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Acute Toxicity: oral

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Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Refer to analogue justification provided in IUCLID section 13.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
BASF-TEST: In principle, the methods described in the OECD Guideline 401 were used. Young adult laboratory rats were purchased from breeder. Several groups of 10 rats per sex and dose were treated simultaneously by gavage with preparations of the test substance in suitable vehicle. The concentrations of these preparations were used to achieve comparable volumes per kg body weight. Group-wise documentation of clinical signs was performed over the 14 day study period. Body weight was determined before the start of the study as well as after day 2, 5, 7 and 13.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Weight at study initiation:
1210 mg/kg bw: 179 g males/178 g females
1780 mg/kg bw: 188 g males/180 g females
2000 mg/kg bw: 180 g males/182 g females
2610 mg/kg bw: 188 g males/187g females
- Housing: 5 animals per cage
- Diet: Ssniff R, ad libitum
- Water: ad libitum
- Acclimation period: at least one week
- Fasting period before study: 16 h

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
DOSAGE PREPARATION
- Stock solutions prepared:
12.1% for the 1210 mg/kg bw dose group
17.8% for the 1780 mg/kg bw dose group
20.0% for the 2000 mg/kg bw dose group
26.1% for the 2610 mg/kg bw dose group

DOSE VOLUME APPLIED:
10 mL/kg bw
Doses:
1210 mg/kg bw; 1780 mg/kg bw; 2000 mg/kg bw; 2610 mg/kg bw
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Frequency of weighing: prior to the start of the experiment and on day 2, 5, 7, 13
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 1 780 - < 2 000 mg/kg bw
Sex:
male
Dose descriptor:
LD50
Effect level:
1 913 mg/kg bw
Sex:
female
Dose descriptor:
LD50
Effect level:
1 780 mg/kg bw
Mortality:
No mortalities were observed in the lowest dose group. At 2000 mg/kg bw all females and 7/10 males died (see table 1). In the highest dose group still half of the males survived.
Clinical signs:
1210 mg/kg bw: no effects
1780 mg/kg bw: males dyspnea, apathy, ataxia, shaggy fur, poor general state; fully reversible within 5 days /females dyspnea, apathy, ataxia, abnormal positions, spastic gait, exiccosis, diarrhea, shaggy fur, saliva, poor general state; fully reversible within 1 day
2000 mg/kg bw: males dyspnea, apathy, ataxia, shaggy fur, poor general state; fully reversible within 1 day/females dyspnea, apathy, ataxia, atony, exiccosis, poor general state
2610 mg/kg bw: males dyspnea, apathy, ataxia, aggressiveness, diarrhea, piloerrection, poor general state; fully revesible within 1 day/females: dyspnea, apathy, ataxia, atony, shaggy fur, poor general state
Body weight:
1210 mg/kg bw: body weight gain male 106 g/ 46 g female
1780 mg/kg bw: body weight gain male 95 g/ 47 g female
2000 mg/kg bw: body weight gain male 93 g/ - (all animals died)
2610 mg/kg bw: body weight gain male 97 g/ - (all animals died)
Gross pathology:
Animals that died:
stomach: redness and/or bloody ulceration of the glandular part of the stomach, redness of the mucous membrane, general hyperemia
gut: atonic, redness of the mucous membrane, bloody mucous content, general hyperemia
Animals which were sacrificed:
nothing abnormal detected

