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Administrative data

Description of key information

13-week oral-gavage study, rat, highest dose 200 mg/kg bw, no guideline, Ichniowski 1946. No signs of toxicity or histopathological changes. Leucopenia suspected, but not reproducible in second, specific hematology study.
67-day drinking water study, mouse, 250mg/kg, no guideline, Drebinger 1952. No signs of toxicity
Combined 3-generation study, mouse, no guideline, non-standard method, Wright 1967. Depression of physical condition, shortening of survival time, no increase in mammary carcinoma.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study published in a peer-reviewed journal. Performed before GLP and OECD guidelines were introduced. Experimental details documented, but no data on housing, no individual animal records (body weight, food consumption, mortality, etc.). Maximum dose (200 mg/kg bw) too low for limit test. Sufficient numbers of animals (10 M, 10 F per dose), hematology and histology performed, but not reported in detail. Death rates similar in all dose groups, all deaths attributed to faulty (intratracheal) administration, on the basis of necropsy findings.
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Gavage application 13 weeks, 5 times/week, post mortem examination, hematology and histopathology in some animals, recovery time 3-7 weeks in some animals. No control group; application only five days per week; no data on acclimatization and housing; only summary data on weight development, rudimentary clinical laboratory data; high losses due to intratracheal application.
GLP compliance:
no
Remarks:
GLP not available at study time
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Weight at study initiation: 100 - 130 g
- Fasting period before study: no
- Housing, diet, water, acclimation period: no data

ENVIRONMENTAL CONDITIONS
- no data
Route of administration:
oral: gavage
Vehicle:
other: 0.5% gum tragacanth in water
Details on oral exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): stability of test substance, tolerability of vehicle (confounding effect of alcohols)
- Concentration in vehicle: depending on dose
- Amount of vehicle (if gavage): 10 or 20 ml/kg bw
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 times per week, totally 67 doses
Remarks:
Doses / Concentrations:
5, 25, 50, 100, and 200 mg/kg bw
Basis:
other: applied by gavage
No. of animals per sex per dose:
10 males, 10 females
Control animals:
no
Details on study design:
- Dose selection rationale: 1, 5, 10, 20, and 40 times average human adult dose
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: Some animals sacrificed at end of treatment, for hematologic studies; others injected with 4% formaldehyde for histologic examination, 3 - 7 weeks after cessation of treatment
- Post-exposure recovery period in satellite groups: 3 - 7 weeks
- Section schedule rationale (if not random): no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, but no results reported
- Time schedule: no data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes, but only summary findings reported
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption: No data
- Compound intake: total: 70 mg - 13400 mg / animal, calculated from gavage amounts

FOOD EFFICIENCY:
- No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: sacrifice at end of treatment
- Anaesthetic used for blood collection: No
- Animals fasted: No data
- How many animals: 19 (allocation to dose groups not stated)
- Parameters checked: prothrombin time, coagulation time, hemoglobin, erythrocyte count, leukocyte count (differential count in case of abnormal numbers)

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- post-mortem examination on all animals dying on test or sacrificed afterward

