Registration Dossier

Administrative data

Description of key information

Acute toxicity oral:

LD50 < 2000 mg/kg bw (WoE, eq. OECD 401 in rats, non-GLP, rel.2 & study in mice, non-OECD, non GLP, rel.4)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
28 September 1966
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
pre-OECD guideline 401 (1987)
Deviations:
yes
Remarks:
(no details on test substance, age at study initiation and some environmental conditions of animal room not reported, observation during 10 days instead of 14 days)
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Charles river
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Females (if applicable) nulliparous and non-pregnant: not reported
- Age at study initiation: not reported
- Weight at study initiation: Average 106 g
- Fasting period before study: not reported.
- Housing: not reported
- Diet: not reported
- Water: not reported
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS: not reported

IN-LIFE DATES: not reported
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE: Propylene glycol
MAXIMUM DOSE VOLUME APPLIED: not specified All the animals received the same volume of liquid per kilogram body weight. This volume corresponds to the highest dose of the solution at 0.125 g/ml of substance. For lower doses, the volume was obtained with the addition of the vehicle.
Doses:
660, 1060, 1680, 2670 mg/kg bw
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 10 days
- Frequency of observations and weighing: observed for 10 days and then weighted
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
1 660 mg/kg bw
Based on:
test mat.
Mortality:
All the animals (10/10) died at 2670 mg/kg bw in less than 24 hours post exposure 5/10 animals died at 1680 mg/kg bw in less than 24h post exposure. No other animal died.
Clinical signs:
- Signs of serious damage during the first hour post exposure at 2670 mg/kg bw
- For two days the surviving animals exposed to 1680 mg/kg bw (5/10) were apathetic, curled up and ruffled.
- Animals exposed to 1060 mg/kg bw were curled up, ruffled and are apathetic the first two days.
Body weight:
- For two days the surviving animals exposed to 1680 mg/kg bw (5/10) have a relative anorexia and then recover. However, body weight increase is only of 20% during observation period of 10 days instead of 90% for control animals.
- Animals exposed to 1060 mg/kg bw had body weight increase of 47%. Even the animals receiving the lowest dose have a body weight increase lower than controls.
Gross pathology:
The liver is pale and sometimes has whitish border; the kidneys are pale; the spleen is almost always small and pink. The stomach of animals which died in less than 24 hours contained the test product. The bladder contains, in some cases, urine with clearly the odour of the test product.
Other findings:
None

Table 7.2.1/1 Observations of dead animals

Doses

(mg/kg bw)

Number of dead animals observed after gavage (day 1 to 10)

 

1

2

3

4

5

6

7

8

9

10

Total

660

0

0

0

0

0

0

0

0

0

0

0/10

1060

0

0

0

0

0

0

0

0

0

0

0/10

1680

5

0

0

0

0

0

0

0

0

0

5/10

2670

10

0

0

0

0

0

0

0

0

0

10/10

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the test conditions, the test material is classified as category 4 according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS since rat Oral LD50 is lower than 2000 mg/kg bw
Executive summary:

In an acute oral toxicity study, 4 groups of female rats (10/group) were administered single oral doses of test material at 660, 1060, 1680 and 2670 mg/kg bw by gavage. Animals were then observed for mortality, clinical signs and bodyweights for 10 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

Less than 24 hours post exposure, all the animals (10/10) died at 2670 mg/kg bw and 5/10 animals died at 1680 mg/kg bw. No other animal died during the observation period of 10 days.

Before the death of the animals, signs of serious damage during the first hour post exposure at 2670 mg/kg bw. For two days the surviving animals exposed to 1680 mg/kg bw (5/10) were apathetic, curled up and ruffled. They have a relative anorexia and then recovered. However, body weight increase is only of 20% during observation period of 10 days instead of 90% for control animals. Animals exposed to 1060 mg/kg bw were curled up, ruffled and are apathetic the first two days. Their body weight increase is of 47%. Even the animals receiving the lowest dose have a body weight increase lower than controls.

