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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study well documented. However, only one dose was tested, type of application was not sufficiently described and all animals were infected in this study. The observed effects could have been secondary to the infectious disease. Accordingly, no reliable conclusions on possible systemic effects after dermal administration can be drawn from this study.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Investigation into subacute and subchronic percutaneous tolerance of disinfactants in the 28 and 90 day test following epicutaneous application using the example of peroxyethanoic acid
Author:
Kramer A. et al.
Year:
1982
Bibliographic source:
Pharmazie, 37, H 1, 41-46 (in German with English translation)

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
(only one dose, examinations limited)
Principles of method if other than guideline:
Method: study was performed on the basis of OECD 410 with a limited extent of examinations.
Major deficiencies with respect to conduct and reporting of the study:
• All animals suffered of pneumonia
• It is not stated whether an occlusive, semi-occlusive or no dressing was applied.
• Mortalities were indirectly indicated in tables but not specified in text.
• Only one dose level was tested.
• Limited number of haematological and histopathological parameters were determined.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
guinea pig
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
- Source: not indicated
- Age: not indicated
- Weight at study initiation: 300 - 500 g
- room temperature: 17 to 22 degrees Celsius
- relative atmospheric humidity: 46 to 52 %

Administration / exposure

Type of coverage:
not specified
Vehicle:
water
Details on exposure:
Area covered: 3 x4 cm
Concentration topically applied: 0.12 % peracetic acid
Total volume applied: 0.16 mL/100g body weight
Duration of each daily exposure: 24 h
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
5 days per week, twice daily (no application during weekend).
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.16 ml/100 g bw of a 0.3 % Wofasteril solution = 1.6 ml/kg bw of 0.12 % peracetic acid solution twice daily
Basis:
nominal per unit area
Remarks:
Doses / Concentrations:
4 mg peracetic acid/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
Groups of Guinea pigs were dermally exposed to 0.16 mL/100g bw twice daily to 0.12 % PAA in water.
Positive control:
not applicable.

Examinations

Observations and examinations performed and frequency:
- Clinical signs: Behaviour (daily), test area and fur (daily), heart action (twice weekly)

- Mortality: not examined/observed on a regular basis.

- Body weight: weekly.

- Water consumption: yes, time periods not indicated.

- Haematology: performed on all animals; time point: beginning and end of study; parameters: leucocyte number, osmotic resistance of erythrocytes, haematocrit.

- Clinical chemistry: performed on all animals; time point: beginning and end of study; parameters: Asparagine aminotransferase (ASAT), alanine aminotransferase (ALAT), LDH isoenzyme, serum creatinine, total serum protein, serum albumin, serum thiocyanate .

- Food consumption, ophthalmoscopy, urinalysis was not performed.

Sacrifice and pathology:
- Organ weights: liver, kidneys, adrenals, spleen, brain, heart, lung, pancreas of 14 treated and 10 control animals.

- Gross and histopathology: Macroscopic assessment of liver, kidneys, adrenals, spleen, brain, heart, lung, pancreas and histopathological examination of liver skin of 14 treated and 10 control animals.
Other examinations:
None.
Statistics:
U and Wilcoxon test

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
see other results for details
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Description (incidence):
see other results for details
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
28 days group: slight decrease on days 20 and 28 90 days group: slight decrease from day 44 onwards, after termination of application rapid normalisation
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
see other results for details
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
see other results for details
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:
no effects observed
Details on results:
- Clinical signs and mortality:
An initially slight and later on a marked hair loss was noted in treated animals. Greyish discolouration at the treatment sites was related to the bleaching potential of hydrogen peroxide contained in the formulation. Heart rate was higher in some cases (also in controls, although not to the same extend). At the end of the observation period mean values were practically identical for control and treated animals.

- Body weight gain: slight decrease on days 20 and 28.

- Water consumption: Drinking water consumption did not show differences between treatment and control group.

- Haematology: The serum creatinine level was elevated at the end of the application period.

- Clinical chemistry: ASAT and LDH (I and III, respectively) isoenzyme levels were increased.

- Organ weights: Relative liver weights were increased.

- Gross and histopathology: No gross findings. Histologically a slight activation of the stellate cell system of the liver and small to medium size adipose degeneration of liver cells were seen. 2 animals showed central necrobiotically modified granulomae in the liver.

- Other findings: Pneumonia was observed in all animals including controls with an increased severity in the treated animals. According to the authors this could be due to an infection that was possibly aggravated by inhalation of PAA vapours originating from the treated skin. In the kidneys of the test animals, but not of controls, interstitial lymphocyte infiltration were observed in the glomeruli.

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
4 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: based on peracetic acid; applied 5 d/wk
Dose descriptor:
LOAEL
Effect level:
3.2 other: mL of a 0.12% peracetic acid solution (in two daily doses)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Clinical signs:

1 animal of the 90 days group: rough and thin fur, loss of hair (day 71), tremor and fever (day 74), apathy, 6 days after completion of the 90 day application the condition had largely ameliorated, the animal appeared normal 40 days after termination of the application.

 

14 animals of the test group showed slight to pronounced erythema, intensity decreasing after day 25. Transient erythema were also seen in control animals.

 

In the 28- and 90- day studies, an initially slight and later on a marked hair loss was noted in treated animals. Greyish discolouration at the treatment sites was related to the bleaching potential of hydrogen peroxide contained in the formulation.

 

Heart rate was higher in some cases (also in controls, although not to the same extend). At the end of the observation period mean values were practically identical for control and treated animals

 

Mortality:

Not specifically mentioned in publication. However, it can be deduced from the tables that 1 animal of the dose group (week 2) and 1 animal of the control group (week 3) died. Exact time and reason for these mortalities are not indicated.

Haematology:

Leukocytes were significantly increased, serum creatinine levels decreased at the end of the 90 day administration period. In the 28 days group the serum creatinine level was elevated at the end of the application period. The changes in the 90-day study were shown to be reversible in the post-exposure recovery period.

Clinical chemistry:

ASAT and LDH (I and III, respectively) isoenzyme levels were increased in both treatment groups (28 and 90 days). ALAT levels were increased only in the 90 days group. Both ASAT and ALAT levels were demonstrated to have returned to pre-treatment values during the post-observation period.

Applicant's summary and conclusion

Conclusions:
A multitude of unspecific symptoms were observed in Guinea pigs when dermally treated with PAA solutions of 0.12 % (0.16 mL/100 g bw twice per day) for 28 days. All animals including controls showed signs of a moderate to very marked degree, which might have influenced the result. Due to bacterial infection and no clear separation of control animals from treated groups, the results of this study are considered to be of limited value only.
Executive summary:

Groups of Guinea pigs were dermally exposed to 0.16 mL/100g bw twice daily to 0.12 % PAA in water for 28 days (4 mg peracetic acid/kg bw/day applied 5 days/week). Animals showed erythema, alopecia, reduced body mass, increased heart rate, increased liver, spleen and kidney weights, increases in leukocytes, ASAT, ALAT, LDH I and LDH III. All animals including controls showed signs of pneumonia. The latter might be the reason for the observed effects, although the findings were more pronounced in treated animals. In view of the infection of animals and the observable inflammatory processes, changes in blood biochemistry are regarded to be a secondary mechanism to primary infections and inflammation, respectively. This is substantiated by the reversibility of these changes during the post-observation period.

Due to bacterial infection and no clear separation of control animals from treated groups, the results of this study are considered to be of limited value only.