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Description of key information

LD50 oral (rat): > 5000 mg/kg bw. Therefore ITC 288/S is considered as not Harmful by oral route.
LD50 dermal (rat): > 2000 mg/kg bw. Therefore ITC 288/S is considered as not Harmful by dermal route.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 14 september 1992 to 7 october 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
Purity of the test material is based on the phosphonate composition, with no direct measure of % sodium. ITC 288 is not the "Reaction mass of tetrasodium-phosphonoethane-1,2-dicarboxylate and hexasodium-phosphonobutane-1,2,3,4--tetracarboxylate" (EC 410-800-5) rather the substance "Reaction mass of trisodium-phosphonoethane-1,2-dicarboxylate and pentasodium-phosphonobutane-1,2,3,4--tetracarboxylate" (EC 701-079-0) as demonstrated by the manufacturing specs reported in Section 1.2, legal entity composition.
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Manston, Kent, U.K.
- Age at study initiation: five to eight weeks old
- Weight at study initiation: males weighed 130-161 g, females weighed 125-146 g
- Fasting period before study: an overnight fasting immediately before dosing and for approximately two hours after dosing
- Housing: 5 by sex in solid-floor polypropylene cages with sawdust bedding
- Diet : ad libitum, rat and mouse expended diet No. 1, special Diet services Limited, Witham, essex, U.K.)
- Water : ad libitum
- Acclimation period: at least five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-20
- Humidity (%): 46-67
- Air changes (per hr): 15
- Photoperiod : 12 hrs dark / 12 hrs light


IN-LIFE DATES: From: 14 september 1992 To: 7 October 1992
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 500 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data







Doses:
5000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for death or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days. Individual bodyweights were recorded prior to dosing on Day 0 and on days 7 and 14.
- Necropsy of survivors performed: yes
Statistics:
No statistics were performed.
Preliminary study:
1 animal/sex was tested at 5000 mg/kg bw. The female was found dead one day after dosing. Signs of systemic toxicity noted in the female were hunched posture, lethargy, decreased respiratory rate, ptosis and ataxia. Based on this information, a dose level of 5000 mg/kg bw was selected for the main study.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
other: No signs of systemic toxicity were noted during the study.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
No data

 Table 7.2.1/2: Number of animals dead

 

Dose
(mg/kg bw)

Mortality (# dead/total)

Time range of deaths (hours)

Number with evident toxicity(#/total)

Male

Female

Combined

Male

Female

Combined

5000

 0

 0

 0

 -

 0

 0

 0

 

Interpretation of results:
not classified
Remarks:
according to the CLP Regulation (EC n.1272/2008)
Conclusions:
Under the conditions of this test, the acute oral median lethal dose (LD50) of ITC 288/S was found to be greater than 5000 mg/kg body weight in the Sprague-dawley strain rat. Therefore no classification is required according to the EU legislation (CLP regulation (1272/2008) and Directive 67/548/EEC).
Executive summary:

In an acute oral toxicity study (Tuffnell PP, 1992) a group of ten fasted animals (five males and five females) was given a single oral dose of the test material, as a solution in distilled water at dose level of 5000 mg/kg bodyweight. The animals were observed for 14 days after the day of dosing and were then killed for gross pathological examination. There were no deaths. No signs of systemic toxicity were noted during the study. Moreover, all animals showed expected gain in bodyweight during the study. No abnormalities were noted at necropsy. Under the conditions of this test, the LD50 combined of ITC 288/S was found to be greater than 5000 mg/kg body weight. Based on the present results in males and females, ITC 288/S is not classified according to the EU legislation (CLP regulation (1272/2008) and Directive 67/548/EEC).

This acute oral study is classified as acceptable. It satisfies the guideline requirement for an acute oral study in the rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Study conducted according to internationally accepted testing guidelines and performed according to GLP.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not stated.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Principles of method if other than guideline:
Not applicable.
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
Purity of the test material is based on the phosphonate composition, with no direct measure of % sodium. ITC 288 is not the "Reaction mass of tetrasodium-phosphonoethane-1,2-dicarboxylate and hexasodium-phosphonobutane-1,2,3,4--tetracarboxylate" (EC 410-800-5) rather the substance "Reaction mass of trisodium-phosphonoethane-1,2-dicarboxylate and pentasodium-phosphonobutane-1,2,3,4--tetracarboxylate" (EC 701-079-0) as demonstrated by the manufacturing specs reported in Section 1.2, legal entity composition.
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Manston, Kent, U.K.
- Age at study initiation: 10-14 weeks old
- Weight at study initiation: 234-243 g (males) 207-229 g (females)
- Fasting period before study:
- Housing: individually
- Diet : ad libitum
- Water : ad libitum
- Acclimation period: at least five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 60-75
- Air changes (per hr): 15
- Photoperiod : 12 hrs dark / 12 hrs light


IN-LIFE DATES: From: 23 September 1992 To: 7 October 1992
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: no data
- % coverage: 10
- Type of wrap if used: A piece of surgical gauze measuring 7 cm x 4 cm was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage (Hypertie). The bandage was further secured with a piece of BLENDERM wrapped around each end.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): The treated skin and surrounding hair were wiped with cotton wool moistened with distilled water to remove any residual test material.
- Time after start of exposure: 24 hr


