Pyrithione zinc

Repeated dose toxicity: inhalation

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:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3465 (90-Day Inhalation Toxicity)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Source: Harlen
Weight at study initiation: male = 209-262g, female = 204-249g

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

Dose preparation: Test substance was aspirated from a motorized revolving disc delivery system coupled to a Venturi Aspirator. Dust/aerosol generated was then diluted with filtered air in a vacuum flask apparatus and sprayed directly into the chamber. Airflow into the chamber was maintained through the use of a calibrated orifice plate at a rate of 95-169 air changes per hour. Airflow was recorded at 30 minute intervals during the exposure period, and was sufficient to ensure an oxygen content of at leas 19% of the exposure atmosphere. Temperature and humidity were recorded at 30 minute intervals during the exposure period from a Taylor wet bulb/dry bulb hygrometer located in the exposure chamber.

Duration of treatment / exposure:

21 days

Frequency of treatment:

6 hours/5 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
2.0 mg/m sq
Basis:

Doses / concentrations 2

Remarks:

Doses / Concentrations:
5.0 mg/m sq
Basis:

Doses / concentrations 3

Remarks:

Doses / Concentrations:
12.0 mg/m sq
Basis:

No. of animals per sex per dose:

20

Control animals:

yes, sham-exposed

Examinations

Observations and examinations performed and frequency:

Clinical signs: twice daily on treatment days, daily on non-treatment days
Mortality: twice daily on treatment days, daily on non-treatment days
Body weights: days 0, 5, 7, 14, 21
Ophthalmoscopic: day 21
Clinical chemistry: days 7 and 21

Sacrifice and pathology:

Organ weights: adrenal glands, thymus, liver, kidneys, spleen, brain, testes, epididymides, ovaries, uterus, heart, and lungs w/trachea
Gross pathology: Control and high-dose groups. A gross necropsy will be conducted on each animal at termination of the study or at the time of discovery after death, and the results recorded. The gross necropsy shall include the following:

1. Gross observations of external surfaces and all orifices; gross observations of cranial, thoracic, and abdominal cavities.
2. The weight of the following tissues will be recorded: liver, brain, kidneys, adrenals, testes, epididymides, uterus, ovaries, thymus, spleen, heart, and lungs w/trachea.

3. The salivary glands, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, liver, pancreas, brain, pituitary, peripheral nerve, spinal cord, eyes, adrenals, parathyroids, thyroids, trachea, lung, pharynx, larynx, nose, aorta, heart, bone marrow, lymph nodes, spleen, thymus, kidneys, urinary bladder, prostate, testes, epididymides, seminal vesicles, uterus, ovaries, female mammary gland, all gross lesions and masses, and a sample of the skin of each animal will be saved in 10% neutral buffered formalin for possible histopathologic examination.

Other examinations:

Functional Observational Battery was conducted on each animal weekly on Days 9 and 16. Observations of home cage behaviour included bar were not limited to assessment of posture, involuntary (clonic and tonic) motor movement, vocalization, and palpebral closure. Ease of handling and reaction to being handled were also assessed, as were open-field measurements such as number of rears, arousal, mobility, and gait. Reactivity to stimuli (approach, touch, click, and tail pinch) was also assessed, and the righting reflex was evaluated. The animals were also observed for any indication of bizarre behaviour such as circling, pacing, or stereotypic grooming. Grip strength was only measured pre-dose and post-dose prior to the interim and terminal sacrifices.

Statistics:

The effect of the test substance will be evaluated by the relationship between the dose tested, the incidence and severity of abnormalities including behavioral and clinical abnormalities, gross lesions, identified target organs, body weight changes, effect on mortality and any other general or specific toxic effects. When applicable, all observed results, quantitative and qualitative, will be evaluated by an appropriate statistical method

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:

effects observed, treatment-related

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:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

