Salicylamide

Endpoint summary

Description of key information

Oral: LD50= 980 mg/kg bw (C.I. 817-1176 mg/kg bw), male, rat, OECD 401, Boxill 1958
Oral: LD50 >1600 <2000 mg/kg bw, rat, OECD 401, Ichniowski 1946
Oral: LD50=1400 mg/kg bw, rat, no guideline, Hart 1947
Oral: LD50=1200 (960-1500) mg/kg bw, male/female, rat, no guideline, Way 1953
Oral: LD50=1600 mg/kg bw, rat, no guideline, Bekemeier 1955
Oral: LD50=1490 mg/kg bw, rat, no guideline, Drebinger 1952

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1958 or before

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study published in a peer-reviewed journal, according to scientific standards. Experimental details well documented, but no data on acclimatization and housing. Results: LD50 after 1,2,4 and 7 days, incl. statistical evaluation. Performed 1958, before GLP and OECD guidelines were introduced. Sufficient numbers of animals investigated, but only one sex (males). No necropsy reported for any animals that died during the study or were sacrificed thereafter.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

Principles for LD50 derivation followed as described in guideline

Deviations:

yes

Remarks:

One sex only, no necropsy, no body weight development, no data on acclimatization and housing

GLP compliance:

no

Remarks:

GLP not available at study time

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: H L A

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 95-180 g
- Fasting period before study: 15-17 hours
- Housing: no data
- Diet: ad libitum, except during 6-h observation period after application
- Water: ad libitum, except during 6-h observation period after application
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24.4 - 25.5

Route of administration:

oral: gavage

Vehicle:

other: 10% gum acacia suspension in water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: depending on dose (not stated)
- Amount of vehicle (if gavage): 10 - 20 ml / kg

MAXIMUM DOSE VOLUME APPLIED: 20 ml / kg

Doses:

5 doses to calculate LD50, not individually stated

No. of animals per sex per dose:

10 males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days (for LD50 calculation), 21 days for some recovery experiments
- Frequency of observations: 6 d, 1, 2, 4, 7 d for LD50; no weighing
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Statistics:

Litchfield JT & Wilcoxon F, J. Pharmacol. Exptl. Therap. 96:99 (1949)

Sex:

male

Dose descriptor:

LD50

Effect level:

980 mg/kg bw

Based on:

act. ingr.

95% CL:

817 - 1 176

Remarks on result:

other: fasted animals, observation of mortality at 7 days

Sex:

male

Dose descriptor:

LD50

Effect level:

1 020 mg/kg bw

Based on:

test mat.

95% CL:

842 - 1 234

Remarks on result:

other: fasted animals, observation of mortality at 4 days

Sex:

male

Dose descriptor:

LD50

Effect level:

1 100 mg/kg bw

Based on:

test mat.

95% CL:

921 - 1 310

Remarks on result:

other: fasted animals, observation of mortality at 1 and 2 days

Sex:

male

Dose descriptor:

other: TD50 minimal neurological deficit dose

Effect level:

71 mg/kg bw

Based on:

test mat.

95% CL:

59 - 84.5

Remarks on result:

other: fasted animals, mean body weight 139.8 g, 24 h observation

Sex:

male

Dose descriptor:

other: TD50 minimal neurological deficit dose

Effect level:

82 mg/kg bw

Based on:

test mat.

95% CL:

61 - 110

Remarks on result:

other: fasted animals, mean body weight 208.8 g, 24 h observation

Clinical signs:

other: Ataxia, depression (progressing to hypnosis at higher doses). Labored respiration and cyanosis prior to death (result of respiratory failure). Occasionally (in some animals) bizarre motions (rapid vertical or horizontal movements of the head, rapid circul

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Study suitable for use as part of a weight-of-evidence assessment.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1946 or before

