The oral repeated dose toxicity of acetophenone to male and female Osborne-Mendel rats was studied over a period of 17 weeks. The test substance was added in the food at doses of 1000, 2500 and 100000 ppm to ten males and ten females in each dose group. A untreated control group was investigated in parallel. All animals were weanling at the beginning of the study. The body weight, food consumption and general condition of animals were recorded regularly. Haematological investigations were performed after 3 months. At the end of the study all animals were sacrificed. Gross pathology was performed on every rat and organs were weighed. Sections were prepared from relevant organs for histopathological studies, which were performed for a representative fraction of animals (6 or 8) in high dose and control groups evenly divided by sex. No effects on growth or haematology, and no macroscopic or microscopic change in the tissues were found at the end of the study up to 100000 ppm dose level. It was concluded that the no-effect level (NOEL) was at 100000 ppm or 750 mg/kg bw/day in male and female Osborne-Mendel rats. Considering 31 % of acetophenone loss from laboratory animal diet during a 7-day period, the corrected NOEL is 518 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
578 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Two reliable studies, one subacute and one subchronic, with read across substance acetophenone are available.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no repeated dose toxicity data on 4'-methylacetophenone.

- Repeated dose toxicity: oral (read across from acetophenone)

A repeated dose toxicity study is available for acetophenone, which is a read-across substance for 4'-methylacetophenone. The substance is deemed to not show classifiable specific target organ toxicity. One reliable subacute study conducted according to OECD TG 422 and GLP in rats is available (Thorsrud 2003) using oral (gavage) dose levels of acetophenone at 0, 75, 225 and 750 mg/kg bw/day. The NOAEL for repeated dose toxicity of acetophenone was 225 mg/kg bw/day (equivalent to 251 mg/kg bw/day 4'-methylacetophenone), based on neurobehavioural findings at 750 mg/kg bw/day acetophenone. Therefore, the LOAEL was 750 mg/kg bw/day acetophenone (equivalent to 838 mg/kg bw/day 4'-methylacetophenone).

Another reliable subchronic study (17-week) conducted in rats according to scientific principles is also available (Hagan et al 1967). Using oral (feeding) dose levels of acetophenone at 0, 1000, 2500 and 100000 ppm, the NOEL was determined at 100000 ppm. Assuming 400 g rat body weight and 30 mg food consumption per day, 100000 ppm corresponds to 750 mg/kg bw/day dose. In this feeding study, 31 % loss of acetophenone from laboratory animal diet during a 7-day period should be considered. Therefore the NOEL should be reduced to 518 mg/kg bw/day acetophenone (equivalent to 578 mg/kg bw/day 4’-methylacetophenone).

The NOEL from the subchronic feeding study (578 mg/kg bw/day) was selected as a starting point for the DNEL derivation as the more reliable result of a prolonged subchronic study (17-weeks or 119 days).

According to CLP Regulation, the classification of a substance for repeated dose toxicity is based on the LOAEL defined in a subchronic study. The LOAEL obtained from a subacute toxicity study may be converted by applying an uncertainty factor of 3. Consequently, a 28-day LOAEL value of equal to or less than 300 mg/kg bw/day would trigger classification. The LOAEL for acetophenone (and the LOAEL calculated for 4'-methylacetophenone) is considerably greater than 300 mg/kg bw/day. Classification for repeated dose toxicity is not required.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The reliable subchronic study available for acetophenone was taken as read across to 4'-methylacetophenone.

Justification for classification or non-classification

- Repeated dose toxicity, oral:

Based on the above stated assessment of the specific target organ toxicity potential after repeated oral exposure to acetophenone, 4'-methylacetophenone does not need to be classified according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) or according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

 

- Repeated dose toxicity, dermal:

As no data on of the specific target organ toxicity potential after repeated dermal exposure of 4'-methylacetophenone is available a classification is not possible according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

 

- Repeated dose toxicity, inhalation:

As no reliable data on of the specific target organ toxicity potential after repeated inhalation exposure of 4'-methylacetophenone is available a classification is not possible according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.