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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
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: No guideline stated (but protocol provided), study not performed according to GLP (but Quality Assurance Statement provided).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A four week inhalation toxicity study was performed with a dust of ACL 85 Sanitizer (BDN-79-032). Four groups of 10 male and 10 female Sprague-Dawley rats were exposed six hours per day, five days per week for four weeks. The cumulative mean exposure concentrations for Groups I, II, III and IV were 0, 3.2, 10.1 and 31 milligrams per cubic meter (mg/m3), respectively. The average aerodynamic mass median diameter (AMMD) was 3.9 micrometers and the range of geometric standard deviations (GSD) was from 2.4 to 3.8.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name of test material: ACL 85® Sanitizer (trichloroisocyanuric acid)
Physical state: fine white powder
Lot/batch No.: KK 09-5387 (Monsanto Co.)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Test animals:
Source: Charles River Breeding Laboratories, Wilmington Massachussetts
Age at study initiation: 51 days old
Weight for males at study initiation: 269 g (mean value) 236-304 g (range value)
Weight for females at study initiation: 178 g (mean value) 155-207 g (range value)
Housing during exposure period: paired in stainless steel wire mesh cages
Housing during non-exposure period: individual in hung stainless steel wire mesh bottom cages.
Diet: standard rat chow (ad libitum)
Water: tap-city water with automatic waterign system (ad libitum)
Acclimation period: 16 days

Environmental conditions:
- Photoperiod (hrs dark / hrs light): 12 hours light on, 12 hours light off.

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: Average Mass Median Aerodynamic Diameter (MMAD): 4.6, 3.3 and 3.9 micrometers corresponding to 3.2, 10.1 and 31 mg/m3 respectively.
Geometric Standard Deviations (GSD): 2.4-3.8, 2.5-4.2 and 2.5-2.8 corresponding to 3.2, 10.1 and 31 mg/m3 respectively.
Details on inhalation exposure:
Generation of test atmosphere / chamber description:
- Exposure apparatus: stainless steel and glass exposure chambers of a total volume of one cubic meter and an effective volume of 760 Liters.
- System of generating particulates/aerosols: dry air was passed through the dust-feed generating a dust-laden airstream. This air stream was directed into a 1000-milliliter three-necked flask mounted on its side which impacted out the larger sized particles.
- Air flow rate: 235 liters per minute.
- Air change rate: one air change every 4.3 minutes.

Test atmosphere
- Brief description of analytical method used: Three air samples were collected from each exposure chamber using Gelman glass fiber filters (type A/E) and a Thomas pump (Model 107CA) on each exposure day. The amount of dust collected on each filter was determined by extracting the test material from the filter paper with water and titrating the water extract with sodium thiosulfate. The exposure levels were determined by computation of the ratio of dust collected to sample volume (Monsanto Chemical Company, Standard Analytical Method 12,906).
- Samples taken from breathing zone: yes.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Nominal concentrations of test material were analytically verified by atmospheric sampling using the method described above, in Details on inhalation exposure/Test atmosphere/Brief description of analytical method used.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/m3 (control)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
3.2 mg/m3
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
10.1 mg/m3
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
31 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Positive control:
None

Examinations

Observations and examinations performed and frequency:
Cage side observations: Yes
- Time schedule: observations carried out during the four weekly observation period.

Detailed clinical observations: Yes
- Time schedule: daily for abnormal signs, a full recorded physical assessment was performed weekly.

Body weight: Yes
- Time schedule for examinations: weekly

Haematology: Yes
- Time schedule for collection of blood: Blood collection was performed prior to the first exposure and just prior termination of the four weeks exposure.
- How many animals: 5/sex/group

Clinical chemistry: Yes
- Time schedule for collection of blood: clinical chemistry parameters were evaluated prior to the first exposure and at end of study.
- Animals fasted: No
- How many animals: 5/sex/group

Urinalysis: Yes
- Time schedule for collection of urine: end of study
- Animals fasted: No
- How many animals: 5/sex/group

Neurobehavioural observation: No
Sacrifice and pathology:
Gross pathology and histopathology: high and low dose groups.

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, gall bladder (mouse), lymph nodes, peripheral nerve, bone marrow, skin, eyes.

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 specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
Mortality
All animals survived the duration of the study.

Clinical signs
An increased incidence of nasal discharge, moist rales, excessive salivation and excessive lacrimation was observed in both the 10.1 and 31 mg/m3 groups in a concentration response pattern.

Bodyweight gain
No effects found

Food consumption
Not examined

Ophtalmoscopic examination
No examinations

Haematology
The mean leukocyte values in the 3.2 and 31 mg/m3 female rats was significantly decreased during week 4. The significantly decreased value in the 31 mg/m3 groups was unusually low although the differential counts for all groups were generally comparable making the biological significance of the observed value questionable.

Clinical chemistry
Elevations of blood urea nitrogen levels were observed for the 10.1 and 31 mg/m3 female rats when compared to the control values.

Urinalysis
No effects found.

Neurobehavior
Not reported.

Organ weights
Increased relative adrenal weights in the 10.1 and 31 mg/m3 male and 31 mg/m3 female rats and increased relative lung weights in the 31 mg/m3 females and 3.2 mg/m3 males.

Gross pathology
No effects found.

Histopathology:
No effects found.

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
> 31 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: All animals survived the duration of the study. No adverse effects were reported in gross pathology and histopathology.
Dose descriptor:
NOAEL
Effect level:
> 31 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: No adverse effects were reported in gross and histopathology.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

All animals survived the duration of the study. An increased incidence of nasal discharge, moist rales, excessive salivation and excessive lacrimation was observed in both the 10.1 and 31 mg/m3 groups in a concentration response pattern.

Body weights were generally unremarkable. Haematology values were generally unremarkable with the possible exception of mean leukocyte values in the 31 mg/m3 group female rates. All clinical parameters appeared normal although elevations of blood urea nitrogen levels were observed from the 10.1 and 31 mg/m3 female rats when compared to the control values. Urinalysis results were generally unremarkable.

Comparison of organ weights and organ/body weight ratios showed increased relative adrenal weights in the 10.1 and 31 mg/m3 male and 31 mg/m3 female rats and increased relative lung weights in the 31 mg/m3 females. All other findings were considered unremarkable.

Gross and microscopic examinations of tissues from the 0 and 31 mg/m3 did not reveal any effects that may be attributed to daily inhalation of the test material.

Applicant's summary and conclusion

Conclusions:
LOAEL and NOAEL were estimated to be above 31 mg/m3 for males and females rats.