Registration Dossier

Administrative data

Description of key information

For acute oral toxicity, a study report (Bio-Fax, 1971; Rel. 2) has been chosen as key study, reporting oral LD50 891 mg/kg in rats. Publications by Hasegawa et al (1989) and Schlede et al. (1995) on NaS (both Rel. 2) were chosen as supporting studies.
For acute dermal toxicity, one Rel. 1 study report (Bomhard, 1989) has been chosen as key study. No mortality and no local changes were noted, with dermal LD50 > 2000 mg/kg.
For acute inhalation toxicity, only one Klim. 3 on SA itself is available (BioFax, 1971). Salicylic acid was administered as a dust at 0.9 mg/l, at which concentration no mortality occurred, with signs of slight irritation only in one animal during exposure. Since this study alone is not sufficient to fulfil this endpoint, it is used by weight of evidence with a subacute inhalation toxicity study (Gage, 1970) on methyl salicylate vapour, which supports a conclusion of low potential for systemic toxicity by inhalation.

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:
data not available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Few details are available, but the parameters are similar to OECD guideline. No information on test substance purity.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
IOnly male rats (strain not specified) were tested. No information on test substance purity. Insufficient detail on method in report to exclude other possible deviations.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: from 173g to 179g (mean body weight per group)
- Source, Age at study initiation, Fasting period before study, Housing, Diet, Water, Acclimation period: data not available


ENVIRONMENTAL CONDITIONS
- Temperature, Humidity, Air changes, Photoperiod: data not available


IN-LIFE DATES: data not available
Route of administration:
other: oral, probably gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 25%
- Amount of vehicle (if gavage): data not available
- Justification for choice of vehicle: data not available
- Lot/batch no.: data not available
- Purity: data not available


MAXIMUM DOSE VOLUME APPLIED: data not available


DOSAGE PREPARATION: data not available
Doses:
464, 681, 1000 and 1470 mg/kg
No. of animals per sex per dose:
5 male rats per group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the animals were weighted at study initiation (all groups) and termination (only the 464 mg/kg group).
They were observed for symptoms and mortality at 0-4h, 4-12h, 12-24h, and then after 2, 3, 4, 5, 6, 7 and 8-14 days
- Necropsy of survivors performed: yes
Statistics:
data not available
Sex:
male
Dose descriptor:
LD50
Effect level:
891 mg/kg bw
95% CL:
699 - 1 140
Mortality:
Mortality was observed at 681 mg/kg (1 animal), 1000 mg/kg (3 animals) and 1470 mg/kg (5 animals) (see Table 1)
Clinical signs:
Hypoactivity, muscular weakness
Body weight:
No data
Gross pathology:
In survivors, no significant effects were observed.
In decedents, an inflammation of gastrointestinal tract was observed.

Table 1: Onset of symptoms and mortality

Dosage mg/kg

Conc. %

Onset of Symptoms (S) Mortality (M)

Cumulative Deaths

Body weight

g

      Time of recovery (Day) 

Hours

Days

0-4

4-12

12-24

2

3

4

5

6

7

8-14

I

T

464

25

0 / 5

179

227

 

681

25

S

M (1)

1 / 5

176

-

  Day 2

1000

25

S

M (1)

M (1)

M (1)

3 / 5

173

-

  Day 5

1470

25

S

M (2)

M (2)

M (1)

5 / 5

175

-

 

S: onset of symptoms

M: onset of mortality (number of animals)

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance is considered as harmful according to EU criteria and is classified in Category 4 according to the GHS (UN/EU)
Executive summary:

The acute oral toxicity of salicylic acid (purity unknown) was tested in a test similar to OECD guideline 401. Five male Albino rats per group (4 groups) were administrated a single dose of the test substance in a corn oil suspension. The dose were 464, 681, 1000 and 1470 mg/kg bw. The animals were then observed for 14 days.

Under the conditions of this test, the LD50 was 891 mg/kg bw. Signs of intoxication were hypoactivity and muscular weakness. At necropsy, no significant findings were observed in survivors, whereas inflammation of the gastrointestinal tract was observed in decedents. Based on the results of this study, salicylic acid would be classified as harmful in male rats by oral route, according to the Directive (67/548/EEC) on dangerous substance.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
891 mg/kg bw
Quality of whole database:
Reliability 2 study on the substance itself

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Weight of evidence on reliability 2 studies

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:
study completed in 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study conducted according to GLP.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
Temperature, Humidity (%), Air changes (per hr), Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: no data
Type of coverage:
occlusive
Vehicle:
other: cremophor EL
Details on dermal exposure:
TEST SITE
- Area of exposure: no data
- % coverage: no data
- Type of wrap if used: no data