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- For solids, paste formed: yes


Duration of exposure:
24 hr
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: none
Statistics:
No statistics were performed.
Preliminary study:
No preliminary study was performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
other: No signs of systemic toxicity were noted during the study.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
No data

Table 7.2.3/2: Number of animals dead

 

Dose
(mg/kg bw)

Mortality (# dead/total)

Time range of deaths (hours)

Number with evident toxicity(#/total)

Male

Female

Combined

Male

Female

Combined

2000

 0

 0

 0

 -

 0

 0

 0

 

Interpretation of results:
not classified
Remarks:
according to the CLP Regulation (EC n.1272/2008)
Conclusions:
Under the conditions of this test, the acute dermal median lethal dose of ITC 288 in the rat was found to be greater than 2000 mg/kg bodyweight. The test substance is not classified according to the EU legislation (CLP regulation (1272/2008) and Directive 67/548/EEC).
Executive summary:

In an acute dermal toxicity study (Tuffnell, 1992), male and female Sprague-Dawley rats were dermally treated for 24 hours with ITC 288, up to at least 10 % of the body surface was in contact with the test material, at a dose level of 2000 mg/kg bw. Animals were observed for 14 days after the day of treatment and were then killed for gross pathological examination. There were no deaths. No signs of systemic toxicity or skin irritation were noted during the study. Moreover, body weight gains were acceptable during the study period. Under the conditions of this test, the LD50 of ITC 288 in rats is greater than 2000 mg/kg bw. Based on these results, no classification is required according to the EU legislation ( CLP regulation (1272/2008) and Directive 67/548/EEC).

This acute dermal study is classified as acceptable. It satisfies the guideline requirement for an acute dermal study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Study conducted according to internationally accepted testing guidelines and performed according to GLP.

Additional information

1- Acute oral toxicity:

Two studies were available with reliability 1 and 2 according to Klimisch rating (Kr).

- A study report (Tuffnell, 1992) has been chosen as key study for this endpoint (Kr: 1). This study was conducted according to OECD guideline 401 and in compliance with GLP. Groups of Sprague-Dawley rats (5/sex/group) were administered by gavage a single dose of ITC 288/S as a solution in distilled water at dose level of 5000 mg/kg bw and observed for 14 days. There were no deaths. No signs of systemic toxicity were noted during the study. Moreover, all animals showed expected gain in body weight during the study. No abnormalities were noted at necropsy. The oral LD50 combined of ITC 288/S was found to be greater than 5000 mg/kg bw.

- A study report (Cuthbert and Jackson, 1991) has been chosen as supporting study (Kr: 2). Groups of Sprague-Dawley rats (five males and five females) were given a single oral dose of ITC 288/S, as a solution in distilled water at dose level of 2000 mg/kg body weight and observed for 14 days. As in the key study, there were no deaths, no clinical signs and no abnormalities at necropsy.The LD50 (males and females) of ITC 288/S was found to be greater than 2000 mg/kg bw.

Taken together these results show that ITC 288/S is not harmful via oral route.

2- Acute dermal toxicity:

Two studies were available with reliability 1 and 2 according to Klimisch rating (Kr).

- A study report (Tuffnell, 1992) has been chosen as key study for this endpoint (Kr: 1). This study was conducted according to OECD guideline 402 and in compliance with GLP. Groups of Sprague-Dawley rats (5/sex/group) were dermally exposed to ITC 288/S undiluted at dose level of 2000 mg/kg bw and observed for 14 days. There were no deaths. No signs of toxicity or skin irritation were noted during the study. Moreover, all animals showed expected gain in body weight. No abnormalities were noted at necropsy. The dermal LD50 combined of ITC 288/S was found to be greater than 2000 mg/kg bw.

- A study report (Cuthbert and Jackson, 1991) has been chosen as supporting study (Kr: 2). Groups of Sprague-Dawley rats (five males and five females) were dermally treated for 24 hours with ITC 288/S undiluted at dose level of 2000 mg/kg body weight and observed for 14 days. As in the key study, there were no deaths, no clinical signs related to treatment and no abnormalities at necropsy. The LD50 (males and females) of ITC 288/S was found to be greater than 2000 mg/kg bw.

Taken together these results show that ITC 288/S is not harmful via dermal route.

3- Acute inhalation toxicity:

No data available for this route of administration.

Justification for classification or non-classification

1- Acute oral toxicity:

Not classified according to the EU legislation (Directive 67/548/EEC and the CLP regulation (1272/2008)) as the oral LD50 combined of ITC 288/S was found to be greater than 5000 mg/kg bw.

2- Acute dermal toxicity:

Not classified according to the EU legislation (Directive 67/548/EEC and the CLP regulation (1272/2008)) as the dermal LD50 combined of ITC 288/S was found to be greater than 2000 mg/kg bw.

3- Acute inhalation toxicity:

No classification is possible due to lack of data.