After autopsia, the osbervations are as follows: The liver is pale and sometimes has whitish border; the kidneys are pale; the spleen is almost always small and pink. The stomach of animals which died in less than 24 hours contained the test product. The bladder contains, in some cases, urine with clearly the odour of the test product.

 

Oral LD50 = 1660 mg/kg bw (Confidence limit 95% = 1420 to 1930 mg/kg bw)

 

Under the test conditions, the test material is classified as category 4 according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS since rat Oral LD50 is lower than 2000 mg/kg bw

This study is not considered sufficient in its own to satisfy the requirement for acute oral toxicity endpoint. Therefore a weight of evidence was considered.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
No data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
materials and methods and results not reported; documentation insufficient for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Acute oral toxicity in mice was performed according to Kou's method.
GLP compliance:
no
Test type:
other: not specified
Limit test:
no
Species:
mouse
Strain:
other: Kunming white mice
Sex:
not specified
Details on test animals and environmental conditions:
No data
Route of administration:
oral: unspecified
Vehicle:
not specified
Details on oral exposure:
No data
Doses:
No data
No. of animals per sex per dose:
No data
Control animals:
not specified
Details on study design:
No data
Statistics:
No data
Preliminary study:
No data
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
1 608 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 95% confidence limits: 1253-2064 mg/kg bw
Mortality:
No data
Clinical signs:
No data
Body weight:
No data
Gross pathology:
No data
Other findings:
No data

None

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the test conditions, the oral LD50 for test item is 1608 mg/kg bw (95% confidence limits: 1253-2064 mg/kg bw) in mice therefore it is classified as "Category 4" according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.
Executive summary:

In an acute oral toxicity study, Kunming white mice was given a single oral dose of test item.

 

The oral LD50: 1608 mg/kg bw (95% confidence limits: 1253-2064 mg/kg bw).

 

Under the test conditions, the test material is classified as category 4 according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS since rat Oral LD50 is lower than 2000 mg/kg bw.

This study is not considered sufficient in its own to satisfy the requirement for acute oral toxicity endpoint. Therefore a weight of evidence was considered.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18 October to 04 November 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Non GLP study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
purity of test item not reported
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: CD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Company of Calco, Italy.
- Age at receipt: 40 days
- Weight at reeipt: Males: 100-125 g; Females: 75-100 g
- Fasting period before study: Animals were fasted 16 h before the administration of test item.
- Housing: Animals were housed in stainless steel wire grill cages suspended over automatically flushed racks.
- Diet: Pellet-form feed, ad libitum
- Water: Drinking water, ad libitum
- Acclimation period: One week

ENVIRONMENTAL CONDITIONS
- Temperature: 22-24 °C
- Humidity: 60 ± 20 %
- Air changes: 15 air changes per hour
- Photoperiod: Subdued natural lighting

IN-LIFE DATES: 18 October to 04 November 1983
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 100, 200, 250, 310, 350 and 390 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION
Estimated amounts of the test item were weighed for each dosage and dissolved in a calculated volume of corn oil (Commercial brand: CARAPELLI) so that the concentration of the dosing solution was kept constant for all dosage levels and the amount received by each animal did not exceed 10 mlLkg bw.
Doses:
Preliminary study: 2000, 3000 and 5000 mg/kg bw
Main study: 1000, 2000, 2500, 3100, 3500 and 3900 mg/kg bw
No. of animals per sex per dose:
Preliminary study: 1 animal/sex/dose
Main study: 5 animals/sex/dose
Control animals:
yes
Remarks:
corn oil
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Following administration, the animals were observed for mortality and toxic effects twice during the first day and once daily thereafter for 14 days.
- Frequency of weighing: The body weight of the animals was recorded on the day before the final trial, the day of the final trial and on days 1, 2, 4, and 14 after administration.
- Necropsy of survivors performed: Yes; all animals dying during the observation and those killed on day 14 were subjected to gross pathology to detect possible lesions.
Statistics:
Data was evaluated according to the method of Litchfield and Wilcoxon (1949).
Preliminary study:
Mortality was observed in 1/2, 2/2 and 2/2 animals at 2000, 3000 and 5000 mg/kg bw, respectively.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 320 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 95% confidence limits: 2010 - 2660 mg/kg bw
Mortality:
Death occurred within two days after administration in 0, 3, 5, 8, 10 and 10 animals (the mortality percentage was 0, 30, 50, 80, 100 and 100) at 1000, 2000, 2500, 3100, 3500 and 3900 mg/kg bw, respectively.
Clinical signs:
- All animals displayed listlessness during the initial 24 h after treatment. In those at the higher doses, this lasted up to 48 h.
- Some animals also manifested chromodacryorrhea.
- For the remaining observation period, no untoward signs were noted among the survivors.
Body weight:
Only a slight body weight loss was observed among the animals at higher dosages (2500 and 3100 mg/kg bw).
Gross pathology:
All animals that died during the experiment were found to have gastro-intestinal and pulmonary hemorrhaging and in some cases both were observed.
Other findings:
None

