Registration Dossier

Administrative data

Description of key information

Oral, rat: LD50 = 1610 mg/kg bw (males), LD50 = 1360 mg/kg bw (females)

Inhalation (OECD 403), rat: LC50 > 2.871 mg/L air

Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw

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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: The test material was administered to male rats orally to assess acute oral toxicity.
- Short description of test conditions: Ten animals per dose group were orally administered six doses of the test substance in Lutrol as vehicle as a single dose via gavage. Animals were observed for 14 days.
- Parameters analysed / observed: mortality, clinical signs, necropsy, body weights
GLP compliance:
no
Test type:
other: acute oral toxicity
Limit test:
no
Species:
rat
Strain:
other: Wistar TNO W 74
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: approximately 9 weeks
- Weight at study initiation: 176 g (average weight)
- Housing: 5 animals per sex in Makrolon cages, type III, on dust-free wood granules
- Diet: R 1324 (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 + 1.5
- Humidity (%): 60 + 5
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
other: Lutrol
Details on oral exposure:
VEHICLE
- Amount of vehicle:20 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw
Doses:
1000, 1300, 1500, 2000, 2500 and 3100 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 and weighing: Observations were made several times on the day of treatment and twice daily (once daily on weekends and holidays) for 14 days after treatment. The animals were weighed at the start and at the end of the 14 day observation period.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
Probit analysis according to Fink and Hund for calculation of the LD50 value with the practical limit of error for p ≤ 0.05
Sex:
male
Dose descriptor:
LD50
Effect level:
1 610 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 390 - <= 1 850
Mortality:
1000 mg/kg bw: no mortalities occurred
1300 mg/kg bw: 3/10 animals died (8 h after application)
1500 mg/kg bw: 6/10 animals died (4/10 animals 2 h after application, 1/10 animal 4 h after application, 1/10 animal 24 h after application)
2000 mg/kg bw: 6/10 animals died (2/10 animals 1 h after application, 4/10 animals 2 h after application)
2500 mg/kg bw: 9/10 animals died (8/10 animals 2 h after application, 1/10 animal 4 h after application)
3100 mg/kg bw: 10/10 animals died (3/10 animals before 1 h after application, 4/10 animals 1 h after application, 1/10 animals 2 h after application, 2/10 animal 4 h after application)
Clinical signs:
1000 mg/kg bw: No clinical signs of toxicity were observed up to the end of the 14-day observation period.
1500, 2000, 2500 and 3100 mg/kg bw: Clinical signs included narcosis, laying flat on their bellies, trembling and general reduction of well being. The signs were fully reversible within 3 days post-administration up to 2000 mg/kg bw/day. At 2500 mg/kg bw 1/10 animal showed clinical signs up to the end of the 14 day observation period. Since all animals died within 4 h after application at the highest dose group reversibility of clinical signs was not applicable.
Body weight:
Results of the body weight determination are not provided.
Gross pathology:
Necropsy revealed no substance-related findings.

Table 1: Results of acute oral toxicity testing in male rats

Dose [mg/kg bw]

Mortality*

Time of death

Clinical signs*

1000

0/10

-

0/10

1300

3/10

8 h

10/10

1500

6/10

2 – 24 h

10/10

2000

6/10

1 – 2 h

10/10

2500

9/10

2 – 4 h

10/10

3100

10/10

< 1 – 4 h

10/10

* number of animals/ number of animals used

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
CLP: Acute Oral 4, H302
Executive summary:

A study for acute oral toxicity in the rat was conducted with the test substance. 10 male Wistar rats per group received 1000, 1300, 1500, 2000, 2500 and 3100 mg/kg bw test substance as a solution in Lutrol as vehicle by single-dose oral gavage. Observations were made frequently on the day of treatment and twice each working day and once daily on weekends throughout the 14-day observation period. Surviving animals were weighed at the start and at the end of the observation period. Animals found dead and animals sacrificed at study termination were selectively dissected. No mortalities or clinical signs occurred at the lowest dose group. All animals died in the highest dose group between < 1 - 4 h after application. Mortalities of animals treated with 1300, 1500, 2000 and 2500 mg/kg bw (3/10 animals, 6/10 animals, 6/10 animals and 9/10 animals, respectively) occurred between 1 and 24 h post-dosing. The clinical signs observed in all animals from 1300 mg/kg bw were narcosis, lying flat on their bellies, trembling, and general reduction of well-being. The signs were fully reversible within 3 days post-administration up to 2000 mg/kg bw/day. At 2500 mg/kg bw 1/10 animal showed clinical signs up to the end of the 14 day observation period. Under the conditions of this study the LD50 was calculated to be 1610 mg/kg bw for male rats. According to Regulation (EC) No 1272/2008 the test material needs to be classified with Acute Tox. 4; H302: Harmful if swallowed.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: The test material was administered to female rats orally to assess acute oral toxicity.
- Short description of test conditions: Ten animals per dose group were orally administered six doses of the test substance in Lutrol as vehicle as a single dose via gavage. Animals were observed for 14 days.
- Parameters analysed / observed: mortality, clinical signs, necropsy, body weights
GLP compliance:
no
Test type:
other: acute oral toxicity
Limit test:
no
Species:
rat
Strain:
other: Wistar TNO W 74
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: about 14 weeks
- Weight at study initiation: 169 g (average weight)
- Housing: 5 animals per sex in Makrolon cages, type III, on dust-free wood chips
- Diet: Altromin R 1324 (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 + 1.5
- Humidity (%): 60 + 5
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
other: Lutrol
Details on oral exposure:
VEHICLE
- Amount of vehicle:20 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw
Doses:
500, 1000, 1300, 1400, 1500 and 2000 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 and weighing: Observations were made several times on the day of treatment and twice daily (once daily on weekends and holidays) for 14 days after treatment. The animals were weighed at the start and at the end of the 14 day observation period.
- Necropsy of survivors performed: yes (selectively)
- Other examinations performed: clinical signs, body weight
Statistics:
Probit analysis according to Fink and Hund for calculation of the LD50 value with a confidence range for p ≤ 0.05
Sex:
female
Dose descriptor:
LD50
Effect level:
1 360 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 170 - <= 1 560
Mortality:
500 mg/kg bw: no mortalities occurred
1000 mg/kg bw: 3/10 animals died (1/10 animal 1 h after application, 1/10 animal 2 h after application, 1/10 animal 24 h after application)
1300 mg/kg bw: 3/10 animals died (2/10 animals 8 h after application, 1/10 animal 24 h after application)
1400 mg/kg bw: 4/10 animals died (2/10 animals 4 h after application, 2/10 animals 8 h after application)
1500 mg/kg bw: 6/10 animals died (2/10 animals 4 h after application, 3/10 animals 8 h after application, 1/10 animal 24 h after application)
2000 mg/kg bw: 10/10 animals died (4/10 animals 2 h after application, 5/10 animals 4 h after application, 1/10 animals 24 h after application)
Clinical signs:
500 mg/kg bw: No clinical signs of toxicity were observed up to the end of the 14-day observation period.
1000, 1300, 1400, 1500 and 2000 mg/kg bw: Clinical signs included narcosis, prone position, convulsive tremors and deterioration of general state of health. The signs were fully reversible within 2 days post-administration up to 1500 mg/kg bw/day. Since all animals died within 24 h after application at the highest dose group reversibility of clinical signs was not applicable.
Body weight:
Results of the body weight determination are not provided.
Gross pathology:
Necropsy revealed no substance-related findings.