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study published in a peer-reviewed journal, according to scientific standards. Experimental details documented, but no data on acclimatization and housing. Results: Mortalities tabulated after 1 and 7 days, but no statistical determination of LD50. Performed 1946, before GLP and OECD guidelines were introduced. Sufficient numbers of animals investigated, but sex not stated.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

Principles for LD50 derivation followed as described in guideline

Deviations:

yes

Remarks:

Sex not stated, only 7 days of observation, no data on acclimatization and housing, no body weight data

GLP compliance:

no

Remarks:

GLP not available at study time

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: gavage

Vehicle:

other: 0.5% gum tragacanth in water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 20 % suspension
- Amount of vehicle (if gavage): 2 - 10 g/kg body weight
- Justification for choice of vehicle: stability of test substance, tolerability of vehicle (confounding effect of alcohols)
- Lot/batch no. (if required): no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: approx. 10 ml/kg body weight

Doses:

Preliminary experiment: 400, 600, 800, 1000, 1600, and 2000 mg/kg body weight
Main experiment: 500, 1000, and 2000 mg/kg body weight

No. of animals per sex per dose:

Preliminary experiment: 5 (sex not specified)
Main experiment: 15 (sex not specified)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations: 15, 30, 60, 90 min, 2, 3, 5, 24 h, daily until day 7; no weighing reported
- Necropsy of animals dying on test: yes
- Necropsy of survivors: not reported
- Other examinations performed: clinical signs

Statistics:

None

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 1 600 - <= 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No statistical evaluation; no mortalities at 1000 and 1600 mg/kg; at 2000 mg/kg mortality 1/5 in preliminary test, 9/15 in main test

Mortality:

No mortalities up to 1000 and 1600 mg/kg
At 2000 mg/kg: mortality 1/5 in preliminary test, 9/15 in main test
All mortalities within 24 h after application (7/15 within 1 hour)

Clinical signs:

other: Depression (dose-dependent, no response to tail pinch), hind leg incoordination Recovery of survivors within 24 hours

Gross pathology:

Congestion and edema of the lungs
Some cases of local hemorrhages and hyperemia of the liver
All other organs grossly normal

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Study suitable for use as part of a weight-of-evidence assessment.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1946 or before

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study published in a peer-reviewed journal, according to scientific standards. Some experimental details documented, but no data on acclimatization and housing. Results: Mortalities up to 48 hours considered for graphical determination of LD50. Performed 1946, before GLP and OECD guidelines were introduced. Sufficient numbers of animals per group, but sex not stated.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Acute oral LD50, with 15 or more animals per dose (sex not specified). No doses and mortalities per dose tabulated. Observation period only 48 hours; no necropsy reported. Main emphasis on analgesia test.

GLP compliance:

no

Remarks:

Performed 1946, before GLP and OECD guidelines were introduced.

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: gavage

Vehicle:

other: 1-1.5 % gum tragacanth in water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 5 or 10 % suspension
- Amount of vehicle (if gavage): no data
- Justification for choice of vehicle: No appropriate solvents found to produce a true solution under physiological conditions. Suspensions satisfactorily stable.

MAXIMUM DOSE VOLUME APPLIED: no data

Doses:

No data

No. of animals per sex per dose:

15 or more

Control animals:

no

Details on study design:

- Duration of observation period following administration: 48 hours (occasional later deaths considered due to extraneous factors)
- Frequency of observations and weighing: No data
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs

Statistics:

LD50 approximated graphically

Sex:

not specified

Dose descriptor:

LD50

Effect level:

1 400 mg/kg bw

Based on:

test mat.