HISTOPATHOLOGY: Yes
- 46 treated surviving animals (allocation to dose groups unclear)
Clinical signs:
no effects observed
Description (incidence and severity):
Significant, but fully attributed to technical accidents (intratracheal application), not related to test substance
Mortality:
no mortality observed
Description (incidence):
Significant, but fully attributed to technical accidents (intratracheal application), not related to test substance
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Weights: steady increased steadily. No dose effect. Male weight range 200-310 g at end of treatment (EOT), 240-370 g 4 weeks later. Female weight range 160-205 g at EOT, 185-235 g 4 weeks later.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Prothrombin times normal (29.26 - 36.55 sec); coagulation times relatively high (5-7 min); erythrocytes+hemoglobin: lower normal range. Leucocytes: wide range (300-5300 in 3 animals, >10000 in 2 animals), no influence on differential count
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Hyperemic hemorrhagic lungs, seropurulent pleurisy, pericarditis in animals dying - fully attributed to accidental intratracheal administration. No significant abnormal changes in rats necropsied at EOT.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No significant abnormal changes upon microscopical examination of internal organs at any dose.
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Maximum dose administered
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Critical effects observed:
not specified
Conclusions:
No significant changes were observed at any dose, including the maximum. Non-guideline study, not considered to be reliable.
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Mostly a review article on various toxicological and pharmacological properties of salicylamide; however, author cites an own 67-day repeated-dose experiment with mice. No experimental details, little information on clinical symptoms. No guideline followed.
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Application of 250 mg salicylamide/kg bw in the drinking water for 67 days
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
not specified
Sex:
not specified
Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
67 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
250 mg/kg body weight
Basis:
nominal in water
No. of animals per sex per dose:
no data
Control animals:
yes, concurrent no treatment
Dose descriptor:
NOEL
Effect level:
>= 250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: No observable distinction from control animals
Critical effects observed:
not specified

No detectable difference between treated and control animals at the end of the study (67 days).

Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Non-guideline study not performed under GLP. Non-standard study design. 3 –generations Studied in mice. Only a low level of experimental detail reported. Route of administration was in the diet at 0.1%, 0.5% or 1.0%. No data provided to show achieved concentration, homogeneity or stability in the diet preparations. Purity/composition/origin of test substance not given. Food consumption not shown but achieved doses reported as 143, 688 or 1345 mg/kg/day respectively representing 10%, 70% and 95% of the acute oral LD50. Results do not give detail of the clinical condition of the animals other than a condition percentage that was assessed on a 5 weekly basis. No record of the animal breeding procedures. Reproductive parameters are not measured in detail (44%-45% of all females across all dose groups and generations did not litter. However no dose response and no further data given) – number of females to litter (%) and pups born that were raised to weaning age (%) were reduced in all treated groups with no dose response. Parental survival time was significantly reduced compared with controls for all dose groups. As was percentage of pups raised to weaning age. A NOAEL was not derived.
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Male and female mice in mated and unmated groups of five were powder-fed with 0.1, 0.5, and 1.0% of the test substance in the diet, starting at weaning in each generation. The condition of the mice was recorded at 5-week intervals. Food consumption and animal weight (weekly) were recorded for 50 weeks. Litters and survival of pups, as well as neoplasm formation and deaths (survival times) are reported as averages.
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
other: ABC-A, albino, inbred for 25 generations
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: developed in author's laboratory, derived from ABC mice (Dr. J.J. Bittner)
- Age at study initiation: weanling
- Weight at study initiation: no data
- Fasting period before study: no
- Housing: cages of 5, mated groups: 2 males and 3 females
- Diet (ad libitum): Purina Labeena, Ralston-Purina Co., St. Louis, USA
- Water (ad libitum): tap water
- Acclimation period: none

ENVIRONMENTAL CONDITIONS
- Temperature (°C), humidity (%), air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 14 hours dark, 10 hours light

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Remarks:
powder feeding
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): twice weekly
- Mixing appropriate amounts with (Type of food): commercial food (Purina Labeena), finely ground
- Storage temperature of food: room temperature

VEHICLE
- none
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
lifetime (averages 45.6 to 50.0 weeks in first generation) , start at weaning
Frequency of treatment:
continuous, daily
Remarks:
Doses / Concentrations:
0.1, 0.5, and 1.0% in feed
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
143, 688, and 1345 mg/kg bw/day
Basis:
other: mean uptake calculated for whole dose groups, from food intake
No. of animals per sex per dose:
52-54 in first generation (both sexes, no details on sex)
35-54 in second generation (both sexes, no details on sex)
9-21 in third generation (both sexes, no details on sex)
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: 2, 10, and 20 times the expected maximal human therapeutic dosage
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: mated and unmated groups, not further specified
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): animals maintained until spontaneous death
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily (for mortality, litters)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 5-week intervals

