Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: weight of evidence on ECHA guidance based calculations
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: weight of evidence on ECHA guidance based calculations
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.3 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Value:
45.4 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification for route to route (high oral and dermal absorption).

AF for interspecies differences (allometric scaling):
4
Justification:
interspecies allometric scaling for rat
AF for intraspecies differences:
5
Justification:
intraspecies for worker
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Introduction

In this section, data from all end-points are examined and analyzed in order to determine for which it is relevant and possible to establish a DNEL value. The method followed is that proposed in the guidance for the implementation of REACH (Chapter R.8: Characterisation of dose (concentration)-response for human health, May 2008).

CLP harmonised classification:

Salicylic acid is classified in CLP regulation (Index No. 607-732-00-5, ATP13):

- Category 4 H302 (harmful if swallowed)

- Category 1 H318 (irreversible effects on the eye)

- Category 2 H361 Suspected of damaging the unborn child

 

Where possible, derivation of DNELs for the relevant endpoints has been made using data on Salicylic Acid (SA) itself. Where no such reliable studies are available, data from other salicylates, principally methyl salicylate (MeS) but also acetylsalicylic acid (ASA) and sodium salicylate (NaS). Read-across from these salicylates for derivation of systemic DNELs is considered valid since all are readily absorbed and are rapidly hydrolysed in vivo to free salicylate (SA) as the initial step in metabolism. Full justification for read-across is given in the endpoint summary for toxicokinetics.

 

1. Acute / short-term exposure - systemic effects

Cutaneous route

In the key studies (Bio-Fax, 1971 and Bomhard, 1989) no mortality and no local changes were noted at a limit dose of 2000 mg/kg. The dermal LD50 is therefore greater than 2000 mg/kg and SA is not classified as hazardous via the dermal route.

No short-term systemic DNEL needs to be derived for cutaneous exposure.

 

Inhalation

In the only acute inhalation study (BioFax, 1971), SA was administered for 1 hour at a single nominal concentration of 0.9 mg/l to 6 rats as a dust. There was no mortality or signs of systemic toxicity. The LC50 is greater than 0.9 mg/l. The result suggests that salicylic acid would not be toxic 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. These studies support a conclusion of low potential for systemic toxicity by inhalation.

No short-term systemic DNEL needs to be derived for inhalation exposure.

 

2. Acute / short-term exposure - local effects

Irritation and corrosion

 

Skin irritation

In the key study (RCC, 2008) and a supporting study (Bio-fax, 1971) SA did not elicit any skin reactions. SA is not classified as a skin irritant.

No short-term local DNEL needs to be derived for cutaneous exposure.

 

Eye irritation

In the key study (Sugai, 1991) and a supporting study (Bio-fax, 1971) SA induced severe irritation not recovering within 21 days of treatment. SA is therefore considered to be a severe eye irritant.

No DNEL can be derived from this study because only one dose was tested.

A qualitative approach to risk assessment and management is required because SA is self-classified as a severe eye irritant.

 

Inhalation

 

The only acute inhalation study (BioFax, 1971) is not adequate to reliably derive a short-term DNEL for local effects. Although this study allow 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, over 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

A qualitative approach could be taking a three-fold factor over the inhalation long-term local DNEL (12.4 mg/m3): DNEL(acute inhalation local) = 37 mg/m3.

This concentration is not realistic, and far over the limit for inert dust of 5 mg/m3, so no DNEL has to be derived.

 

Sensitization

SA was tested as part of the evaluation of the Mouse Ear Swelling Test (MEST) (Gad et al, 1986) and was evaluated as being not sensitizing when tested at 10%, the maximum concentration soluble in the vehicle (acetone). SA was also tested in three studies evaluating the LLNA, at up to 25% concentration. Only one of the studies (Gerberick, 1992) reported SI >3 at 20%, concluding SA to be a weak to moderate sensitizer, while another (Basketter, 1998) showed no evidence of sensitization at 25% concentration. Overall, it is concluded that SA does not have significant sensitization potential.

 

Since SA is not classified as a skin sensitizer it is not relevant to derive a DNEL for this endpoint.

 

3. Long-term exposure - systemic effects

 

No repeated dose toxicity studies have been carried out on SA itself. DNELs for systemic effects have been derived based on read-across from other salicylates (see Introduction).

