Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 2008-01-02 till 2008-02-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline-conform study under GLP without deviations.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report date:
2008

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
96/54/EG, B.7; OECD 407 (1995)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
483-300-8
EC Name:
-
Cas Number:
99580-93-5
Molecular formula:
Hill formula: C3H13N2O3P CAS formula: C2H8N2.CH5O3P
IUPAC Name:
1,2-Ethanediamine methylphosphonate
Test material form:
solid: bulk
Details on test material:
Batch number: FEB 278-810

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
rat, Wistar Hsd:RccHan (SPF)
Age at start of study 7-8 weeks

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Method of administration:
Gavage of a suspension, using a stomach tube
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Mean Recovery Rate of the Test Item Concentration in the Test Samples:
50 mg/5 mL: 104 % of nominal (n = 4; SD = 5 %)
150 mg/5 mL: 105 % of nominal (n = 4; SD = 3 %)
1000 mg/5 mL: 105 % of nominal (n = 4; SD = 7 %)
Duration of treatment / exposure:
Test duration: 28 days
In total 28 applications per animal were administered.
Frequency of treatment:
Once daily,
Dosing regime: 7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 150, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5 male / 5 female
Control animals:
yes, concurrent vehicle
Details on study design:
The highest dose level was chosen with the aim of inducing toxic effects but not death or severe suffering. Thereafter, a descending sequence of dose levels was selected with a view to demonstrate any dosage related response and no-observed-adverse effects at the lowest dose level (NOAEL).
Positive control:
not applicable

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
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 observations:
No mortality occurred during the study period.

There were no test substance-related clinical signs in any
dose group. In males (statistically significant) and females
diminished body weight development was noted at 1000 mg/kg
bw/d when compared to controls. Decrease (statistically
significant) in food consumption in males and females at
1000 mg/kg bw/d corresponded to reduced body weight gain in
animals treated at this dose level.

No test substance-related effects were detected during
functional and behavioral assessments, responses to reflex
testing, and sensory reactivity assessments.

Laboratory findings:
No test substance-related differences of toxicological
significance were noted in haematology, clinical
biochemistry and urinalysis parameters when compared with
the control values.

Effects in organs:
The assessment of organ weight revealed statistically
significant increases in absolute kidney weights in females
and in relative kidney weights in males treated at 1000
mg/kg bw/d. In females statistically significant increases
in absolute liver weight were determined at 150 mg/kg bw/d
and in relative liver weight at 1000 mg/kg bw/d. For the
adrenal weight slightly decreased (statistically
significant) absolute weight was found for females at 1000
mg/kg bw/d. Slightly decreased absolute epididymides weight
was found for the 1000 mg/kg bw/d males. Concerning the
brain weight statistically significant increased absolute
weight was seen in females at 50 mg/kg bw/d, as well as
slightly lower relative weight in females at 150 mg/kg bw/d,
and statistically significant increased relative weight in
males at 1000 mg/kg bw/d. Since the changes in organ weight
of the liver, brain and epididymides did not be correlate to
histopathologic lesions, the significant differences in
organ weight were considered to be of no toxicological
relevance.

No relevant changes occurred upon necropsy.

Histopathology revealed test substance-related findings in
the kidneys and adrenal glands. In the kidney, a
dose-related tubulopathy in medulla and cortex was noted in
males and females at 150 and 1000 mg/kg bw/d, being more
prominent in males. The lesion was characterized by
basophilic/regenerating tubules in the outer medulla,
medullary rays and distal cortical tubules, scattered
dilated tubules, as well as rare hyaline casts and
tubuloepithelial degeneration. In the adrenal gland, 3/5
males treated at 1000 mg/kg bw/d showed a minimal or mild
diffuse vacuolation of the zona glomerulosa.

Effect levels

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
dissolved
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Discussion:

Statistically significant differences were found between some dose groups and the corresponding Control groups both in male and female animals. As none of the mean and individual values per se showed marked pathological deviations, significant differences in general represent variation within a normal range and were of no toxicological relevance. Some deviations are discussed below:

All mean and individual AST and ALT values were within the biological range. For the AST values significant difference was found for the male LD and HD group. As all individual values were within the biological range, the calculated significance is not considered to be of toxicological relevance.

Concerning the assessment of AP values, individual values were borderline low in the female LD and MD groups. As those values were borderline, no toxicological relevance was concluded. For the male animals all individual AP values were within the biological range. No significant differences were found. Determination of CHOL values revealed statistical significance for the female LD group, which showed slightly higher values compared to the corresponding Control group. As all values were within the biological range, this finding is of no toxicological relevance.

Most GLU values were at the upper limit, or slightly above the biological range. This occurred in dose- as well as in Control-groups and is therefore considered to be not compound-related. No dose-dependency could be observed. Assessment of ALB values revealed statistical significance for the female MD and HD groups. No toxicological significance of this finding was concluded, as all individual and mean values are within the biological range. No single deviation was observed for the assessment of Na values. Regarding the K values all individual values are within the biological range with the exception of one borderline low value in the female Control group. The calculated significance for the male HD is considered to be of no toxicological relevance. In the determination of the Urine-values a slight proteinuria was detected in the male dose groups, being the most evident in the male HD group. This finding is most probably related to the tubulopathy found in the histopathological evaluation. For the female animals no relevant differences between test- and control groups were found.

Applicant's summary and conclusion

Conclusions:
Considering the reported data of this toxicity study it can be stated, that the Low Dose of 50 mg/kg BW is the no observed adverse effect dose level
(NOAEL) of the test substance after a total of 28 applications by gavage in aqua ad inject. over a period of 28 days. All rats treated orally with the substance survived throughout the test period without showing severe clinical-toxic effects. The histopathological findings in kidney are not considered "significant and/or severe toxicity".