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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1982
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report date:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
No Guideline stated in report. However, the methods used widely correspond to OECD 408 (1998) and OPPTS 870.3100 (EPA, 90-Day oral toxicity, rodents)
Deviations:
not applicable
Principles of method if other than guideline:
The methods used widely correspond to OECD 408 (1998) and OPPTS 870.3100 (EPA, 90-Day oral toxicity, rodents).
Deviations from current legislation were the following:
-Animals were dosed on 5 days per week (which is acceptable, but should have been justified in the study report).
-No assessments of motor activity, grip strength and sensory reactivity were conducted (no Guideline requirement in 1982)
-Not all remaining animals were terminally assessed, but 10 male and 10 females per group is sufficient to meet the Guideline requirements.
In haematology, no blood clotting parameters or platelet/reticulocyte counts were performed.
No adrenal, thymus and uterus weights were taken at necropsy.
Brain and spinal cord were not examined histopathologically at three section levels, but only at one level.

These minor deviations are not considered to have an impact on the validity or the scientific outcome of the study. There is no indication that the missing parameters play a role on the substance target organ toxicity.
GLP compliance:
no
Remarks:
At the time the study was performed, GLP was not compulsory.
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dihydrogen bis[monoperoxyphthalato(2-)-O1,OO1]magnesate(2-)
EC Number:
279-013-0
EC Name:
Dihydrogen bis[monoperoxyphthalato(2-)-O1,OO1]magnesate(2-)
Cas Number:
78948-87-5
Molecular formula:
C16H8MgO10.2H
IUPAC Name:
dihydrogen bis[monoperoxyphthalato(2-)-O1,OO1]magnesate(2-)
Details on test material:
Test material: Magnesium-monoperoxyphthalate-hexahydrate, H48 Bleach
- Source and lot/batch No.of test material: 0525
- Further relevant properties: White powder with a faint pungent odour

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Labs, (Wilmington, MA)
- Age at study initiation: 6 weeks
- Weight at study initiation: males 153-156 grams, females 125 -127 grams
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Duration of treatment / exposure:
28 days (interim sacrifice), 91 days (terminal sacrifice), no postexposure period
Frequency of treatment:
5 days per week (65 doses)
Doses / concentrationsopen allclose all
Dose / conc.:
12 mg/kg bw/day (nominal)
Dose / conc.:
124 mg/kg bw/day (nominal)
Dose / conc.:
620 mg/kg bw/day (nominal)
Remarks:
620-1244: The high dose received 620 mg/kg for days 1-19, 1244 mg/kg for days 20-43 and 910 mg/kg for days 44-91
No. of animals per sex per dose:
20 male and 20 female animals per group. 1 control, 3 dose groups
6 male and 6 female animals were randomly selected for interim sacrifice after 4 weeks (Day 29)
10 male and 10m female animals were selected for terminal sacrifice on day 92 to 93
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
Clinical signs: Yes (twice each day on 7 days per week)
Mortality: Yes (twice each day on 7 days per week)
Body weight: Yes (once weekly)
Food consumption: Yes (once weekly)
Water consumption: No
Ophthalmoscopic examination: Yes (prior to necropsy in each animal)

Haematology: Yes, number of animals: 6 males and 6 females prior to interim sacrifice, 10 males and 10 females per group at the end of the study
Parameters: haemoglobin, hematocrit, red blood count, white blood cell count, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, mean corpuscular volume and differential white blood cell count.

Clinical Chemistry: Yes, number of animals: 6 males and 6 females prior to interim sacrifice; 10 males and 10 females per group at the end of the study.
Parameters: magnesium, calcium, phosphorus, chloride, sodium, potassium, fasting glucose, SGPT (=ALT), SGOT (=AST), BUN, creatinine, albumin, total bilirubin, total serum protein
Urinalysis: Yes, number of animals: 6 males and 6 females prior to interim sacrifice; 10 males and 10 females per group at the end of the study.
Parameters: appearance, pH, specific gravity, glucose, protein, ketones, bilirubin, blood, deposits (by microscopy)
Faecal analyses: Once per week in 5 males and 5 females per group. Faecal pellets were analysed for occurrence of occult blood
Sacrifice and pathology:
Organ Weights: Yes, number of animals: 6 males and 6 females per group at interim sacrifice; 10 males and 10 females per group at terminal sacrifice.
Organs: liver, kidney, heart, brain, ovaries or testes
Gross and histopathology: Yes, number of animals: 6 males and 6 females per group at interim sacrifice; 10 males and 10 females per group at terminal sacrifice.
High dose group and controls: lung, heart, aorta, tongue, trachea, oesophagus, thyroid, parathyroid, lymph nodes, stomach, liver, duodenum, jejunum, ileum, caecum, colon, urinary bladder, kidney, reproductive organs, adrenal, muscle, spleen, pancreas, bone with marrow, brain, spinal cord, sciatic nerve, salivary gland, pituitary gland, eyes, thymus, any lesions
Low and mid dose: liver, kidney, heart, lungs, stomach, duodenum, jejunum, ileum, caecum, colon
Other examinations:
n.a.
Statistics:
Yes, at a p ≤ 0.05 level

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Low dose
12 mg/kg bw.: no overt signs of toxicity
Mid dose
124 mg/kg bw: chromodacryorrhea in one male and one female animal on individual days
High dose
620 mg/kg bw.: chromodacryorrhea in one male on day 19
1244 mg/kg bw.:chromodacryorrhea in four males on individual days; excess salivation in all animals; laboured breathing, diarrhea and decreased motor activity in a number of animals, but not in all
910 mg/kg bw.: salivation was most frequent in males and females; some incidences of chromodacryorrhea, diarrhea and rough coat in males
Mortality:
mortality observed, treatment-related
Description (incidence):
Low dose
12 mg/kg bw.: 1 male ( day 52) and one female (day 30). Died due to natural death/false intratracheal administration; (both pre-terminal deaths unrelated to test item)
Mid dose
124 mg/kg bw: no pre-terminal deaths
High dose
620 mg/kg bw.: 1 male (day 7)
1244 mg/kg bw.:2 males (days 34, 42) and 1 female (day 28)
910 mg/kg bw.: 2 females (days 45, 52)
(In total, 6 of the high dosed animals died preterminally. It was assumed that 4 of the 6 deaths were attributable to the high dose level. There were no signs of toxicity preceding deaths)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
No effects in female rats. In high-dosed males, bodyweights were significantly reduced during the second half of the study during most weeks.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption in females was significantly decreased from the third study week onwards, when the dose was increased from 620 to 1244 mg/kg bw.
After week 6, when the dose was decreased to 910 mg/kg bw., food consumption returned to normal.
In males a similar pattern was observed, however, food consumption did not return to normal after dose decrease.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Liver weights were significantly increased in mid and high dosed females after 28 days and in the female high dose group at termination.
Relative kidney weights increased significantly in males and females at termination. (The increase in absolute weights only after 4 weeks in mid and high dosed animals was not dose-related and therefore not considered treatment-related).
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
124 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Due to the minor and reversible effects in the females at 124 mg/kg bw, this dose level can be considered as non adverse. Thus the overall NOAEL would be 124 mg/kg bw.

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a study performed under GLP and widely complies to current Guidelines such as OECD 408 and US EPA (OPPTS 870.3100, 90-day oral toxicity in rodents) Wistar derived rats (20 males and 20 females per group) were administered the test substance over 91 days. The animals were dosed 5 days per week by oral gavage at 3 dose levels. Due to minor and reversible effects in the females at 124 mg/kg bw, this dose level can be considered as non adverse. Thus the overall NOAEL was set with 124 mg/kg bw.

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