None

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Under the test conditions, the oral LD50 for test item is 2320 mg/kg bw (95% confidence limits: 2010 - 2660 mg/kg bw) in rats therefore the substance should not be classified according to the Regulation (EC) No. 1272/2008 (CLP). Based on the mortality observed, it should be classified in Category 5 according to the GHS criteria.
Executive summary:

In an acute oral toxicity study performed similarly to OECD Guideline 401, CD rats (5/sex/dose) were given a single oral (gavage) dose of test item in corn oil at 0, 1000, 2000, 2500, 3100, 3500 and 3900 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and were all sacrificed for macroscopic examination. The dose levels selected on the basis of results of preliminary study (2000, 3000 and 5000 mg/kg bw; 1/sex/dose).

 

All animals displayed listlessness during the initial 24 h after treatment. In those at the higher doses, this lasted up to 48 h. Some animals also manifested chromodacryorrhea. For the remaining observation period, no untoward signs were noted among the survivors. Death occurred within two days after administration in 0, 3, 5, 8, 10 and 10 animals (the mortality percentage was 0, 30, 50, 80, 100 and 100) at 1000, 2000, 2500, 3100, 3500 and 3900 mg/kg bw, respectively. Only a slight body weight loss was observed among the animals at higher dosages (2500 and 3100 mg/kg bw). All animals that died during the experiment were found to have gastro-intestinal and pulmonary hemorrhaging and in some cases both were observed.

 

The combined LD50: 2320 mg/kg bw (95% confidence limits: 2010 - 2660 mg/kg bw).

 

Under the test conditions, the oral LD50 for test item is 2320 mg/kg bw (95% confidence limits: 2010 - 2660 mg/kg bw) in rats therefore the substance should not be classified according to the Regulation (EC) No. 1272/2008 (CLP). Based on the mortality observed, it should be classified in Category 5 according to the GHS criteria.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 608 mg/kg bw
Quality of whole database:
Weight-of evidence: non-OECD and non GLP-compliant study on rat (Klimisch score = 2) + non-OECD and non-GLP study on mice (Klimisch score = 4)

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Not required for substances at the REACH Annex VII tonnage level.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
No reliable study was available. Not required for substances at the REACH Annex VII tonnage level.

Additional information

Acute toxicity: oral

Three studies were identified on the substance. They were used in a weight-of-evidence approach since they were neither OECD-compliant nor GLP-compliant. The lowest LD50 value was selected as the dose descriptor for this endpoint.

1/ Institut de physiologie, 1966, rel. 2:  this acute oral toxicity study was performed before the adoption of the OECD test guidelines and GLP, but was conducted similarly to OECD test Guideline No. 401. Four groups of female rats (10/group) were administered single oral doses of test material at 660, 1060, 1680 and 2670 mg/kg bw by gavage. Animals were then observed for mortality, clinical signs and bodyweights for 10 days and at the end of the study the surviving animals were sacrificed for macroscopic examination. Less than 24 hours post exposure, all the animals (10/10) died at 2670 mg/kg bw and 5/10 animals died at 1680 mg/kg bw. No other animal died during the observation period of 10 days. Before the death of the animals, signs of serious damage during the first hour post exposure at 2670 mg/kg bw. For two days the surviving animals exposed to 1680 mg/kg bw (5/10) were apathetic, curled up and ruffled. They have a relative anorexia and then recovered. However, body weight increase is only of 20% during observation period of 10 days instead of 90% for control animals. Animals exposed to 1060 mg/kg bw were curled up, ruffled and are apathetic the first two days. Their body weight increase is of 47%. Even the animals receiving the lowest dose have a body weight increase lower than controls.

