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EC number: 203-253-7 | CAS number: 104-93-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study (OECD) which was conducted under GLP conditions.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 995
- Report date:
- 1995
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 4-methylanisole
- EC Number:
- 203-253-7
- EC Name:
- 4-methylanisole
- Cas Number:
- 104-93-8
- Molecular formula:
- C8H10O
- IUPAC Name:
- 1-methoxy-4-methylbenzene
- Details on test material:
- - Name of test material (as cited in study report): p-Methylanisole
- Physical state: liquid, yellowish
- Analytical purity: > 99 %
- Storage condition of test material: at room temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: K. Thomae GmbH, Biberach/Riss, Germany
- Average weight at study initiation: males ca. 184 g, females ca. 148 g
- Age at study initiation: 42 days
- Housing: singly in type DK III stainless steel wire cages (Becker & Co., Castrop-Rauxel, Germany)
- Diet: Kliba rats/mice/hamsters maintenance diet, 343 meal (Klingentalmühle AG, Kaiseraugst, Switzerland), ad libitum throughout the study
- Water: ad libitum
- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 24 °C
- Humidity: 30 - 70 %
- Air changes (per hr): fully air-conditioned rooms
- Photoperiod: 12 hrs dark / 12 hrs light
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on oral exposure:
- The animals were administered dose levels of 100, 300 and 1000 mg/kg bw based on results from prevous studies and controls received olive oil.
Before the start of the administration period the animals were distributed according to weight among the individual test groups separated by sex.
Individual animals of test groups 1- 3 received the corresponding doses daily from Monday - Friday by gavage in varying concentrations, depending on the latest body weight determination. The animals of the vehicle control group received the vehicle by gavage.
The administration volume used in the study was 5 ml/kg body weight. The test substance was administered as a solution. The doses were prepared in the first two weeks daily and from the 15 day on once a week. The test substance was weighed and diluted to the appropriate volume with olive oil. The doses were dissolved using a magnetic stirring apparatus.
At the end of the administration period the animals were fasted for about 16 hours (withdrawal of food) and sacrificed.
Observations included: food consumption, body weight gain, clinical observations, mortality, clinical chemistry and hematology and pathology. - Analytical verification of doses or concentrations:
- yes
- Remarks:
- Investigations to characterize the test substance with respect to purity and homogeneity were conducted prior to the start of the study.
- Details on analytical verification of doses or concentrations:
- Analytical check of the stability of p-methylanisole in the vehicle over a period of 5 days was performed before the start of the study. Gaschromatography was used to determine the content of p-methylanisole in the undiluted test substance and in the applied doses.
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- 5 days/week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
100, 300, 1000 mg/kg bw in olive oil DAB 9
Basis:
actual ingested
- No. of animals per sex per dose:
- 5 animals per sex per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The animals were administered dose levels of 100, 300 and 1000 mg/kg bw based on results from prevous studies and controls received olive oil.
Before the start of the administration period the animals were distributed according to weight among the individual test groups separated by sex.
Individual animals of test groups 1- 3 received the corresponding doses daily from Monday - Friday by gavage in varying concentrations, depending on the latest body weight determination. The animals of the vehicle control group received the vehicle by gavage.
The administration volume used in the study was 5 ml/kg body weight. The test substance was administered as a solution. The doses were prepared in the first two weeks daily and from the 15 day on once a week. The test substance was weighed and diluted to the appropriate volume with olive oil. The doses were dissolved using a magnetic stirring apparatus.
At the end of the administration period the animals were fasted for about 16 hours (withdrawal of food) and sacrificed.
Observations included: food consumption, body weight gain, clinical observations, mortality, clinical chemistry and hematology and pathology.
Examinations
- Observations and examinations performed and frequency:
- CLINICAL EXAMINATIONS:
Food consumption:
The food consumption over a period of 7 days was determined weekly and calculated as mean food consumption in grams per animal and day.
Body weight data:
The body weight was determined before the start of the administration period in order to randomize the animals. During the conduct of the study, the body weight was determined on day 0 (start of administration period) and thereafter in weekly intervals. The difference between the body weight on the respective day of weighing and the body weight on day 0 was calculated as the body weight change.
Clinical observations:
The general state of health of the animals was checked twice a day (Mondays to Fridays) and once a day (Saturdays, Sundays and public holidays). Furthermore the animals were checked for the appearance of clinical signs before and after each test substance administration.
Mortality:
A check was made for dead or moribund animals twice a day (Mondays to Fridays) and once a day (Saturdays, Sundays and public holidays).
