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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study to GLP
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Octylphosphonic acid
EC Number:
225-218-5
EC Name:
Octylphosphonic acid
Cas Number:
4724-48-5
Molecular formula:
C8H19O3P
IUPAC Name:
octylphosphonic acid
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): (4724-48-5) Octylphosphonic acid

Test animals

Species:
rat
Strain:
other: Wistar: Hoe: WISKf (SPF 71)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: HOECHSTAG, Kastengrund; SPF-Zucht
- Age at study initiation: six weeks old
- Fasting period before study: yes
- Housing: groups of five animals/cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 50 +/- 20%
- Air changes (per hr): 12 times per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: the test material was prepared at the appropriate concentrations as a solution in sesame oil. A stability test was performed on the substance using this preparation method, and it was verified to be stable.

DIET PREPARATION
- Rate of preparation of diet (frequency): one per week
- Storage temperature of food: room temperature



Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
the OPA concentration in the test material formulations was determined.
Duration of treatment / exposure:
28 days
Frequency of treatment:
once per day, 7 days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 12, 60 and 300 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: the dose levels were chosen based on the results of a range-finding study (14 days)
- Rationale for selecting satellite groups: no satellite groups were tested in this study
Positive control:
Not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality and clinical signs

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: twice per week

FOOD CONSUMPTION:
- Time schedule: twice weekly

FOOD EFFICIENCY: No

WATER CONSUMPTION : Yes
- Time schedule for examinations: once per week

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at ternmination
- Parameters examined: haemoglobin concentration, reticulocyte count, haematocrit, erythrocyte count, leucocyte count, thrombocyte count, differential blood cell count, Heinz bodies and clotting time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at terminaton
- Parameters examined: Sodium, Potassium, inorganic Phosphorus, Uric acid, Bilirubin, Creatinine, Glucose, Urea Nitrogen, Calcium, Chloride, ASAT, ALAT, AP, GGT, Protein and Albumin

URINALYSIS: Yes
- Time schedule for collection of urine: at termination

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY & HISTOPATHOLOGY: Yes: heart, lung, liver, kidneys, spleen, stomach, jejunum, colon, thymus, testes, adrenals and bone marrow (femur).
Other examinations:
The following organs were weighed: heart, lung, liver, kidneys, spleen, testes and adrenals
Statistics:
Statistical analysis was conducted for the following:
Bodyweight, bodyweight gain, absolute and relative organ weights, haematological and clinical chemistry parameters, pH and specific gravity of urine.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
300 mg/kg bw/d: Mortaility: 1 male, 1 female. Reduced activity, piloerection, hunched posture and unregular respiration. One male showed salivation; gasping/bad condition was noted in one female
Mortality:
mortality observed, treatment-related
Description (incidence):
300 mg/kg bw/d: Mortaility: 1 male, 1 female. Reduced activity, piloerection, hunched posture and unregular respiration. One male showed salivation; gasping/bad condition was noted in one female
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight of the rats of the 300 mg/kg bw/d dose group was significantly reduced.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption of rats in the 300 mg/kg bw/d dose group was decreased.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Waterconsumption of rats in the 300 mg/kg bw/d dose group was increased
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Increase in granulocyte and leukocyte count and decrease of reticulocyte count at 300 mg/kg bw/day.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Creatinine and Urea Nitrogen were increased at 300 mg/kg/day. Inorganic Phosphorus level was significantly increased.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Specific gravity was reduced in the high dose group and the urine appeared milky to bright. The urine of two males and three females contained haemoglobin.
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative kidney weights as well as the relative lung, adrenal and testes weights were increased in the high dose group.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
High dose: kidneys enlarged and yellow/brown colored, surface of stomach crenated and brightened, adrenals and bone marrow was brightened, thymus reduced. Mid dose: one male and one female brightened enlarged kidneys.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
High dose: massive damage of the kidneys, depression of bone marrow, erosion of the stomach epithelium, and thymus atrophy. Increase in haemosiderosis in spleen in females. Mid dose: similar but to a lesser degree.
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
Two animals of the high dose group (one male, one female) died on application day 28. All other animals survived. Clinical signs were noted at 300 mg/kg bw/d: reduced activity, piloerection, hunched posture and unregular respiration. One male showed salivation; gasping/bad condition was noted in one female. No deaths or clinical signs occurred in the rats of the remaining dose groups.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain of the rats at 12 and 60 mg/kg bw/d exposure was unaffected. The body weight of the rats of the 300 mg/kg bw/d dose group was significantly affected.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no effects upon the mean daily food and water consumption observed in the 12 and 60 mg/kg bw/d dose groups. Food consumption of rats in the 300 mg/kg bw/d dose group was decreased, the water consumption was increased.