 

Cutaneous route

Since SA may be absorbed by the skin, it is relevant to derive a DNEL for SA for long term exposure by cutaneous route even though it is not classified as hazardous by cutaneous exposure.

No valid repeated dose dermal toxicity data are available for SA. The DNEL has been derived based on read-across from methyl salicylate (MeS) data. The only available dermal toxicity study on MeS was conducted at very high doses, was limited in design and in reporting detail and is not useful for risk assessment.

A route to route extrapolation has been carried out (oral-to-dermal) based on an oral long term study performed on MeS (Webb, 1965). MeS was administered to rats at dietary concentrations of 0, 0.1%, 0.5%, 1.0% or 2.0% (equivalent to 0, 50, 250, 500, and 1000 mg/kg bw/day) for two years. Body weight of both sexes were significantly decreased in both the 1.0% and 2.0% groups and an increased amount of cancellous bone was present in the metaphyses in rats treated at 1.0% or 2.0%, with minimal increase for one rat at 0.5%.

The NOAEL was 0.1% (50 mg/kg bw/day, equivalent to 45.4 mg/kg bw/day as SA). The LOAEL was 0.5% (250 mg/kg bw/day) for body weight gain reduction and bone lesions in rats.

 

Dose Descriptor:

NOAEL rat (oral) = 45.4 mg/kg bw/day

 

Modification of Dose Descriptor

Route-to-route:           Since SA is readily absorbed by both oral and dermal routes, no correction was required.

Dermal NAEL(corrected)= oral NOAEL x 1 =45.4 mg/kg bw/day.

 

Assessment factor (AF):

Interspecies factor (allometric scaling for metabolic rate)    4 (rat)

Interspecies factor (remaining differences)                           1 (NOAEL rat & dog similar)

Intraspecies factor (default value for worker variability)        5

Exposure duration:                                                                             1 (chronic study)

Dose-response:                                                                                 1 (NOAEL)

Overall assessment factor (OAF):                                     20

 

DNEL= NAEL(corrected)/OAF = 45.4 mg/kg / 20= 2.27 mg/kg/day

DNEL(long-term dermal systemic)=2 mg/kg/day

 

Inhalation

No repeated dose inhalation toxicity data are available for SA. DNEL derivation has been made using read-across from MeS data.

One subacute inhalation toxicity study on MeS at a single limit dose level (saturated vapour) and chronic oral studies in rats and dogs are available for risk assessment.

 

Assessment based on subacute inhalation study

Four rats were exposed to a saturated atmosphere (700 mg/m3, 635 as SA) of MeS for 7 hours per day, 5 days per week for 4 weeks. MeS did not cause any adverse effects (Gage, 1970).

 

Dose Descriptor:

NOEC rat = 635 mg/m3 (for sub-acute exposure).

 

Modification of Dose Descriptor

 

Conversion of an inhalatory rat NOAEC into a corrected inhalatory NAEC for workers:

 

NAECcorrected= NOAECinhalatory= 635 x 7h/8h× 6.7 m3/10 m3

NAECcorrected= 372 mg/m3

 

6.7 m3/person: respiratory volume without activity for general population;

10 m3/person: respiratory volume light activity for workers (8h exposure)

7h:time exposure of rats in Gage study

8h:time exposure of workers

 

Assessment factor (AF):

Interspecies factor (allometric scaling for metabolic rate)    1 (not applicable)

Interspecies factor (remaining differences)                           1 (NOAEL rat & dog similar)

Intraspecies factor (default value for worker variability)        5

Exposure duration:                                                                             6 (subacute to chronic study)

Dose-response:                                                                                 1 (NOAEL)

Overall assessment factor (OAF):                                     30

 

DNEL= NAEC(corrected)/OAF = 372 mg/m3 / 30= 12.4 mg/kg/day

DNEL(long-term inhalation systemic)=12.4 mg/m3

 

Assessment based on chronic dietary rat study

A route to route extrapolation has been carried out (oral-to-inhalation) based on an oral long term study performed on MeS (Webb, 1965). MeS was administered to rats at dietary concentrations of 0, 0.1%, 0.5%, 1.0% or 2.0% (equivalent to 0, 50, 250, 500, and 1000 mg/kg bw/day) for two years. Body weight of both sexes were significantly decreased in both the 1.0% and 2.0% groups and an increased amount of cancellous bone was present in the metaphyses in rats treated at 1.0% or 2.0%, with minimal increase for one rat at 0.5%.