Mortality:

Not tabulated

Clinical signs:

other: Depressant (or possibly paralytic) action

Gross pathology:

No data

AD50 (amount required to produce significant analgesia in 50 % of the rats): 60 mg/kg

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Study suitable for use as part of a weight-of-evidence assessment.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

before 1953

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study published in a peer-reviewed journal, according to scientific standards, years before OECD guidelines were developed. Main focus was laid on analgetic activity, approximate median lethal dose (LD50) was determined in parallel, in the same animals that were used for pain response. Observation time was only 48 hours. Only few experimental details and no individual result data are reported.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline available

Principles of method if other than guideline:

6-10 male and female rats were treated with salicylamide by the oral route at several logarithmical-spaced dosage levels, and tested in a pressure analgesiometric method (on the tail) at several time points, to determine the threshold force that elicited a cry response. Mortality was recorded in the same treated animals during a 48-hour observation period, and used to calculate an approximate median lethal dose (LD50). No husbandry conditions and no symptoms, body weights, necropsy results etc. are recorded.

GLP compliance:

no

Test type:

other: approximate LD50 from 48-hour mortality in analgetic activity study

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 50-80g
- Housing, diet, water, acclimation: no data

ENVIRONMENTAL CONDITIONS
- no data

Route of administration:

oral: unspecified

Vehicle:

other: probably 0.25% tragacanth in water (which was used for i.p. injection)

Details on oral exposure:

no data

Doses:

logarithmically spaced, sufficient to calculate an LD50 with confidence limits, but not individually reported

No. of animals per sex per dose:

6-10 males and females, exact numbers per sex not specified

Control animals:

no

Statistics:

Litchfield JT & Wilcoxon F, J. Pharmacol. Exp. Therapeutics (1949) 96: 99

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

1 200 mg/kg bw

Based on:

test mat.

95% CL:

960 - 1 500

Median analgetic dose (AD50): 440 (373 - 520) mg/kg body weight

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Study suitable for use as part of a weight-of-evidence assessment.

Reference 5

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: see 'Remark'

Remarks:

Study published in a peer-reviewed journal, according to scientific standards. Some experimental details documented, but emphasis on cat data, and on comparison with other literature. Observation period only 1 week. Performed 1955, before GLP and OECD guidelines were introduced.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

LD50 determination (oral, gavage) in 6-7 groups of 5 animals each. Mortality count after 1 week.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source, age, weight: no data
- Fasting period before study: yes (application in the morning after fasting)
- Housing, diet, water, acclimation: no data


ENVIRONMENTAL CONDITIONS
- no data

Route of administration:

oral: gavage

Vehicle:

other: 2% methyl cellulose (tylose), neutral or weakly alkaline

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 3%
- Amount of vehicle (if gavage): dose dependent, no individual data

Doses:

6-7 dose groups, individual doses not specified

No. of animals per sex per dose:

5 (sex not specified)

Control animals:

no

Statistics:

LD50 calculation according to Behrens, in: Burn, Biolog. Auswertungsmeth., Springer 1937

Sex:

not specified

Dose descriptor:

LD50

Effect level:

1 600 mg/kg bw

Based on:

test mat.

Clinical signs:

other: Paresis of hind limbs at 300 - 1000 mg/kg (transient: 30-90 min), narcosis at (sub-)lethal doses, respiratory paralysis as cause of death. Rapid recovery of survivors, no delayed or persistent symptoms.

Gross pathology:

Hyperemia of liver and lungs, meninges, and gastro-intestinal tract; hemorrhages of lung alveoli and lung edema. Some rats showed a diffuse fatty degeneration of the liver and the convoluted tubuli of the kidney.

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Study suitable for use as part of a weight-of-evidence assessment.

Reference 6

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1952 or before

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Mostly a review article on various toxicological and pharmacological properties of salicylamide; however, author reports LD50 values found in own experiments. No experimental details, few informations on clinical symptoms. No guideline available.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Determination of LD50, no details given

GLP compliance:

no

Test type:

other: Acute LD50, not further specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Doses:

no data

No. of animals per sex per dose:

no data

Control animals:

not specified

Sex:

not specified

Dose descriptor:

LD50

Effect level:

1 490 mg/kg bw

Based on:

test mat.

Clinical signs:

other: Sedation, ataxia, hind limb paresis; moribund animals: deep coma, respiratory paralysis.

More toxic by slow intravenous injection: 300 mg/kg body weight lethal.

