Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline without GLP, acceptable with restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

EC Number:

218-216-0

EC Name:

Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

Cas Number:

2082-79-3

Molecular formula:

C35H62O3

IUPAC Name:

octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

Details on test material:

- Physical state: white powder

Test animals

Species:

rat

Strain:

other: RAI f

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: bred on the premises of CIBA-GIEGY limited
- Age at study initiation: 5-6 weeks
- Weight at study initiation: males 174-178 g; females 172-176 g
- Housing: 5/cage
- Diet (e.g. ad libitum): pelleted standard diet, Nafag No. 890 (NAFAG, Gossau SG, Switzerland)
- Water (e.g. ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±10
- Air changes (per hr): 15

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

clean air

Remarks on MMAD:

MMAD / GSD: Particle size analysis of the chamber airborne particles showed that > 70 % were smaller than 7 micron in diameter (20 to 30 % above 7 µm; 30 to 40 % 3-7 µm; 25 to 35% 1-3 µm; 15-25 % 0-1 µm)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- According to the method of Sachsse et al. (In: Proceedings of the Europ. Soc. for the Study of Drug Toxicity. Vol. XV, pp. 239-251, Zurich, June 1973)
- Method of holding animals in test chamber: The animals were kept separately in PVC tubes which were positioned radially around the exposure chamber.
- System of generating particulates/aerosols: The test article was generated as a dust in three different amounts with the help of a Grafix Exaktomat Injector (Cerutti AG., Bern, Switzerland) into an airstream discharged into the exposure chamber through a nozzle under a pressure of 2 atm, at a rate of 20 L/min.
- Temperature, humidity in air chamber: ca. 25 °C, 43-61 %
- Method of particle size determination: Gravimetrically with a 4 stage Cascade Impactor on selectron filters, pore size 0.2 um and 25 mm diameter (Schleicher und Schuell, Feldbach, Switzerland)

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetrically on selectron filters, pore size 0.2 um and 50 mm in diameter (Schleicher und Schuell, Feldbach, Switzerland)
- Samples taken from breathing zone: yes, in the vicinity of the animals throughout the exposure time

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

21 days

Frequency of treatment:

6 h/day, 5 times/week

Doses / concentrations

Remarks:

Doses / Concentrations:
23±3, 128±8, 543±12 mg/m3
Basis:
analytical conc.

No. of animals per sex per dose:

10

Control animals:

yes, sham-exposed

Details on study design:

- Post-exposure recovery period in satellite groups: 21 days (all groups)

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: mortality, symptoms

BODY WEIGHT: Yes
- Time schedule for examinations: daily, except weekends

FOOD CONSUMPTION:
- Food consumption for each animal determined: Yes, twice weekly

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weekly
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at test day 21
- Anaesthetic used for blood collection: No
- Animals fasted: Yes, overnight
- How many animals: 5 males and 5 females
- Parameters checked: Haemoglobin (Hb), Methaemoglobin (MHb), Erythrocytes (RBC), Packed Cell Volume (PCV), Mean Corpuscular Volume (MCV), Mean Corpuscular Haemoglobin (MCH), Reticulocytes, Inclusion Bodies (Heinz Bodies), Thrombocytes, Prothrombin Time, Activated Partial Thromboplastin Time, Leucocytes (total count and differential count)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at test day 21
- Animals fasted: Yes, overnight
- How many animals: 5 males and 5 females
- Parameters checked: Glucose, Urea (Urea-N), Glutamate-Oxalacetate Transaminase (GOT), Glutamate-Pyruvate Transaminase (GPT), Lactate Dehydrogenase (LDH), Alkaline Phosphatase (AP), Y-Glutamyl Transpeptidase (y-GT), Total Protein, Protein Electrophoresis, Electrolytes (Na, K)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

The following organs were weighed: heart, lungs, liver, kidneys, adrenals, thymus, brain, gonads. Organ to body weight and organ to brain weight ratios were calculated for each of these organs.

Statistics:

- for Laboratory Investigations, Student's "t" test and the analysis of variance were employed to assess the significance of difference between concentration groups and controls whenever indicated.
- for others than Laboratory Investigations, a uni-variate statistical analysis was conducted.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

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:

CLINICAL SIGNS AND MORTALITY:
During the exposure and recovery period no toxic symptoms were observed in the rats of the test and control groups.

BODY WEIGHT AND WEIGHT GAIN:
No differences in the bodyweights were observed in the rats of the test and control groups during the exposure and recovery period.

FOOD CONSUMPTION:
There was only a slight but significant (sign.l = 0.01) reduction of food consumption in male rats of highest dose group at day 13 of the exposure period.

FOOD EFFICIENCY:
The mean food conversion of all treated rats was comparable to that of the controls during the 21-day exposure and the following recovery period.

OPHTHALMOSCOPIC EXAMINATION:
No ocular changes were observed

HAEMATOLOGY:
The observed haematological findings between treated rats and controls were generally unremarkable.

CLINICAL CHEMISTRY:
In the assessment of blood chemistry values the findings were unremarkable and comparable to those of the controls.

ORGAN WEIGHTS:
There were no obvious differences in absolute organ weights, organ to body weight and organ to brain weight ratios between the treated and control rats.

GROSS PATHOLOGY:
No compound related gross anatomical changes were noted in the treated animals.

HISTOPATHOLOGY: NON-NEOPLASTIC:
All microscopical findings were only incidental in nature and not related to treatment.

Effect levels

Dose descriptor:

NOEC

Effect level:

>= 543 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects at the highest dose tested.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

There were no reactions to treatment for all the parameters investigated. It can be inferred from the observations made during the above study that the "no observable effect level" is above 543 mg/m3 air for male and female rats.