The NOAEL was 0.1% (50 mg/kg bw/day, equivalent to 45.4 mg/kg bw/day as SA). The LOAEL was 0.5% (250 mg/kg bw/day) for body weight gain reduction and bone lesions in rats.

 

Dose Descriptor:

NOAEL rat (oral) = 45.4 mg/kg bw/day

 

Modification of Dose Descriptor

Route-to-route:           Since SA is readily absorbed by both oral and dermal routes, no correction was required.

Conversion of an oral rat NOAEL into a corrected inhalatory NAEC for workers:

NAECcorrected= NOAELoral45.4 x 70 kg / 10 m3

NAECcorrected= 317.8 mg/m3 

 

70 kg person

10 m3/person: respiratory volume light activity for workers (8h exposure)

 

Assessment factor (AF):

Interspecies factor (allometric scaling for metabolic rate)    4 (rat)

Interspecies factor (remaining differences)                           1 (NOAEL rat & dog similar)

Intraspecies factor (default value for worker variability)        5

Exposure duration:                                                                             1 (chronic study)

Dose-response:                                                                                 1 (NOAEL)

Overall assessment factor (OAF):                                     20

 

DNEL= NAEC(corrected)/OAF = 317.8 mg/m3 / 20= 15.89 mg/m3

DNEL(long-term inhalation systemic)=16 mg/m3

For practical considerations we propose to use the lower limit for inert dust of 5 mg/m3

 

Carcinogenicity

No study is available on SA. However, a read-across was made with MeS.

The chronic study (Webb, 1965) described above was selected as a key study. No carcinogenic effect was observed. By analogy with MeS, SA is not considered as carcinogenic.

 

Since SA is not considered as carcinogenic (by read-across with MeS), no DNEL or DMEL should be derived for this endpoint.

 

Reprotoxicity

According to the RAC Opinion (March 2016), salicylic acid is classified as a category 2 reproductive toxicant. The classification is based on adverse developmental effects in two animal species (rat and monkey).

In 2018, the SCCS published an updated opinion. Following review of the available toxicology data, the pivotal study (for deriving the point of departure (POD) as a toxicological benchmark for the safety evaluation of salicylic acid) remains the same in this dossier as was concluded by the SCCNFP in 2002, namely the developmental toxicity study on salicylic acid by Tanaka et al., 1973a. The POD is expressed as a no observed adverse effect level (NOAEL) of 75 mg/kg/day relating to the most sensitive toxic endpoint i.e. teratogenicity in the rat as the most sensitive species.

This NOAEL for teratogenicity in rat is not the most critical effect for systemic toxicity, as the NOAEL for systemic effects after long-term exposure is lower (i.e. chronic NOAEL = 45.4 mg/kg bw/d in rat based on lower body weight and cancellous bon effect). Thus no specific DNEL for teratogenicity is derived, as it is covered by the long-term exposure DNELs for systemic effects).

 

4. Long-term exposure - local effects

 

Cutaneous route

 

No data on repeated cutaneous exposure are available.

Since SA is not classified as irritating to the skin, no long-term local DNEL needs to be derived for cutaneous exposure.

 

Inhalation

 

No repeated dose inhalation studies are available for SA. Read-across from MeS is not appropriate for local effects on the respiratory system. The only study which can be considered for assessment is a low reliability acute toxicity study on SA (BioFax, 1971) in which SA was administered for 1 hour at a single nominal concentration of 0.9 mg/l to 6 rats as a dust. Clinical signs of irritation were restricted to salivation, nasal discharge, and lacrimation in one animal at 15 -30 minutes after exposure only.

 

As the long term systemic DNEL has been set to 5 mg/m3 and the short term effect being only nasal discharge, in 1 animal, as for inert dust, we propose to use the same DNEL as a local long term DNEL.