Table 1: Results of acute oral toxicity testing in female rats

Dose [mg/kg bw]

Mortality*

Time of death

Clinical signs*

500

0/10

-

0/10

1000

3/10

1 – 24 h

10/10

1300

3/10

8 – 24 h

10/10

1400

4/10

4 – 8 h

10/10

1500

6/10

4 – 24 h

10/10

2000

10/10

2 – 24 h

10/10

* number of animals/ number of animals used

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
CLP: Acute Oral 4, H302
Executive summary:

A study for acute oral toxicity in the rat was conducted with the test substance. 10 female Wistar rats per group received 500, 1000, 1300, 1400, 1500 and 2000 mg/kg bw test substance as a solution in Lutrol as vehicle by single-dose oral gavage. Observations were made frequently on the day of treatment and twice each working day and once daily on weekends throughout the 14-day observation period. Surviving animals were weighed at the start and at the end of the observation period. Animals found dead and animals sacrificed at study termination were selectively dissected. No mortalities or clinical signs occurred at the lowest dose group. All animals died in the highest dose group between 2 and 24 h after application. Mortalities of animals treated with 1000, 1300, 1400 and 1500 mg/kg bw (3/10 animals, 3/10 animals, 4/10 animals and 6/10 animals, respectively) occurred between 1 and 24 h post-dosing. The clinical signs observed in all animals from 1000 mg/kg bw were narcosis, prone position, convulsive tremors and deterioration of general state of health. The signs were fully reversible within 2 days post-administration up to 1500 mg/kg bw/day. Under the conditions of this study the LD50 was calculated to be 1360 mg/kg bw for female rats. According to Regulation (EC) No 1272/2008 the test material needs to be classified with Acute Tox. 4; H302: Harmful if swallowed.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 360 mg/kg bw
Quality of whole database:
The available information comprises acceptable studies (Klimisch score 2), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
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.
Reason / purpose:
read-across source
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.86 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.871 mg/L air
Based on:
test mat.
Remarks:
dust concentration (highest attainable concentration)
Exp. duration:
4 h
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
2 871 mg/m³
Quality of whole database:
The available information comprises an adequate and reliable OECD guideline study conducted according to GLP (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
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.
Reason / purpose:
read-across source
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 - < 5 000 mg/kg bw
Based on:
test mat.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The available information comprises an adequate and reliable OECD guideline study conducted according to GLP (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Acceptable data regarding acute oral and inhalation toxicity are available for the target substance sodium p-chloro-m-cresolate (CAS 15733-22-9). There are no data available regarding acute dermal toxicity of sodium p-chloro-m-cresolate (CAS 15733-22-9). In addition acceptable data regarding acute oral, inhalation and dermal toxicity are available for the analogue substance p-chloro-m-cresol (CAS 59-50-7). The assessment was therefore based on studies conducted with the target substance and supported with studies on the analogue substance p-chloro-m-cresol (CAS 59-50-7) as part of a read across approach, which is in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Oral:

CAS 15733-22-9

A study for acute oral toxicity in male rats was conducted with the target substance sodium p-chloro-m-cresolate (Löser, 1982). 10 male Wistar rats per group received 1000, 1300, 1500, 2000, 2500 and 3100 mg/kg bw test substance as a solution in Lutrol as vehicle by single-dose oral gavage. Observations were made frequently on the day of treatment and twice each working day and once daily on weekends throughout the 14-day observation period. Surviving animals were weighed at the start and at the end of the observation period. Animals found dead and animals sacrificed at study termination were selectively dissected. No mortalities or clinical signs occurred at the lowest dose group. All animals died in the highest dose group between < 1 - 4 h after application. Mortalities of animals treated with 1300, 1500, 2000 and 2500 mg/kg bw (3/10 animals, 6/10 animals, 6/10 animals and 9/10 animals, respectively) occurred between 1 and 24 h post-dosing. The clinical signs observed in all animals from 1300 mg/kg bw were narcosis, lying flat on their bellies, trembling, and general reduction of well-being. The signs were fully reversible within 3 days post-administration up to 2000 mg/kg bw/day. At 2500 mg/kg bw 1/10 animal showed clinical signs up to the end of the 14 day observation period. Under the conditions of this study the LD50 was calculated to be 1610 mg/kg bw for male rats. According to Regulation (EC) No 1272/2008 the test material needs to be classified with Acute Tox. 4; H302: Harmful if swallowed.

