Pentapotassium bis(peroxymonosulphate) bis(sulphate)

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:

1980-09-22 - 1981-08-12

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

The fact, that only male rats were used, is not considered to have compromised the study results, as male rats were shown to be the more sensitive sex in the acute inhalation toxicity study (please refer to A6.1.3/01, IUCLID section 7.2.2). This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

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

Version / remarks:

No guideline available at time of study conduct

Deviations:

yes

Remarks:

Only male rats were used , particle size not analysed, no individual animal data available, food consumption not investigated

GLP compliance:

no

Remarks:

GLP was not obligatory at the time of the study conduct; laboratories in the U.S.A. are not certified by any governmental agency, but are subject to official inspections. The study was performed according to good scientific practise.

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Pentapotassium bis(peroxymonosulphate) bis(sulphate)

EC Number:

274-778-7

EC Name:

Pentapotassium bis(peroxymonosulphate) bis(sulphate)

Cas Number:

70693-62-8

Molecular formula:

H3K5O18S4

IUPAC Name:

pentapotassium bis((hydroperoxysulfonyl)oxidanide) hydrogen sulfate sulfate

Test material form:

solid

Test animals

Species:

rat

Strain:

other: Crl:CD

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Not stated
- Age at study initiation: 8 weeks
- Weight at study initiation: 230 – 266 g

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

head only

Vehicle:

other: unchanged (no vehicle); dilution with clean air only

Remarks on MMAD:

MMAD / GSD: not indicated

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE

- System of generating particulates/aerosols: Dust aerosol atmospheres of Oxone were generated with a 3 stage glass generator composed of a dust reservoir, cyclone generator, and elutriator.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical concentrations are given under "Doses/concentrations"

Duration of treatment / exposure:

2 weeks, 6 hours per day

Frequency of treatment:

5 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/L air

Doses / concentrations 2

Dose / conc.:

0.001 mg/L air (nominal)

Remarks:

0.0014 mg/L (analytical)

Doses / concentrations 3

Dose / conc.:

0.01 mg/L air (nominal)

Remarks:

0.0101 mg/L (analytical)

Doses / concentrations 4

Dose / conc.:

0.05 mg/L air (nominal)

Remarks:

0.0431 mg/L (analytical)

No. of animals per sex per dose:

10/group

Control animals:

yes, concurrent no treatment

Details on study design:

not indicated

Positive control:

Not applicable

Examinations

Observations and examinations performed and frequency:

Observations
- Clinical signs: yes
- Mortality: yes

Body weight: yes (daily)

Food consumption: No

Water consumption: No

Ophthalmoscopic examination: yes

Haematology: Yes, blood samples were taken after the 10th and 13th observation day. Measurements included erythrocyte count, haemoglobin concentration, mean corpuscular volume, platelet count, leukocyte count, and relative number of neutrophils, lymphocytes, eosinophils, monocytes, and basophils. The haematocrit, mean corpuscular haemoglobin, and mean corpuscular haemoglobin concentration were calculated from these data.

Clinical Chemistry: Yes, blood serum measurements included alkaline phosphatase, glutamic-pyruvic transaminase, glutamic-oxalacetic acid, urea nitrogen, creatinine, and total protein.

Urinalysis: Yes, after the 9th exposure and the 12th observation day all test animals were individually housed in stainless steel metabolism cages for overnight (16 hours) urine collection.
The measurement included urine volume, osmolality, pH, and tests for sugar, blood, protein, bilirubin, urobilinogen, and acetone. The urine colour and appearance were noted and sediment from pooled specimens was examined macroscopically.

Sacrifice and pathology:

Yes, after the 10th exposure, 5 rats from each level were selected at random and sacrificed for gross and histopathological examination.

Remaining rats were sacrificed on the 13th observation day for an identical examination.
Organs weighed at necropsy: thymus, spleen, heart, lungs, kidneys, testes

Organs examined: ear pinna, skin thymus, mediastinal tissue, spleen, bone marrow (sternum), heart, trachea, lungs, oesophagus, stomach, small intestines (duodenum, jejum, and ileum), large intestines (caecum and colon), liver, kidneys, testes, epididymides, thyroids, adrenals, brain, eyes

Other examinations:

not indicated

Statistics:

LSD and Dunnett test was used as statistical model.