A toxicological TF within the GermanVCI discussed the derivation of DNEL for local irritating compound with a limited database. The experts developed upper boundary values for irritating and/or corrosive compounds based on available data. In particular the expert TF evaluated the German MAK-values published in the TRGS900 in 2009. For irritating compounds labelled with R36 or R38 but without relevant inhalation toxicity data available the TF developed a generic upper boundary value of 10 mg/m3, while for compounds with corrosive properties (R34 or R35) a respective value of 1 mg/m3 was developed.

SA is an eye irritant, labelled with R41. The expert TF did not indicate a threshold for compounds labelled with R41 but taking a conservative approach, the long-term DNEL for local effects is proposed as 5 mg/m3, close to corrosive substances. This value is alsol conservative compared to MAK values for such corrosive compounds as formic acid (MAK value: 9.5 mg/m3), HCl (3 mg/m3), Ammonium (14 mg/m3) Chlorine (1.5 mg/m3) or nitric acid (5.2 mg/m3) Concerning short term exposure we propose 10 mg/m3 as the upper boundary value of ASA in GESTIS.

 

Both the specific calculation based on the SA acute inhalation study and the conservative approach ofVCItherefore lead to the similar DNEL value:

 

DNEL(long-term inhalation local)= 5 mg/m3

 

Conclusion onDNEL(long-term inhalationfor Risk Assessment

 

Since local irritation of the respiratory system is considered the lead effect for risk assessment, the local DNEL value (5mg/m3) is to be taken in preference to the systemic DNEL (14 or 16 mg/m3). This is also the international GESTIS value for ASA with a short term value of 10 mg/m3.

Critical DNEL value for risk assessment:

DNEL(long-term inhalation local) =5 mg/m3


General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: Calculated from DNEL worker / 3
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
45.4 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification for route to route (high oral and dermal absorption).

AF for interspecies differences (allometric scaling):
4
Justification:
interspecies allometric scaling for rat
AF for intraspecies differences:
10
Justification:
intraspecies factor for general population
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
45.4 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEL
Value:
162 mg/kg bw/day

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Introduction

In this section, data from all end-points are examined and analyzed in order to determine for which it is relevant and possible to establish a DNEL value. The method followed is that proposed in the guidance for the implementation of REACH (Chapter R.8: Characterisation of dose (concentration)-response for human health, May 2008). But normally general population is not exposed to SA dust, which is an industrial or professional substance

CLP harmonised classification:

Salicylic acid is classified in CLP regulation (Index No. 607-732-00-5, ATP13):

- Category 4 H302 (harmful if swallowed)

- Category 1 H318 (irreversible effects on the eye)

- Category 2 H361 Suspected of damaging the unborn child

 

Where possible, derivation of DNELs for the relevant endpoints has been made using data on Salicylic Acid (SA) itself. Where no such reliable studies are available, data from other salicylates, principally methyl salicylate (MeS) but also acetylsalicylic acid (ASA) and sodium salicylate (NaS). Read-across from these salicylates for derivation of systemic DNELs is considered valid since all are readily absorbed and are rapidly hydrolysedin vivoto free salicylate (SA) as the initial step in metabolism. Full justification for read-across is given in the endpoint summary for toxicokinetics.

 

1. Acute / short-term exposure - systemic effects

Cutaneous route

In the key studies (Bio-Fax, 1971 and Bomhard, 1989) no mortality and no local changes were noted at a limit dose of 2000 mg/kg. The dermal LD50 is therefore greater than 2000 mg/kg and SA is not classified as hazardous via the dermal route.

No short-term systemic DNEL needs to be derived for cutaneous exposure.

 

Inhalation

General population exposure to SA as a dust is not anticipated, therefore the acute inhalation study on SA (BioFax, 1971) is not relevant. 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. This study supports a conclusion of low potential for systemic toxicity by inhalation.

No short-term systemic DNEL needs to be derived for inhalation exposure.

 

Oral route

SA is classified as harmful if swallowed. Acute oral exposure is not anticipated, but a systemic DNEL can be calculated based on a set of subchronic (6-12-week) oral studies on MeS (Abbott & Harrison, 1978). MeS was administered to rats at dietary concentrations of 0.2%, 0.36%, 0.63%, 1.13%, or 2.0% (equivalent to 90, 162, 288, 504 and 900 mg/kg/day ) MeS. Bone lesions and growth retardation were observed in rats fed MeS at 1% and 2% in diet.