In addition, a study for acute oral toxicity in female rats was conducted with the target substance sodium p-chloro-m-cresolate (Löser, 1982). 10 female Wistar rats per group received 500, 1000, 1300, 1400, 1500 and 2000 mg/kg bw test substance as a solution in Lutrol as vehicle by single-dose oral gavage. Observations were made frequently on the day of treatment and twice each working day and once daily on weekends throughout the 14-day observation period. Surviving animals were weighed at the start and at the end of the observation period. Animals found dead and animals sacrificed at study termination were selectively dissected. No mortalities or clinical signs occurred at the lowest dose group. All animals died in the highest dose group between 2 and 24 h after application. Mortalities of animals treated with 1000, 1300, 1400 and 1500 mg/kg bw (3/10 animals, 3/10 animals, 4/10 animals and 6/10 animals, respectively) occurred between 1 and 24 h post-dosing. The clinical signs observed in all animals from 1000 mg/kg bw were narcosis, prone position, convulsive tremors and deterioration of general state of health. The signs were fully reversible within 2 days post-administration up to 1500 mg/kg bw/day. Under the conditions of this study the LD50 was calculated to be 1360 mg/kg bw for female rats. According to Regulation (EC) No 1272/2008 the test material needs to be classified with Acute Tox. 4; H302: Harmful if swallowed.

 

CAS 59-50-7

A study for acute oral toxicity in the rat was conducted with the source substance p-chloro-m-cresol (Bomhard & Löser,1992). 10 male Wistar rats per group received 1000, 1500, 2000, 3100 and 5000 mg/kg bw test substance as a solution in Polyethyleneglycol 400 as vehicle by single-dose oral gavage. Observations were made frequently on the day of treatment and twice each working day and once daily on weekends throughout the two-week observation period. Surviving animals were weighed before treatment, after one week and at study termination. Pathological-anatomical examinations were performed on all animals. The clinical signs observed were increased diuresis, sedation, respiratory disturbance, side position, tremor and tonical cramps. All animals died in the highest dose group within 1 h after application. Mortalities of animals at the dose groups 2000 and 3100 mg/kg bw (7/10 and 8/10 males died, respectively) occurred between 3 h and 2 d post-dosing. 4/10 animals died at 1500 mg/kg bw at 2 – 7 d after test substance administration. No mortalities occurred at 1000 mg/kg bw. Clinical signs in all animals at all dose groups included increased diuresis, sedation, respiratory disturbance, side position, tremor and tonical cramps. Under the conditions of this study the LD50 was considered to be 1830 mg/kg bw for male rats. According to Regulation (EC) No 1272/2008 the test material needs to be classified with respect to the oral route with Acute Tox. 4; H302.

 

Inhalation:

CAS 15733-22-9

A study for acute inhalation toxicity in the rat was conducted with the target substance sodium p-chloro-m-cresolate (Mihail, 1981). 10 male and 10 female Wistar rats were exposed for 4 h to 0.256 and 0.583 mg/L test substance as aerosol. Observations were conducted during 7 days after exposure. No mortalities occurred during the study period. The clinical signs observed were light decrease in the general well-being (apathy, dishevelled fur) for up to 24 h after exposure in all animals exposed to the low dose as well as for up to 48 h in males and for up to 24 h in females of the high dose group. Under the conditions of this study the LC50 value was considered to be > 0.583 mg/L air for male and female rats. According to Regulation (EC) No 1272/2008 the LC50 is not sufficient to conclude on a potential classification with regard to acute inhalation toxicity. Thus, the read across approach is applied from data of the reference source substance.