HAEMATOLOGY/CLINICAL CHEMISTRY
There was an increase in granulocyte and leukocyte count and furthermore a decrease of the reticulocyte count noted at 300 mg/kg bw/d. Creatinine and Urea Nitrogen were also increased in this dose group. Furthermore, the inorganic Phosphorus level was significantly increased.

URINALYSIS
Specific gravity was reduced in the high dose group and the urine appeared milky to bright. The urine of two males and three females contained Haemoglobin.

ORGAN WEIGHTS
Absolute and relative kidney weights as well as the relative lung, adrenal and testes weights were increased in the high dose group.

GROSS PATHOLOGY
Kidneys of animals of the high dose group were enlarged and yellow/brown colored. The surface of stomachs was crenated and brightened at 300 mg/kg bw/d. Adrenals and bone marrow was also brightened. The thymus was reduced.
In one male and one female of the mid dose group brightened enlarged kidneys were noted.

HISTOPATHOLOGY: NON-NEOPLASTIC
The histopathological examination of animals of the high dose group showed a massive damage of the kidneys, depression of bone marrow, erosion of the stomach epithelium, and thymus atrophy. In females an increase in haemosiderosis in the spleens was noted. These findings were also made in animals of the mid dose group but to a less degree.


Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
12 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: gross pathology; histopathology
Dose descriptor:
LOAEL
Effect level:
60 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the observed severe damage of kidneys, increase of serum urea nitrogen and creatinine, depression of bone marrow and erosion of stomach epithelium observed in rats at 300 and 60 mg/kg bw.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
Based on the observed severe damage of kidneys, increase of serum Urea Nitrogen and Creatinine, depression of bone marrow and erosion of stomach epithelium observed in rats at 300 mg/kg bw/d and the similar less severe symptoms in the mid dose group, the NOAEL is considered to be 12 mg/kg bw/day and the LOAEL is considered to be 60 mg/kg bw/day
Executive summary:

The test substance octylphosphonic acid was administered in sesame oil to 5 male and 5 female Wistar rats by oral gavage at 0, 12, 60 and 300 mg/kg bw/day for 28 days according to OECD Guideline 407 (1981) and in compliance with GLP. Animals were observed twice daily for mortality and clinical signs. Body weights were recorded before treatment and twice weekly during the study, food consumption was also determined twice weekly, water consumption once a week. Haematological examination, clinical chemistry and urinalysis were performed at study termination. The rats were sacrificed on day 29. Organ weights were recorded and macroscopic and histopathological examinations were performed.

Two animals of the high dose group (one male, one female) died on day 28. All other animals survived. Clinical signs noted at 300 mg/kg bw/day included reduced activity, piloerection, hunched posture and irregular respiration. One male showed salivation, while gasping/bad condition was noted in one female. No deaths or clinical signs occurred in the rats of the remaining dose groups. The bodyweight gain of the rats at 300 mg/kg bw/day only was significantly reduced. There were no effects upon the mean daily food and water consumption in the 12 and 60 mg/kg bw/day dose groups while at 300 mg/kg bw/day food consumption was decreased but water consumption was increased. There was an increase in granulocyte and leukocyte count and a decrease of the reticulocyte count at 300 mg/kg bw/day. Creatinine, urea nitrogen and inorganic phosphorus were increased in this dose group. Urine specific gravity was reduced in the high dose group and the urine appeared milky to bright. The urine of two males and three females contained haemoglobin. Absolute and relative kidney weights as well as the relative lung, adrenal and testes weights were increased in the high dose group. Kidneys of animals of the high dose group were enlarged and yellow/brown coloured; the surface of the stomach was crenated and brightened. Adrenals and bone marrow was also brightened. The thymus was reduced. Brightened and enlarged kidneys were also noted in one male and one female of the mid dose group. The histopathological examination of animals of the high dose group showed a massive damage of the kidneys, depression of bone marrow, erosion of the stomach epithelium, and thymus atrophy. In females an increase in haemosiderosis in the spleens was noted. similar findings were also noted in animals of the mid dose group but to a less degree.

Based on the observed severe damage of kidneys, increase of serum urea nitrogen and creatinine, depression of bone marrow and erosion of stomach epithelium observed in rats at 300 mg/kg bw/day and the similar less severe symptoms in the mid dose group, the NOAEL is considered to be 12 mg/kg bw/day and the LOAEL is considered to be 60 mg/kg bw/day.