CLINICAL CHEMISTRY AND HEMATOLOGY:
Blood was taken from the retroorbital venous plexus in the morning from non-fasted, not anesthetized animals. The blood samplings and the subsequent analysis of the blood and serum samples were carried out in a randomized sequence. The list of randomization instructions was compiled with a computer using a random number generator. The assays of blood and serum parameters were performed under internal laboratory quality control conditions with commercial reference controls to assure reliable test results.
The results of the clinicochemical and hematological examinations are expressed in units of the International System (SI). The following examinations were carried out in 5 animals per test group and sex.
Hematological examinations:
The following parameters were determined in blood with EDTA-K3 as anticoagulant using a particle counter (S Plus model, by Coulter, Krefeld, Germany):
- leukocytes
- erythrocytes
- hemoglobin
- hematocrit
- mean corpuscular volume
- mean corpuscular hemoglobin
- mean corpuscular hemoglobin concentration
- platelets
Differential blood count was evaluated visually.
Clotting analyses:
The clotting analyses were carried out using a ball coagulometer (KC 10 model, by Amelung, Lemgo, Germany).
The following parameter was determined:
- thromboplastin time (Hepato Quick's test)
Clinicochemical examinations:
An automatic analyzer (Hitachi 737; by Boehringer, Mannheim, Germany) was used to examine the clinicochemical parameters.
The following parameters were determined:
Enzymes
- alanine aminotransferase
- aspartate aminotransferase
- alkaline phosphatase
- serum-gamma-glutamyltransferase
Blood chemistry
- sodium
- potassium
- chloride
- inorganic phosphate
- calcium
- urea
- creatinine
- glucose
- total bilirubin
- total protein
- albumin
- globulins
- triglycerides
- cholesterol
- magnesium - Sacrifice and pathology:
- The animals were sacrificed by decapitation under CO2 anaesthesia. The exsanguinated animals were necropsied and assessed by gross pathology.
The weight of the animals as well as the weights of liver, kidneys, adrenal glands, testes, thymus and spleen from all animals sacrificed at scheduled dates was determined.
Subsequently the following organs or tissues were fixed in 4 % formaldehyde solution:
liver, heart, stomach, gross lesions, kidneys, thymus, testes, spleen, brain, mesenteric lymph nodes, adrenal glands, salivary glands (Glandula madibularis/sublingualis), all organs with gross lesions.
After the organs had been fixed, processing, the examination by light microscopy and the evaluation of findings was performed. - Statistics:
- Clinical data, clinical chemistry and hematology (except diff. blood count): Kruskal-Wallis-h-test (non-parametric ANOVA); if p-values were =< 0.05, pairwise comparison of each dose group with the control group was performed using the Mann-Whitney-U-test.
Organ weights: KRUSKAL-WALLIS-h test . if p-values were =< 0.05, pairwise comparison of each dose group with the control group was performed using WILCOXON-Test.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw all male and female rats showed clinical signs such as salivation, ataxia and tremor after gavage but not on the following day with one exception where one animal showed signs of labored respiration. At 300 mg/kg bw, some male and female rats showed salivation. At 100 mg/kg bw, no substance related changes were observed.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The body weight and body weight change of the male rats of the 100, 300 and 1,000 mg/kg body weight groups as well as the body weight data of the female rats of the 100 and 300 mg/kg body weight groups showed no substance-related impairment. In the female rats at 1000 mg/kg bw, body weight was statistically significantly increased compared to control on day 21; body weight change was statisically increased on day 21 and 28.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- In females of test group 3 (1,000 mg/kg body weight) the food consumption was increased from day 14 onwards. When compared to controls no other test substance related differences were noted.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No substance-induced changes were observed in the hematological parameters of both sexes.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- After 4 weeks of test sUbstance administration statistically significantly increased cholesterol concentrations were found in the serum of the high-dose females (Tab. 022). This finding is assessed as being treatment-related and is probably due to a slight impairment of liver function (see "Pathology part" of the report ) . No other substance related changes were detected.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw: significantly increased mean absolute and relative liver weights in males and females, significantly decreased mean absolute and relative spleen weights in male rats without morphological changes, significantly increased mean absolute and relative lkidney weights in females without morphological changes and decreased mean relative thymus weight in males without morphological changes.
At 300 mg/kg/d bw: significantly decreased mean absolute spleen weights in males without morphological changes.
