Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04-1975 and 01-1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report date:
1976

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
no details on animal husbandry, exposure 7 h/day instead of 6 h/day, no food consumption measured, lesser haematological parameters measured, no clinical chemistry, lesser organ weights determined, lesser histopathological determinations
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
tert-butyl peracetate
EC Number:
203-514-5
EC Name:
tert-butyl peracetate
Cas Number:
107-71-1
Molecular formula:
C6H12O3
IUPAC Name:
tert-butyl ethaneperoxoate
Details on test material:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in the refrigeratore in the dark between +10 and +30°C

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands
- Weight at study initiation: average bw 67 g
- Diet: ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: glass exposure cylinder with stainless steel interior
- Method of holding animals in test chamber: each exposure cylinder accommodated five male and five female rats, seperated from one another
- Temperature: 23°C
- Air flow rate: 10 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: TBPA was evaporated by passing a measured, filtered and dried air flow through glass evaporation columns, packed with chromosorb W (60 to 80 mesh) at 23°C.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the air were taken at intervals and analysed by means of GLC, using a 0.35 m x 4 mm column of stainless steel tubing packed with QF-1 4.8% / diglycerol 0.13% on Chrom G-AW-DHCS and a flame ionization detector.
Duration of treatment / exposure:
28 days
Frequency of treatment:
7 hours/day, 5 days/week for a four-week period
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
control
Dose / conc.:
2 ppm
Remarks:
equals 10.9 mg/m3
Dose / conc.:
11 ppm
Remarks:
equals 60.4 mg/m3
Dose / conc.:
52 ppm
Remarks:
equals 285.6 mg/m3
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Positive control:
no positive control

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded weekly.
- How many animals: 10 male and 10 female rats per doses

HAEMATOLOGY: Yes
Haematological data (haemoglobin content, haematocrit value, and erythrocyte and leucocyte counts) were collected in week 4.
- How many animals: 10 male and 10 female rats per doses

URINALYSIS: Yes
- Urine examinations were made, including appearance, pH, glucose, protein, occult blood, ketones, using test stripes, and microscopy of the sediment in pooled urine samples of each group.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- The organ weight of the heart, kidneys, liver, spleen and lung was determined of groups of ten male and ten female rats after a test period of four weeks.

HISTOPATHOLOGY: Yes
- Tissue samples of the organs described before and of the head (after removal of the skin, brain and lower jaw) were taken.
Other examinations:
No other examinations
Statistics:
Student's t-test

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Growth of the males of the low and intermediate doses groups was slightly, but statistically significantly retarded during the first weeks (see table 1 other information on results)
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Endocrine findings:
not specified
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant differences in relative organ weight did not occur between the groups, apart from a slightly elevated lung weight in males and a slightly lowered spleen weight in females at the low exposure level. These deviations are not considered of any toxicological importance, because the relative weights of these organs at the higher dose levels did not differ significantly from those of the controls.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Upon gross examination the lungs of both the test and control animals looked normal and there was no evidence of treatment-related changes in any of the other organs. Infrequently occurring gross changes unrelated to the inhalation included pale livers and kidneys, a striking lobular pattern of the liver surface and hydronephrosis.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Neither the respiratory tract nor any of the other organs examined showed lesions that could be associated with the exposure. All changes occurred to about the same degree and frequency in the various groups studied histologically and are, moreover, quite common findings in the strain of rats used.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
52 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to 52 ppm.
Dose descriptor:
NOAEC
Effect level:
0.28 mg/L air
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Dose descriptor:
NOAEC
Effect level:
104 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.
Dose descriptor:
NOAEC
Effect level:
0.56 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Table 1: Mean body weights of groups of ten male and ten female rats

























































































Animal



TBPA [ppm]



Mean body weight at end of week


        0                                                            1                                                            2                                                   3                                           4



Males



1



0



67



124



147



188



221



2



2



66



111***



134***



173**



193*



3



11



67



111***



134***



176*



208



4



52



67



121



145



186



215



Females



1



0



66



105



117



136



149



2



2



67



103



117



138



152



3



11



67



106



118



142



158



4



52



67



106



119



136



149



*p < 0.05, **p < 0.01, ***p < 0.001


 


Table 2: Relative organ weights (in g/100 g body weight) and their standard deviations of groups of ten male and ten female rats after test period of four weeks




















































































TBPA [ppm]



heart



kidneys



liver



spleen



lung



Males



0



0.383 (0.015)



0.80 (0.02)



5.47 (0.20)



0.293 (0.009)



0.61 (0.02)



2



0.417 (0.029)



0.85 (0.06)



5.67 (0.45)



0.303 (0.022)



0.69* (0.04)



11



0.378 (0.011)



0.79 (0.01)



5.26 (0.12)



0.271 (0.012)



0.58 (0.01)



52



0.377 (0.013)



0.77 (0.01)



5.38 (0.11)



0.290 (0.007)



0.63 (0.03)



Females



0



0.397 (0.013)



0.80 (0.02)



4.62 (0.13)



0.300 (0.012)



0.66 (0.03)



2



0.393 (0.014)



0.79 (0.01)



4.76 (0.08)



0.269* (0.008)



0.65 (0.01)



11



0.405 (0.008)



0.78 (0.02)



4.71 (0.07)



0.297 (0.018)



0.64 (0.01)



52



0.386 (0.008)



0.79 (0.01)



4.48 (0.14)



0.288 (0.009)



0.65 (0.02)



*p < 0.05, according to Student's t-test

Applicant's summary and conclusion

Conclusions:
The results of the present four-week inhalation study indicates that the NOAEC of the active ingredient is higher than 52 ppm (correspond to 0.28 mg/L). Hence, the NOAEC for the test material (50% act. ingr. in Shellsol T) is expected to be approx. 0.56 mg/L.
Executive summary:

The sub-acute inhalation toxicity of the test substance (50% active ingredient) was studied in rats by exposing them 7 hours/day, 5 days/week to atmosphere, containing the vapour of the active ingredient at the concentrations 0, 2, 11 and 52 ppm (~ 0.28 mg/L), for a four-week period. Observations were made of behaviour, general appearance, growth, haematology, urine composition, organ weights and gross as well as microscopic pathology. None of the criteria applied revealed treatment-related effects. From the results of the present four-week inhalation study with the test substance it appeared that no deleterious effects could be demonstrated in rats exposed repeatedly to concentrations of the active ingredient of up to 52 ppm (0.28 mg/L) during twenty exposure days. It is concluded, therefore, that the NOAEC is higher than 0.28 mg/L. Therefore, the NOAEC for the test material (50% act. ingr. in Shellsol T) is expected to be approx. 0.56 mg/L.