 

CAS 59-50-7

A study for acute inhalation toxicity in the rat was conducted with the source substance p-chloro-m-cresol according to the OECD Guideline 403 (1981) and in compliance with GLP (Pauluhn, 2003). Five male and five female Wistar rats per dose group were nose-only exposed for 4 h to a solid aerosol (dust) of the test substance at target concentrations of 2 and 3 mg/L air. The average dust concentrations reached were 1.337 mg/L and 2871 mg/L, which was the highest attainable aerosol concentration. 49% and 36.4% of the particles of the 2 and 3 mg/L group were smaller than 3 µm in aerodynamic diameter, respectively. Analysis of the aerosol particle-size distribution from the breathing zone samples demonstrates that the aerosol generated was within the respirable range. Detailed clinical observations were made several times on the day of exposure and at least once daily thereafter. Body weights were taken before exposure, on days 3 and 7, and weekly thereafter. Rectal temperatures were determined within 30 min after exposure and reflex-measurements were performed on the first post-exposure day. A complete gross pathological examination was conducted on each rat at the end of the 14 day post-exposure period. Exposure to the maximum technically attainable concentration of 2.871 mg/L did not result in mortality. The clinical signs observed were indicative of respiratory distress, associated with subdued demeanour, decreased body weights, emaciation, and hypothermia. In some rats the clinical signs lasted until the end of the 14 day post-exposure period. However, most rats showed evidence of recovery during the study period. Necropsy findings consisted of a less collapsed lung and secretions in the trachea. The hypothermia is considered to be related to upper respiratory irritation caused by the high concentrations of aerosol tested. According to the results, the test substance has an irritant potential to the respiratory tract, although it is of low acute inhalation toxicity to rats.Under the conditions of this study the LC50 value was considered to be > 2.871 mg/L for male and female rats corresponding to the highest attainable concentration. According to Regulation (EC) No 1272/2008 the test material does not need to be classified for acute inhalation toxicity.

 

Dermal:

CAS 59-50-7

A study for acute dermal toxicity in the rat was conducted with the source substance p-chloro-m-cresol according to the OECD Guideline 402 (1987) and in compliance with GLP (Sturdivant, 1999). Six male and six female Wistar Hanover rats per sex and dose group received a single dermal dose of 0 and 5000 mg/kg bw test substance. 6 additional females received also a dose of 2000 mg/kg bw. The test substance was prepared as a paste using 0.5 mL (for the 2000 mg dose group) and 1 mL (for the 5000 mg dose group) of de-ionised water and applied occlusively to the shaved skin of the animals (a minimum of 10% of body surface). The dressing was removed after 24 h and residual test substance was removed with paper towels moistened with tap water. The animals were inspected at least twice daily during the 14-day observation period (once on weekends and holidays) for mortality, moribundity and clinical signs of toxicity. The animals were weighed individually directly before administration (day 0) and for all surviving animals on day 7 and 14. Terminal body weights were recorded for all animals found dead. A complete gross necropsy was performed on all animals of the study. As a result of dermal application of the test substance, 2/6 females treated with 2000 mg/kg bw died and 3/6 females in the 5000 mg/kg bw group died. No mortalities occurred in male animals. Compound-related clinical signs were observed in all males and females of the treatment groups and included signs indicative of systemic toxicity (ataxia, decreased activity, eye twitching, clear lacrimation, red lacrimation (females), myoclonus (females) and urine staining) as well as tissue damage and irritation at the application sites. A significant decrease in body weight gain was observed for the males of the 5000 mg/kg bw group on day 7 and was considered to be compound-related. Thereafter, body weight gains were in the normal range. Compound-related gross pathological observations were found at necropsy in females found dead before study termination (lacrimation, urine stained ventrum, discolored urine and discolored treated skin) as well as in all surviving males and females at terminal sacrifice (crusty zones and thickened skin at the application site). Under the conditions of this study the LD50 values were considered to be > 5000 mg/kg bw for male rats and > 2000 - < 5000 mg/kg bw in female rats. According to Regulation (EC) No 1272/2008 the test material does not need to be classified for acute dermal toxicity.

Justification for classification or non-classification

The available data on acute oral toxicity meet the criteria for classification according to Regulation (EC) 1272/2008. The test substance is classified as Acute Tox., Category 4, H302: Harmful if swallowed.

According to Article 13 of Regulation (EC) No 1907/2006, information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to sodium p-chloro-m-cresolate with regard to acute inhalation and dermal toxicity, data will be generated from data of the reference source substance to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

The available data on acute inhalation and dermal toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.