Clinical signs: No observable abnormalities were seen in any Group I animal throughout the study. In Group II, one male and two females experienced temporary very slight swelling around the eyes during the first week of the study. The main clinical sign seen in Group III was an intermittent very slight to slight swelling around the eyes of 8 males and 10 females. Additional signs included intermittent wet fur around the muzzle in 5 males, gasping by 2 males and 1 female, and respiratory gurgles by 2 males and 2 females. One Group III female was found dead in the nose only dosing tube at the end of the Day 2 exposure. One Group IV female and one male were found dead in their cages, prior to the Day 3 exposure and Day 20 prior to necropsy, respectively; one male and one female were found dead in the tube at the end of the exposure period on Days 2 and 3 respectively. Slight to very slight swelling around the eyes was seen in 11 males and 12 females. Twelve males and 9 females had respiratory gurgles, while 6 animals (3 of each sex) exhibited gasping. In addition, 3 males showed activity decrease, two males and one female were cool to the touch, and one female intermittently walked on tip-toes.
Mortality: Mortality occurred in one Group IV male scheduled for terminal sacrifice on Day 2, prior to the interim sacrifice; and one Group IV male and one Group IV female mortality Day 20 found dead in the nose only tube. Additional mortalities included one Group III female on Day 2 (found in dosing tube appeared stuck), one Group IV female on Day 3.
Body weight gain: All groups showed an overall weight loss at necropsy, including controls. This may have been due to the fasting of the animals prior to sacrifice at the interim time point at 5 days and at terminal sacrifice, Day 21. Statistical analyses of weight changes at the interim sacrifice for female rats show no statistical difference between the controls and the low and intermediate dose rate. There is a statistically higher weight loss for Group IV (High Dosed Group) animals than controls at the interim sacrifice. For male rats at the interim sacrifice there was no statistical difference in the weight changes of any group compared to controls. At the terminal sacrifice, male rats in both the medium and high dose groups had significantly greater weight changes than the control male rats. The weight change for male rats in the low dose group was not significantly different than the weight change for the males in the control group. Female rat body weights at terminal sacrifice appeared to be affected by the test substance. The average weight loss did increase with higher doses. However, because of an unexpectedly large weight loss in the female control rats, no statistical differences were seen. The significantly large weight losses in control rats may be due to the stress of dosing since the animals were not acclimated to the nose-only tubes prior to dosing
Ophthalmoscopic: One male from Group IV (High Dose) was observed to have dacryocystitis and mild iritis in both eyes; no other findings were observed in any of the animals on test.
Organ weights: Lung weights at the 5 and 21-day sacrifices were significantly increased (compared to controls) in all exposure groups except for the high dosed group (Group IV) males at day 5 and Group II (low dosed group) males at day 21. These increase correlate with the histopathologic reactions seen in the lungs. There do not appear to be any other dose dependent effects on organ weights.
Gross pathology: Gross necropsies performed on the animals that died on test revealed external findings of matted, discoloured, or urine coated hair in all five animals.
Gross Pathology, Interim Sacrifice (5-Day):
Group I (controls), two males had pale lungs and one had a darkened spleen, enlarged adrenals, discoloured fur, and black scabbing at the base of the tail.
Group II (low dose), one male had red spots on the lymph nodes and pale lungs, while a second male had a mottled pancreas with a third male had a enlarged adrenal gland. One female had black spots on the lungs.
Group III (intermediate dose), one male with pale lungs, and a second male with enlarged adrenals. One female had a pale liver, one female with circular bumps on the lungs and fluid in the uterus. One female had a mottled spleen and two other females had enlarged adrenals.
Group IV (high dose), three males were observed with pale or mottled lungs. Four females were observed with discoloration of the lungs, two females had pale livers and three had enlarged adrenal glands.
Gross Pathology, Terminal Sacrifice (21-Day):
Group I, one male was observed with abnormal seminal vesicles. No abnormal findings in the female animals.
Group II, no findings in male or female animals.
Group III, no findings in male or female animals.
Group IV, one male observed with pale or mottled lungs, and one male with gas distended intestinal tract, and one male with a deformed spleen. One female was observed with discoloration of the lungs.
Histopathology: The main findings in the exposed animals were increased numbers of alveolar macrophages (but not neutrophils) in the alveoli (typical response to inhales particles), inflammation of the nasal mucosa and interstitium around the bronchioles and vessels of the lung, inflammation of the larynx which was ulcerative in some rats, mucous cell hypertrophy of the nasal mucosa and bronchial mucosa (a typical response to irritation), squamous metaplasis of the nasal mucosa, larynx, and trachea (a typical response to irritation), squamous metaplasia of the nasal mucosa, larynx and trachea (a typical reparative response of the lung), and smooth muscle hypertrophy and hyperplasia of the alveolar ducts. The smooth muscle hypertrophy and hyperplasis of the alveolar ducts involved the thin collar of connective tissue and smooth muscle that normally surrounds the mouths of the alveoli as they enter the alveolar duct. These tissue reactions were of similar character and severity in the males and females with the exception of ulcerative laryngitis and interstitial inflammation of the lung. The ulcerative laryngitis was more severe in the male exposure groups and the interstitial inflammation in the females. The biologic significance of these differences between males and females is uncertain.
While these main findings were observed in all treatment groups the severity ranged from minimally perceivable (low dose) to mild (high dose). These reactions increased minimally with dose and only modestly from Day 5 to Day 21.

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

6 mg/m³ air

2

Dose descriptor:

NOAEL

Effect level:

2 mg/m³ air

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

NOAEL= 2.0 mg/m cubed. 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.