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 specified

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

not examined

Ophthalmological findings:

effects observed, treatment-related

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:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS
During the exposure:
The predominant clinical observations were characteristic of eye irritation (please refer to point 4.5).
A red discharge from the noses of control and test rats, and slight lung noise in high dose level rats was observed during exposure.
Post-exposure:
The 13 day observation period allowed only partial recovery from these ocular effects. Most of the clinical signs were still present but their severity had decreased.

MORTALITY
No unscheduled deaths were reported.

BODY WEIGHT AND WEIGHT GAIN
There was a sporadic weight loss in all groups (including controls), with significant weight depression in the intermediate and high levels during the latter part of the exposure period (Please refer to table 1, which is presented under “Remarks on results including tables and figures”).


OPHTHALMOSCOPIC EXAMINATION
No effects were noted in low dose level rats (0.0014 mg/L). Intermediate and high level rats exhibited dose dependent alopecia around the eye, conjunctival swelling, severe opacity, corneal ulceration and haemorrhage, corneal vascularisation, and clear discharge. In general, a dry, crusty scab formed around the eyes, keeping them closed unless forced open. One control rat had a cloudy, glazed right eye.

HAEMATOLOGY
After 10 exposures, rats at the high dose level had higher than normal leukocyte counts, with 3/10 rats having counts outside of the norm established by controls.

CLINICAL CHEMISTRY
High dose level rats tended to have elevated serum glutamic-oxalacetic acid, glutamic-pyruvic transaminase, and depressed levels in alkaline phosphatase, and serum creatinine.
After a 13-day observation period serum glutamic oxalacetic acid transaminase, creatinine, and total protein levels were statistically lower than controls, however, these effects were not considered clinically significant. Low levels in total protein and glutamic oxalacetic acid transaminase are not of toxicological relevance due to the absence of a treatment-related effect for total protein during treatment and due to a non-consistent direction of change for glutamic oxalacetic acid transaminase.
Furthermore, changes seen on glutamic-pyruvic transaminase and alkaline phosphatase were shown to be completely reversible during the recovery period.

URINALYSIS
Rats at the high dose level had an elevated nitrogen activity as well as depressed levels in urine pH.


ORGAN WEIGHTS
Analysis of mean absolute organ weight after 10 exposures and the 13-day observation period did not reveal any dose-dependent effects. Organ/body weight ration analysis likewise did not reveal any dose related responses (Please refer to table 2, which is presented under “Remarks on results including tables and figures”).


GROSS PATHOLOGY
No gross findings were observed in control or low dose level rats. Intermediate and high dose level rats generally had ocular discharge, swollen eyelids with hair loss, and a cloudy appearance of the cornea.

HISTOPATHOLOGY:
Microscopic lesions attributable to the test compound were limited to the eyes and eyelids of rats exposed at the 2 highest exposure levels. These changes included: blepharitis, keratitis, corneal vascularisation, iritis, exflammatory exudate in the anterior and posterior chambers of the eye, haemorrhage mainly in the vitreous body of the eye and degeneration of the lens (cataract). These findings were equal in severity in the 2 high test groups but higher in incidence in the high level. The 13 day observation period allowed only slight recovery of these lesions and it is not expected that complete recovery would occur.

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

0.01 mg/L air (analytical)

Sex:

male

Basis for effect level:

other: based on ocular effects

2

Dose descriptor:

LOAEL

Effect level:

2.73 other: mg/kg bw/d (assuming a respiratory volume of 86.4 L/rat/d and a body weight of 320 g)

Sex:

male

Basis for effect level:

other: based on ocular effects

3

Key result

Dose descriptor:

NOEL

Effect level:

0.001 mg/L air (analytical)

Sex:

male

Basis for effect level:

other: based on histological findings in the eyes at the next higher dose level.

4

Dose descriptor:

NOEL

Effect level:

0.38 other: mg/kg bw/d (assuming a respiratory volume of 86.4 L/rat/d and a body weight of 320 g)

Sex:

male

Basis for effect level:

other: based on histological findings in the eyes at the next higher dose level

Target system / organ toxicity

Key result

Critical effects observed:

no

Any other information on results incl. tables

Table 1: Summary: Body weight (g)

 

Test Day	Dose (mg/L)
-	0	0.0014	0.0101	0.0431
1	249.70	246.90	251.80	249.56
5	237.60	243.60	237.90	240.89
10	259.30	265.70	258.80	247.44#
12	259.70	264.10	243.80#	235.56#
15	278.00	285.00	271.00	256.25+
25	327.60	337.60	329.20	321.00

 

#  Significantly different (P0.05) from control group by Dunnett test and LSD.

+  Significantly different (P0.05) from control group by LSD.