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for groups of animals determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
- number of litters born
-number of young raised to weaning age
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (no table): probably limited to observation of mammary carcinoma
HISTOPATHOLOGY: No
Statistics:
Survival time per dose group (mean and standard error), with significant differences at p <= 0.01
Mean condition percentage for a 60-week period: average of 6 observations (at 10 week intervals), with gradings good (10), fair (5), poor (3), very poor (1), dead (0)
% of mated females having no litters
% of litters not raised to weaning
Mean number of pups born per female
Mean number of pups weaned per female
% of females developing neoplasms
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
mean survival times in first generation: significantly shortened: 60.5 weeks in control, 50.0 weeks at dose 0.1%, 46.1 weeks at dose 0.5%, 45.6 weeks at dose 1.0%. No difference in survival times between generations.
Mortality:
mortality observed, treatment-related
Description (incidence):
mean survival times in first generation: significantly shortened: 60.5 weeks in control, 50.0 weeks at dose 0.1%, 46.1 weeks at dose 0.5%, 45.6 weeks at dose 1.0%. No difference in survival times between generations.
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
0.1% diet: 143 mg/kg/day, 0.5% diet: 688 mg/kg/day, 1.0 % diet: 1345 mg/kg/day
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
no increase in % females with neoplasms
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- condition maintenance percentage, with gradings good (10), fair (5), poor (3), very poor (1), dead (0): similar to controls after 10 weeks, 79% of controls after 20 weeks, steady decline to 29% of controls at 60 weeks (dose 1.0% of diet, first generation)
Dose descriptor:
NOAEL
Effect level:
< 1 000 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Significant shortening of mean survival times
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Critical effects observed:
not specified

Repeated doses of 10%, 70%, and 95% of the acute LD50 decreased the mean survival time up to 1/3 (dose-dependent); the effect was highly significant at all doses. No influence of the test substance on the incidence of mammary carcinoma was observed at any concentration.

Conclusions:
The study is considered to be relevant, but not reliable or suitable for risk assessment or classification and labeling purposes with regard to repeat dose toxicology.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
rat
Quality of whole database:
A number of repeated-dose toxicity studies via the oral route were conducted, but all before the introduction of relevant OECD testing guidelines. No study identified a NOAEL for repeated-dose toxicity for salicylamide and none are regarded as adequate for use in risk assessment and classification and labeling.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The 13 -week rat study of Ichniowski (1946), though not conforming to any guideline, and compromised by high accidental mortalities (intratracheal application), is nevertheless considered relevant, although not reliable. It suggests that the subchronic NOAEL of salicylamide is >200 mg/kg bw, since no adverse effects were observed in the examined parameters, including histopathology and haematology.

 

The 67-day mouse study (Drebinger 1952), though inadequately documented, supports this finding, since no signs of toxicity were found at 250 mg/kg.

 

In contrast, the combined 3-generation mouse lifetime feeding study (Wright 1967) used far higher doses (up to 1345 mg/kg bw/day), at which depression of physical condition (not further specified) and shortening of survival time were observed. A consistent interpretation and comparison is not possible.

 

No study identified a NOAEL for repeated-dose toxicity for salicylamide and none are regarded as adequate for use in risk assessment and classification and labelling.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The 13 -week rat study of Ichniowski (1946), though not conforming to any guideline, and compromised by high accidental mortalities (intratracheal application), is nevertheless considered relevant, although not reliable. It suggests that the subchronic NOAEL of salicylamide is >200 mg/kg bw, since no adverse effects were observed in the examined parameters, including histopathology and haematology.

Justification for classification or non-classification

On the basis of the available data, salicylamide does not meet the criteria for classification and labelling according to Regulation (EC) No. 1272/2008, Annex I, Part 3, 3.9. The available data are not conclusive.