The NOAEL was 0.36% (162mg/kg bw/day as SA).

 

Dose Descriptor:

NOAEL rat (oral) = 162 mg/kg bw/day

 

Modification of Dose Descriptor

No modification of dose descriptor is required.

Oral NAEL(corrected)= oral NOAEL x 1 =162 mg/kg bw/day.

 

Assessment factor (AF):

Interspecies factor (allometric scaling for metabolic rate)    4 (rat)

Interspecies factor (remaining differences)                           1 (NOAEL rat & dog similar)

Intraspecies factor (default value for general population variability)  10

Exposure duration:                                                                             1 (subchronic study used for acute)

Dose-response:                                                                                            1 (NOAEL)

Overall assessment factor (OAF):                                     40

 

DNEL= NAEL(corrected)/OAF = 162 mg/kg / 40= 4.05 mg/kg/day

DNEL(acute oral systemic)= 4 mg/kg/day

 

2. Acute / short-term exposure - local effects

Irritation and corrosion

 

Skin irritation

In the key study (RCC, 2008) and a supporting study (Bio-fax, 1971) SA did not elicit any skin reactions. SA is not classified as a skin irritant.

No short-term local DNEL needs to be derived for cutaneous exposure.

 

Eye irritation

In the key study (Sugai, 1991) and a supporting study (Bio-fax, 1971) SA induced severe irritation not recovering within 21 days of treatment. SA is therefore considered to be a severe eye irritant. However, general population exposure to SA as a dust or as a high concentration solution is not anticipated

No short-term local DNEL needs to be derived for ocular exposure.

 

Inhalation

General population exposure to SA as a dust or in aerosol form is not anticipated.

No short-term local DNEL needs to be derived for inhalation exposure.

 

Sensitization

SA was tested as part of the evaluation of the Mouse Ear Swelling Test (MEST) (Gad et al, 1986) and was evaluated as being not sensitizing when tested at 10%, the maximum concentration soluble in the vehicle (acetone). SA was also tested in three studies evaluating the LLNA, at up to 25% concentration. Only one of the studies (Gerberick, 1992) reported SI >3 at 20%, concluding SA to be a weak to moderate sensitizer, while another (Basketter, 1998) showed no evidence of sensitization at 25% concentration. Overall, it is concluded that SA does not have significant sensitization potential.

 

Since SA is not classified as a skin sensitizer it is not relevant to derive a DNEL for this endpoint.

 

3. Long-term exposure - systemic effects

 

No repeated dose toxicity studies have been carried out on SA itself. DNELs for systemic effects have been derived based on read-across from other salicylates (see Introduction).

 

Cutaneous route

Since SA may be absorbed by the skin, it is relevant to derive a DNEL for SA for long term exposure by cutaneous route even though it is not classified as hazardous by cutaneous exposure.

No valid repeated dose dermal toxicity data are available for SA. The DNEL has been derived based on read-across from methyl salicylate (MeS) data. The only available dermal toxicity study on MeS was conducted at very high doses, was limited in design and in reporting detail and is not useful for risk assessment.

A route to route extrapolation has been carried out (oral-to-dermal) based on an oral long term study performed on MeS (Webb, 1965). MeS was administered to rats at dietary concentrations of 0, 0.1%, 0.5%, 1.0% or 2.0% (equivalent to 0, 50, 250, 500, and 1000 mg/kg bw/day) for two years. Body weight of both sexes were significantly decreased in both the 1.0% and 2.0% groups and an increased amount of cancellous bone was present in the metaphyses in rats treated at 1.0% or 2.0%, with minimal increase for one rat at 0.5%.

The NOAEL was 0.1% (50 mg/kg bw/day, equivalent to 45.4 mg/kg bw/day as SA). The LOAEL was 0.5% (250 mg/kg bw/day) for body weight gain reduction and bone lesions in rats.

 

Dose Descriptor:

NOAEL rat (oral) = 45.4 mg/kg bw/day

 

Modification of Dose Descriptor

Route-to-route:           Since SA is readily absorbed by both oral and dermal routes, no correction was required.

Dermal NAEL(corrected)= oral NOAEL x 1 =45.4 mg/kg bw/day.