No irritating effect on skin: 20% salicylamide ointment causes no skin erythema (no species stated).

Human data (self-test of the author): Daily administration of 3 - 6 g salicylamide for 8 days causes no proteinuria.

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Study suitable for use as part of a weight-of-evidence assessment.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

980 mg/kg bw

Quality of whole database:

None of the published articles on the acute oral toxicity fulfils the data and quality requirements of a study conducted in accordance with present OECD testing guidelines. Nevertheless, the agreement between the results is high, independent of possible differences in animal species and strains, vehicles, and other experimental parameters. The acute oral toxicity of salicylamide can be reliably characterised by applying the weight-of-evidence approach and selecting the most conservative LD50 value.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral toxicity to rats

A large body of information on the acute toxicity of salicylamide is available from articles following scientific standards and published in peer-reviewed journals, but all studies were performed before the introduction of OECD testing guidelines and GLP. However, compared with present-day methods, much larger numbers of animals were tested, and the agreement between different authors is high, independent of possible differences in animal strains, vehicles, and other experimental parameters: For the oral LD50 in rats, values from 980 to 1600 mg/kg bw are reported.

The study by Boxill (1958) is considered to be the most conservative and reliable, based on the quantity of information (including statistical confidence limits) reported, although only males were tested, and the observation period was only 7 days. No sex-specific LD50 values are reported in any of the studies, therefore the more susceptible sex cannot be determined. However, the value for males given by Boxill, 980 mg/kg bw, is 20% less than the lowest value for both sexes, 1200 mg/kg bw (Way, 1953). Since all deaths reported in rats by any of the authors occurred hours or (at latest) a few days after application, it is also unlikely that the limited observation time compromised the result. The lowest LD50, for male rats at 980 mg/kg bw, is selected as the most conservative value and is carried forward for risk assessment and classification and labelling.

Oral toxicity to other species

A wide variety of species was tested and compared with rats. Mice (1100-1400 mg/kg bw) and guinea pigs (1730-1800 mg/kg bw) had LD50 values similar to those found in rats, whereas rabbits (>3000 mg/kg bw) were less responsive. The only reported value for dogs (>800 mg/kg bw, no mortality) does not indicate any particular susceptibility, since no higher doses were tested. In cats, on the other hand, an almost tenfold lower LD50 (<150 mg/kg) and a completely different mode of action was observed. Deaths were delayed by several days, and were caused by kidney failure (glomerulo-tubulonephrosis and uremia), whereas in all other species, respiratory paralysis was the cause of death. This is a well known species-specific effect (Bekemeier, H., Proceedings of the European Society of Toxicology, 1975, 16, 229 -232).

Other routes of application

No experimental data were found on dermal and inhalation toxicity. However, two consistent values for the intraperitoneal LD50 exist: 500 -1000 mg/kg bw (Ichniowski 1946), and 600 mg/kg bw (Way 1953).

The available acute oral toxicity data is considered to be complete and adequate for risk assessment and classification and labelling, based on a weight-of-evidence approach, according to Regulation (EC) No. 1907/2006, Annex XI, section 1.2.

Justification for selection of acute toxicity – oral endpoint
A large body of information on the acute toxicity of salicylamide is available from articles following scientific standards and published in peer-reviewed journals, but all studies were performed before the introduction of OECD testing guidelines and GLP. The study by Boxill (1958) is considered to be the most conservative and reliable, based on the quantity of information (including statistical confidence limits) reported, although only males were tested, and the observation period was only 7 days.

Justification for classification or non-classification

Acute Oral Toxicity

The key value selected for the acute oral toxicity, LD50=980mg/kg bw leads to the classification of the substance as Category 4, H302, Harmful if swallowed, according to the criteria in Regulation (EC) No. 1272/2008, Annex I, Part 3, 3.1.2.

Acute Dermal and Inhalation Toxicity

No experimental data are available which are suitable for the purposes of classification and labelling.