 

 

Table 2:  Organ/Body weight mean relative data of rats sacrificed after 13 day observation period.

Organ	Dose (mg/L)
-	0	0.0014	0.0101	0.0431
Heart	0.3451	0.3320	0.3287	0.3526
Lungs	0.6509	0.6132	0.6263	0.5565
Liver	3.7396	3.7591	3.8695	3.9592
Spleen	0.2508	0.2525	0.2112	0.2020
Kidney	0.7931	0.7655	0.8019	0.7929
Testis	1.0050	0.9866	0.9647	0.9665
Thymus	0.2205	0.2200	0.2088	0.1960

Applicant's summary and conclusion

Conclusions:

The study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability).
14-days LOAEC: 0.0101 mg/L (10.1 mg/m³) corresponding to 2.73 mg/kg bw/d (assuming a respiratory volume of 86.4 L/rat/d and a body weight of 320 g)
14-days NOAEC: 0.0014 mg/L (1.4 mg/m³) corresponding to 0.38 mg/kg bw/d (assuming a respiratory volume of 86.4 L/rat/d and a body weight of 320 g), based on histological findings in the eyes at the next higher dose level.
No classification and labelling in view of repeated dose inhalation toxicity is necessary according to Regulation 1272/2008/EC (CLP).

Executive summary:

Materials and methods

In a 14-day inhalation toxicity study (6 hours per day, 5 days per week), 10 male Crl:CD rats per group were exposed to dust aerosol of KMPS triple salt at exposure levels of 0, 0.0014, 0.0101 and 0.0431 mg KMPS triple salt/L (head only exposure). Animals were examined for clinical signs and mortality. Body weight was examined daily. Haematology and clinical chemistry was performed after the 10th exposure and the 13th observation day. All animals were subjected to gross pathology. Selected organs were weighed.

 

Results and discussion

During the exposure period clinical observations were severe ocular irritation at mid and high dose levels. These included: alopecia around eyes, conjunctival swelling, weeping, severe opacity, and corneal vascularisation, ulceration, and haemorrhaging. In general, a dry crusty scab formed around the eyes keeping them closed unless forced open. Also noted during exposures was a red nasal discharge from both control and test rats and slight lung noise in high level rats. Sporadic weight depression was recorded in the two highest test levels during the latter part of the exposure period. The 13 day observation period allowed only partial recovery from these ocular effects. Most of the clinical signs continued but were less severe.

Following the 10th exposure, rats at the high dose level had elevated leukocyte counts as well as elevated serum glutamic oxalactic acid, glutamic pyruvic transaminase, and urea nitrogen activities. This group also had depressed levels in urine pH, alkaline phosphatase, and serum creatinine. No other clinical pathologic changes were seen in this group. No corresponding changes in haematology or clinical chemistry were evident at the low and mid dose level.

After the observation period, serum glutamic oxalactic acid, creatitine, and total protein levels were statistically lower than controls.

Gross pathology showed significant findings in the ocular area only at the mid and high dose level. These findings included ocular discharge, swollen eyelids with hair loss, and a cloudy appearance of the cornea. Histologic changes attributable to the test compound were also noted in the eyes and blespharitis, keratitis, corneal vascularisation, iritis, exflammatory exudate in the anterior and posterior chambers of the eye, haemorrhage (mainly in the vitreous body of the eye), and degeneration of the lens (cataract). These changes were equal in severity at the mid and high dose level but the incidences were higher at the high dose level. No ocular changes were observed in rats of the low level.

In a 13-days observation period allowed these eye lesions only slightly recovered and complete reversal is not considered likely to occur.

Organ and body weight at the high dose level noted only a significant decrease in body weight on test days 10-16 and at the intermediate dose level on day 12. All rats gained weight at parallel rates during the observation period. Analysis of mean absolute organ weight and organ/body weight ratios did not reveal any dose dependent changes (Please refer to tables 1 and 2, which are presented under “Remarks on results including tables and figures”).