 

Assessment factor (AF):

Interspecies factor (allometric scaling for metabolic rate)    4 (rat)

Interspecies factor (remaining differences)                           1 (NOAEL rat & dog similar)

Intraspecies factor (default value for general population variability)  10

Exposure duration:                                                                             1 (chronic study)

Dose-response:                                                                                           1 (NOAEL)

Overall assessment factor (OAF):                                     40

 

DNEL= NAEL(corrected)/OAF = 45.4 mg/kg / 40= 1.135 mg/kg/day

DNEL(long-term dermal systemic)= 1 mg/kg/day

 

Inhalation

No exposure to dust so no need to derive a DNEL

 

Oral route

SA is classified as harmful if swallowed and used only in the public domain where oral exposure could occur as a result of some uses. It is therefore relevant to derive a DNEL for long term exposure by the oral route.

DNEL calculation is based on an oral long term study on MeS (Webb, 1965). MeS was administered to rats at dietary concentrations of 0, 0.1%, 0.5%, 1.0% or 2.0% (equivalent to 0, 50, 250, 500, and 1000 mg/kg bw/day) for two years. Body weight of both sexes were significantly decreased in both the 1.0% and 2.0% groups and an increased amount of cancellous bone was present in the metaphyses in rats treated at 1.0% or 2.0%, with minimal increase for one rat at 0.5%.

The NOAEL was 0.1% (45.4mg/kg bw/day as SA).

 

Dose Descriptor:

NOAEL rat (oral) = 45.4 mg/kg bw/day

 

Modification of Dose Descriptor

No modification of dose descriptor is required.

Oral NAEL(corrected)= oral NOAEL x 1 =45.4 mg/kg bw/day.

 

Assessment factor (AF):

Interspecies factor (allometric scaling for metabolic rate)    4 (rat)

Interspecies factor (remaining differences)                           1 (NOAEL rat & dog similar)

Intraspecies factor (default value for general population variability)  10

Exposure duration:                                                                             1 (chronic study)

Dose-response:                                                                                            1 (NOAEL)

Overall assessment factor (OAF):                                     40

 

DNEL= NAEL(corrected)/OAF = 45.4 mg/kg / 40= 1.135 mg/kg/day

DNEL(long-term oral systemic)= 1 mg/kg/day

This is below the permissible daily exposure (PDE) dose through ASA medication

 

Carcinogenicity

No study is available on SA. However, a read-across was made with MeS.

The chronic study (Webb, 1965) described above was selected as a key study. No carcinogenic effect was observed. By analogy with MeS, SA is not considered as carcinogenic.

 

Since SA is not considered as carcinogenic (by read-across with MeS), no DNEL or DMEL should be derived for this endpoint.

 

Reprotoxicity

According to the RAC Opinion (March 2016), salicylic acid is classified as a category 2 reproductive toxicant. The classification is based on adverse developmental effects in two animal species (rat and monkey).

In 2018, the SCCS published an updated opinion. Following review of the available toxicology data, the pivotal study (for deriving the point of departure (POD) as a toxicological benchmark for the safety evaluation of salicylic acid) remains the same in this dossier as was concluded by the SCCNFP in 2002, namely the developmental toxicity study on salicylic acid by Tanaka et al., 1973a. The POD is expressed as a no observed adverse effect level (NOAEL) of 75 mg/kg/day relating to the most sensitive toxic endpoint i.e. teratogenicity in the rat as the most sensitive species.

This NOAEL for teratogenicity in rat is not the most critical effect for systemic toxicity, as the NOAEL for systemic effects after long-term exposure is lower (i.e. chronic NOAEL = 45.4 mg/kg bw/d in rat based on lower body weight and cancellous bon effect). Thus no specific DNEL for teratogenicity is derived, as it is covered by the long-term exposure DNELs for systemic effects).

 

4. Long-term exposure - local effects

 

Cutaneous route

 

No data on repeated cutaneous exposure are available.

Since SA is not classified as irritating to the skin, no long-term local DNEL needs to be derived for cutaneous exposure.

 

Inhalation

 

General population exposure to SA as a dust is not anticipated. Some uses imply aerosol formation. The DNEL used is the worker one divided by 3

DNEL long term local : 4 mg/m3