Table 1: Mortalities of rats after oral application of Na4EDTA

1210 mg/kg bw 1780 mg/kg bw 2000 mg/kg bw  2610 mg/kg bw
1 h male  0/10 0/10 3/10 0/10
female 0/10 0/10 1/10 6/10
24 h male  0/10 2/10 7/10 5/10
female 0/10 4/10 10/10 10/10
48 h male  0/10 2/10 7/10 5/10
female 0/10 4/10 10/10 10/10
7 d male  0/10 2/10 7/10 5/10
female 0/10 4/10 10/10 10/10
14 d male  0/10 2/10 7/10 5/10
female 0/10 4/10 10/10 10/10
Interpretation of results:
other: CLP/GHS criteria met; classification required as Acute Tox. 4, H302 according to Regulation (EC) No. 1272/2008
Conclusions:
In this acute oral toxicity study in rats the combined LD50 for male and female rats for the source substance tetrasodium dihydrogen EDTA was determined to be > 1780 < 2000 mg/kg bw. For this substance there exists also a CLP harmonized classification as Acute Tox. 4, H302.
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to OECD 401 guideline study with acceptable restrictions [Body weight was only determined at the beginning of the study (OECD: weekly); Observation period: 7 days (OECD:14 days)]
Principles of method if other than guideline:
BASF-TEST: In principle, the methods described in the OECD Guideline 401 were used. Young adult laboratory rats were purchased from breeder. Usually the source and strain of animals were not documented. Several groups of 5 rats per sex and dose were treated simultaneously by gavage with preparations of the test substance in suitable vehicle. The concentrations of these preparations were used to achieve comparable volumes per kg body weight. Group-wise documentation of clinical signs was performed over the 7 day study period. Body weight was determined before the start of the study only, as it was needed for determination of dose
GLP compliance:
no
Test type:
standard acute method
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Mean body weight at study initiation:
259 g males/ 211 g females
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
DOSAGE PREPARATION:
- Stock solutions prepared: 30 %
- Dose volume applied: 2500 mg/kg bw dose group:
8.33 mL/kg bw
3200 mg/kg bw dose group: 10.66 mL/kg bw
4000 mg/kg bw dose group: 13.33 mL/kg bw
5000 mg/kg bw dose group: 16.66 mL/kg bw
6400 mg/kg bw dose group: 21.4 mL/kg bw
Doses:
2500; 3200; 4000; 5000; 6400 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days;
- The animals were observed for mortality and clinical signs of toxicity;
- Frequency of observations: Several times on the application day, thereafter once each working day;
- Body weights were only recorded at the beginning of the study;
- Necropsy of survivors and animals which died performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 800 mg/kg bw
Mortality:
- One female died in the 2500 mg/kg bw dose group; 9/10 animals died in the 3200 mg/kg bw dose group and all animals of the higher dose groups (see "Any other information on results incl. tables").
Clinical signs:
- 2500, 3200 and 4000 mg/kg bw: directly after application: accelerated respiration, squatting posture, twitching, ataxia, red eyes, some animals showed light secretion, reluctance to move; the next day: squatting posture, contaminated fur, intermittened respiration, reluctance to move; fully reversible within 6 days
- 5000 and 6400 mg/kg bw: directly after application: accelerated respiration, squatting posture, twitching, ataxia, red eyes, some animals showed light secretion, reluctance to move; later: prone position
Body weight:
Body weights were not recorded during and at the end of the observation period
Gross pathology:
Animals which died:
- heart: acute dilatation, venous hyperemia
- liver: congestion
- gut: diarrhea like content
- stomach: dilatation
- kidneys: degeneration
Animals which were sacrificed:
- nothing abnormal detected

