Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 82-4 (90-Day Inhalation Toxicity)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Analytical purity: 40%
- Lot/batch No.: S08706

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 7 weeks
- Weight at study initiation: male 189-237g, female 141-172g

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: water
Remarks on MMAD:
MMAD / GSD: MMAD (mass median aerodynamic diameter) [µm] (+ GSD (geometric standard deviation) [µm]
Group II 1.3 ± 1.81
Group III 1.1 ± 1.94
Group IV1.4 ± 2.09
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Test material diluted in distilled water was metered to a pneumatic atomizer mounted in the top of a 4-L glass atomization chamber. The atomizer was operated with compressed air. Addition compressed air was metered to the atomization chamber to purge the aerosol into the exposure chamber. The concentrated aerosol was diluted to the desired concentration with chamber supply air at the chamber inlet.
Duration of treatment / exposure:
90 days
Frequency of treatment:
5 days/week
6 hours/day
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 2.1, 3.3, 10.0 mg/m3 (the high dose was increased to 23.7 after 6-weeks)
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 0.46, 1.1, 3.8 mg/m3 (after 6 weeks high dose was 8.1)
Basis:
analytical conc.
No. of animals per sex per dose:
15 animals/group
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
-Clinical signs: twice daily
-Mortality: twice daily
-Body weight: weekly
-Ophthalmoscopic examination: weeks 0, 6, 13
-Haematology:
number of animals: all animals
time points: end of study, plus 5 control animals at pretest
Parameters: Haematocrit, haemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration
-Clinical chemistry:
Number of animals: 10 animals per sex per group
time points: 6 and 13 weeks
Parameters: sodium, potassium, glucose, total cholesterol, urea, blood urea nitrogen, total bilirubin, creatinine, total protein, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, chloride, calcium, inorganic phosphorus, globulin, albumin/globulin ratio
-Urinalysis:
Number of animals: 10 animals per sex per grouop
Time points: 6 and 13 weeks
Parameters: color & appearance, volume, specific gravity, pH, protein, glucose, occult blood, microscopic elements, ketones, bilirubin, nitrite, urobilinogen.
Sacrifice and pathology:
-Organ weights: adrenals, liver, testes, ovaries, brain, heart, lung/bronchi (tracheal bifurcation)
-Gross and histopathology: Control and high-dose groups Gross lesions were examined in all animals.
Organs: brain, spinal cord, pituitary, thyroid, parathyroid, thymus, oesophagus, salivary glands, stomach, small and large intestines, liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, aorta, gonads, uterus, female mammary gland, prostate, urinary bladder, lymph nodes, sciatic nerve, bone marrow, skin, eyes, bone (femur), exorbital lachrymal gland, nasal tissue, skeletal muscle (thigh), cervix, vagina
Statistics:
Generally, when the number of animals in any one group was less than or equal to ten, non-parametric analysis was conducted utilizing the Kruskal-Wallis one-way analysis of variance, followed where appropriate, with the Mann-Whitney U. In those cases where the number of animals in all groups was greater than ten and the measurements were at least on an interval scale (continuous data), parametric analysis was conducted utilizing Bartlett’s Chi-Square test for homogeneity of variance and then where appropriate by Dunnett’s t test. In all cases the level of rejection was at the five percent level.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
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:
-Mortality: No mortalities in the controls or at the low, or high dosed groups. An intermediate dosed female died on the last day of the study during the clinical observations
-Body weight gain: The high dose females were observed to have a decrease in body weight gain of approximately 12% starting around week 10 through the remaining portion of the study
-Haematology: At week 6 the high dosed females were observed with depressed hemaglobin. However, while it was statistically significant it was within normal limits and was not considered biologically significant. All other values were unremarkable.
-Clinical chemistry: Alkaline phosphatase levels were depressed in group II males and creatinine levels were depressed in group IV females and glucose levels were elevated in group III females at the 13 week interval. These findings were not considered treatment related as all values were within the normal control range for animals of this age and sex and there was no dose-response relationships.

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
8.1 mg/m³ air
Sex:
male/female
Basis for effect level:
body weight and weight gain
Dose descriptor:
NOAEL
Effect level:
0.46 mg/m³ air
Sex:
male/female
Basis for effect level:
other: no substance-related findings were observed

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL = 0.46 mg/m3
LOAEL = 8.1 mg/m3
The information contained within this robust summary document comes from studies which are in the ownership of Arch Chemicals Inc. and which are protected in several regions globally. This information may not be used for any purpose other than in support of the Chemical safety Report submitted by Arch Chemicals Inc. under Regulation EC 1907/2006.