At 100 mg/kg bw: no substance related changes were observed - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At the highest dose one male animall showed hyperkeratosis and focal hyperplasia of the forestomach.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- At the highest dose, diffuse hypertrophy of the hepatocytes and single cell necrosis of hepatocytes in all male and female rats
- Details on results:
- The administration of p-Methylanisole to male and female Wistar rats for 4 weeks at doses of 100, 300 and 1000 mg/kg body weight led to following
substance-induced findings :
Group 3 (1000 mg/kg body weight group):
- all male and female rats showed clinical signs such as salivation, ataxia and tremor after gavageing, but (with one exception) not on the following day; one male rat showed laboured respiration
- increase in cholesterol in the females
- significantly increased mean absolute and relative liver weights in male and female rats
- diffuse hypertrophy of the hepatocytes and single cell necrosis of hepatocytes in all male and female rats
- significantly decreased mean absolute and relative spleen weights in male rats without a morphological counterpart by light microscopy
- significantly increased mean absolute and relative kidney weights in female rats without a morphological counterpart by light microscopy
- decreased mean relative thymus weight in males without a morphological counterpart by light microscopy
- focal hyperplasia and hyperkeratosis of the mucosa of the forestomach in one male rat
Group 2 (300 mg/kg body weight group):
- some male and female animals showed salivation after gavage of the test substance
- significantly decreased mean absolute spleen weights in male rats without a morphological counterpart by light microscopy.
Group 1 (100 mg/kg body weight group):
- no substance related changes
The clinical symptoms (such as salivation, ataxia, tremor) were observed only after gavageing of the test substance, but not on the following day, with the exception of one female which showed salivation on day 28 in the morning also. These signs are most probably a consequence of the irritating potential of the test substance and are thus only a local, but not a systemic toxic effect. This is confirmed by the fact, that in one male animal of the highest dose group hyperkeratosis and focal hyperplasia were seen in the forestomach. Also the increased food consumption of the animals might be a compensatory reaction on the irritation of the forestomach.
No abnormalities were discovered by light microscopy that might explain the altered weights of spleen, thymus or kidneys.
The other microscopic lesions reported were either single observations or they were equally distributed over the treated and control animals.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other:
- Remarks:
- In the 1000 mg/kg/day dose groups there were some liver effects involving single cell necrosis of hepathocytes and hyperplaiz in the forestomach. At 300 mg/kg bw similar effects were sign on clinical signs but only changes in spleen weights observed, again with no histopathological changes.
Target system / organ toxicity
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 300 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Table 1: Mean food consumption of the animals
Mean Food Consumption (g/animal/day) |
day 7 |
day 14 |
day 21 |
day 28 |
males |
||||
0 mg/kg bw |
23.3 |
24.0 |
23.5 |
23.7 |
100 mg/kg bw |
23.3 |
23.7 |
22.9 |
23.9 |
300 mg/kg bw |
22.6 |
22.9 |
21.6 |
22.6 |
1000 mg/kg bw |
22.5 |
24.3 |
25.4 |
26.4 |
females |
||||
0 mg/kg bw |
16.7 |
15.3 |
15.0 |
16.3 |
100 mg/kg bw |
17.1 |
15.7 |
15.6 |
15.9 |
300 mg/kg bw |
15.3 |
14.8 |
14.8 |
15.6 |
1000 mg/kg bw |
16.7 |
19.2 |
19.0 |
20.6 |
Table 2: Mean body weight of the animals
Mean body weight (g) |
day 0 |
day 7 |
day 14 |
day 21 |
day 28 |
males |
|||||
0 mg/kg bw |
185.2 |
233.4 |
277.3 |
308.9 |
337.9 |
100 mg/kg bw |
182.9 |
232.0 |
275.0 |
302.6 |
333.3 |
300 mg/kg bw |
184.3 |
227.0 |
264.1 |
289.0 |
315.7 |
1000 mg/kg bw |
185.0 |
229.2 |
274.7 |
304.1 |
333.0 |
females |
|||||
0 mg/kg bw |
147.6 |
164.2 |
180.7 |
189.8 |
202.8 |
100 mg/kg bw |
148.5 |
167.1 |
183.6 |
193.4 |
207.3 |
300 mg/kg bw |
147.0 |
160.8 |
173.1 |
188.0 |
200.2 |
1000 mg/kg bw |
148.8 |
169.6 |
187.2 |
208.2 |
225.9 |
Applicant's summary and conclusion
- Conclusions:
- The overall NOEL for this study was 100 mg/kg bw.
- Executive summary:
Wistar rats were exposed to vehicle control, 100, 300 and 1000 mg/kg bw p-metjhylanisole by gavage 5 -days per week for 28-days. Animals in the 1000 mg/kg bw group showed clinical signs of toxicity (salivation, ataxia and tremor) immediately folllowing exposure but not there after. There were also changes in organ but no concomittant histopathological changes. In this dose groups there were some liver effects involving single cell necrosis of hepathocytes and hyperplaiz in the forestomach. At 300 mg/kg bw similar effects were sign on clinical signs but only changes in spleen weights observed, again with no histopathological changes. At 100 mg/kg bw, there were no changes observed. The overall NOAEL for this study was 100 mg/kg bw.
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