Table 1: Mortalities of rats after oral application

2500 mg/kg bw 3200 mg/kg bw 4000 mg/kg bw 5000 mg/kg bw 6400 mg/kg bw
1 h male  0/5 0/5 0/5 0/5 0/5
female 0/5 0/5 0/5 0/5 0/5
24 h male  0/5 3/5 5/5 5/5 5/5
female 1/5 5/5 5/5 5/5 5/5
48 h male  0/5 3/5 5/5 5/5 5/5
female 1/5 5/5 5/5 5/5 5/5
7 d male  0/5 4/5 5/5 5/5 5/5
female 1/5 5/5 5/5 5/5 5/5
Interpretation of results:
other: CLP/GHS criteria not met; no classification required according to Regulation (EC) No. 1272/2008
Conclusions:
In this acute oral toxicity study performed, single doses of 2500, 3200, 4000, 5000 and 6400 mg/kg bw disodium hydrogen EDTA were administered by gavage to male and female rats as 30% solution in carboxymethyl cellulose solution. The dose groups consisted of 5 males and 5 females each and the animals were observed for 7 days. The LD50 was found to be 2800 mg/kg bw.
Reason / purpose for cross-reference:
reference to other study
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Remarks:
only LD50 values stated
Guideline:
other: no information available
Species:
rat
Route of administration:
oral: unspecified
Sex:
not specified
Dose descriptor:
LD50
Effect level:
>= 4 000 - <= 8 000 mg/kg bw
Interpretation of results:
other: CLP/GHS criteria not met; no classification required according to Regulation (EC) No. 1272/2008

Data source

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
Trisodium hydrogen ethylenediaminetetraacetate
EC Number:
205-758-8
EC Name:
Trisodium hydrogen ethylenediaminetetraacetate
Cas Number:
150-38-9
Molecular formula:
C10H16N2O8.3Na
IUPAC Name:
trisodium hydrogen 2,2',2'',2'''-(ethane-1,2-diyldinitrilo)tetraacetate

Results and discussion

Effect levelsopen allclose all
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 1 780 - < 2 000 mg/kg bw
Remarks on result:
other: source: CAS 64-02-8, BASF AG, 1983, rat
Sex:
male
Dose descriptor:
LD50
Effect level:
1 913 mg/kg bw
Remarks on result:
other: source: CAS 64-02-8, BASF AG, 1983, rat
Sex:
female
Dose descriptor:
LD50
Effect level:
1 780 mg/kg bw
Remarks on result:
other: source: CAS 64-02-8, BASF AG, 1983, rat

Any other information on results incl. tables

In an acute oral toxicity study performed with the read-across substance disodium hydrogen EDTA (CAS 139 -33 -3) by BASF (1973), single doses of 2500, 3200, 4000, 5000 and 6400 mg/kg bw Na2EDTA were administered by gavage to male and female rats as 30% solution in carboxymethyl cellulose solution. The dose groups consisted of 5 males and 5 females each and the animals were observed for 7 days. The LD50 was found to be 2800 mg/kg bw. Clinical symptoms were accelerated respiration, squatting posture, contaminated fur, intermittened respiration, reluctance to move. Autopsy of animals which died revealed dilatation of the heart and stomach as well as diarrhoea like content in the gut, congestion of the liver and degeneration of the kidney. The animals which were sacrificed showed no abnormalities during necropsy. For reasons of a conservative (worst case) assessment approach data these data were not used for risk assessment and classification.

An LD50 in rats of >= 4000 - <= 8000 mg/kg bw was determined for the target substance trisodium EDTA (cited in CIR, 2002). However, as no further details on the study design were available, this information was not considered for classification/non-classification.

Applicant's summary and conclusion

Interpretation of results:
other: CLP/GHS criteria met; classification required as Acute Tox. 4, H302 according to Regulation (EC) No. 1272/2008
Conclusions:
An acute oral toxicity study in rats with the source substance tetrasodium EDTA (CAS 64-02-8) was selected as key result for reasons of structural similarity, data reliability and for reasons of a conservative (worst case) risk assessment approach.
The read across approach is justified in the analogue justification. The target and source substances are considered unlikely to differ in their acute oral toxicity potential. The combined LD50 for male and female rats for the source substance tetrasodium EDTA was determined to be > 1780 < 2000 mg/kg bw. For this substance (CAS 64-02-8) there exists also a CLP harmonized classification as Acute Tox. 4, H302. Therefore, an acute toxicity potential is also expected for the target substance trisodium hydrogen EDTA (CAS 150-38-9).

CLP: Acute Tox. 4, H302