After autopsia, the osbervations are as follows: The liver is pale and sometimes has whitish border; the kidneys are pale; the spleen is almost always small and pink. The stomach of animals which died in less than 24 hours contained the test product. The bladder contains, in some cases, urine with clearly the odour of the test product.

Oral LD50 = 1660 mg/kg bw (Confidence limit 95% = 1420 to 1930 mg/kg bw)

2/ Hua, 1988, rel.4:  this published study was performed before the adoption of the OECD test guidelines and GLP. No details on the method was available since the study is only reported as a summary. However, the oral LD50 in mice is 1608 mg/kg bw (95% confidence limits: 1253-2064 mg/kg bw), which confirms the value obtained with rats.

3/ RBM, 1983, rel.2:  in this study performed similarly to OECD Guideline 401, CD rats (5/sex/dose) were given a single oral (gavage) dose of test item in corn oil at 0, 1000, 2000, 2500, 3100, 3500 and 3900 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and were all sacrificed for macroscopic examination. The dose levels selected on the basis of results of preliminary study (2000, 3000 and 5000 mg/kg bw; 1/sex/dose).  All animals displayed listlessness during the initial 24 h after treatment. In those at the higher doses, this lasted up to 48 h. Some animals also manifested chromodacryorrhea. For the remaining observation period, no untoward signs were noted among the survivors. Death occurred within two days after administration in 0, 3, 5, 8, 10 and 10 animals (the mortality percentage was 0, 30, 50, 80, 100 and 100) at 1000, 2000, 2500, 3100, 3500 and 3900 mg/kg bw, respectively. Only a slight body weight loss was observed among the animals at higher dosages (2500 and 3100 mg/kg bw). All animals that died during the experiment were found to have gastro-intestinal and pulmonary hemorrhaging and in some cases both were observed.

Combined LD50: 2320 mg/kg bw (95% confidence limits: 2010 - 2660 mg/kg bw).

As a worst case, the lowest LD50 (1608 mg/kg bw in mice) was selected as the dose descriptor for this endpoint.

It has to be highlighted that in two new studies performed in compliance with the OECD test guidelines and GLP, the substance has been found to be corrosive to the skin (OECD TG 431) and to induce serious eye damage to the eyes (OECD TG 438 ICE). The corrosivity potential of the substance could explain some of the effects observed such a serious damage observed within the first hour of exposure (Institut de physiologie, 1966, rel. 2) or gastro-intestinal and pulmonary hemorrhaging observed after autopsia (RBM, 1983), and maybe mortality observed in all the studies at high doses.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self classification:

Acute toxicity via Oral route:

Based on available data, the substance is classified as category 4 according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS since rat and mice Oral LD50 are lower than 2000 mg/kg bw.

Acute toxicity via Dermal route:

No reliable data was available. Not required for substances at the REACH Annex VII tonnage level. Moreover since the substance was corrosive to the skin, no further in vivo study could be performed.

Acute toxicity (Inhalation):

No data was available. Not required for substances at the REACH Annex VII tonnage level. Moreover since the substance was corrosive to the skin, no further in vivo study could be performed.

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral) for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value (oral) for a Category 2 classification (2000 mg/kg bw≥C > 300 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute oral toxicity study.

Specific target organ toxicity: single exposure (Dermal):

No reliable data was available. Not required for substances at the REACH Annex VII tonnage level. Moreover since the substance was corrosive to the skin, no further in vivo study could be performed.

Specific target organ toxicity: single exposure (Inhalation):

No data was available. Not required for substances at the REACH Annex VII tonnage level. Moreover since the substance was corrosive to the skin, no further in vivo study could be performed.