REMOVAL OF TEST SUBSTANCE
- Washing (if done): water
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): no data



Duration of exposure:
24 hours
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, and gross pathological changes
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality was observed
Clinical signs:
Poor general condition and piloerection: onset of symptoms was 1 h p.a.. On day 2 all animals were free of signs.
Body weight:
No effect on the weight gain of the animals was noted.
Gross pathology:
The gross examination revealed no significant findings.
Other findings:
- Other observations: No local effects  were observed. Two female rats presented a slight  increase in liver size.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Salicylic acid was not considered to be toxic by this route.
Executive summary:

In an acute dermal toxicity study (Bomhard, 1996), groups of Wistar rat (5/sex) were dermally exposed to Salicylic acid in cremophor EL ® for 24 hours at dose of 2000 mg/kg bw. Animals then were observed for 14 days. No death was observed. No local effects and no effect on the weight gain of the animals were noted. Dermal LD50 > 2000 mg/kg bw. Salicylic acid is not classified based on LD50 in both sexes.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Acute oral toxicity:

A study report (Bio-Fax, 1971) has been chosen as key study for this endpoint. This study did not follow a published guideline but was similar to OECD guideline 401. It gives a LD50 = 891 mg/kg. The signs of intoxication were hypoactivity and muscular weakness. At necropsy, inflammation of gastrointestinal tract was reported in dead animals. Publications by Hasegawa et al. (1989) and Schlede et al. (1995) on NaS were chosen as supporting studies. Both were performed with a protocol similar to OECD guidelines and give LD50 of 1580 mg/kg bw and between 500 and 2000 mg/kg bw respectively. All LD50 values were therefore in the range of 500 -2000 mg/kg, demonstrating that salicylic acid is harmful via the oral route.

Acute dermal toxicity:

Two study reports are available for evaluation of this endpoint. In the key guideline study (Bomhard, 1989), in rats, no mortality and no local changes were noted. The acute dermal LD50 was greater than 2000 mg/kg. A similar result was reported in the supporting study (Bio-fax, 197) in rabbits. These results show that salicylic acid is not hazardous via the dermal route.

Acute inhalation toxicity:

One study report on SA is available for this endpoint (BioFax, 1971). Salicylic acid was administered on whole body as a dust. No information on particle size distribution is available in the report, however typical MMAD for the currently produced test substance is approximately 30-50 µm, with less than 5% <4 µm. No mortality was noted, with signs of slight irritation only in one animal during exposure. Results show that LC50 is greater than 0.9 mg/l (concentration derived by analysis of chamber air). The study was classified reliability 3 (not reliable) because it was reported in insufficient detail to determine whether it met the criteria of current standard methods and the result does not allow a definitive conclusion on classification to be made, however the results suggest that salicylic acid would not be toxic or severely irritating via the inhalation route. A subacute inhalation toxicity study (Gage, 1970) on methyl salicylate vapour at an effectively saturated concentration of 700 mg/m3 for 7 hours per day for 4 weeks did not demonstrate any adverse effects. Although this study allows only limited prediction of local effects from SA dust, it supports a conclusion of low potential for systemic toxicity by inhalation including the lungs. In fact SA dust due to the MMAD with less then 5% <4 µm ( the size limit for penetration in rat lung) would have lead to a lung dose of 45 mg/m3, hover the limit of inert dust of 10 or 5 mg:m3 in order to have visibility. The only effect seen for lung was nasal discharge in 1/6 rats.

 



Justification for selection of acute toxicity – dermal endpoint
Reliability 1 study on the substance itself

Justification for classification or non-classification

Acute oral toxicity:

Harmful (Xn), R22 (Harmful if swallowed) according to EU criteria

Category 4 (Harmful if swallowed) according to GHS (UN/EU).

Based on LD50 = 891 mg/kg from Rel 2 study similar to OECD 401 and weight of evidence from other studies giving LD50 values in the range of 500 -2000 mg/kg.

Acute dermal toxicity:

Not classified according to EU DSD or GHS (UN/EU) criteria.

Based on LD50 > 2000 mg/kg from two studies Rel 1 & 2.

Acute inhalation toxicity:

Not classified according to EU DSD or GHS (UN/EU) criteria. Based on Rel 3 data from inhalation of SA dust in rats and Rel 2 data from subacute inhalation of MeS vapour in rats. By weight of evidence, these studies all indicate that salicylic acid would not be toxic via inhalation route.