α-d-Glucopyranoside, β-d-fructofuranosyl, benzoate

Endpoint summary

Description of key information

Read-across from data on benzoic acid:

Repeated oral rat study by Kieckebusch and Lang (1960)

Subactute inhalation rat study by Rop (1981)

Subacute dermal rabbit study (OECD 2001)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

No data on Sucrose benzoate exists. Therefore read-across from data on benzoic acid is used to approach the present endpoint. For inducing systemic effects from repeated exposure the substance has to be absorbed in order to reach the inner organs. Therefore, read-across from data on benzoic acid is considered especially relevant as exposure to sucrose benzoate would not lead to systemic exposure to sucrose benzoate but benzoic acid and sucrose (see toxicokinetic section). See also attached read-across justification to section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

mortality

Key result

Critical effects observed:

no

Conclusions:

No data exists for sucrose benzoate. Therefore data on benzoic acid is used. Based on multi generational studies EFSA concluded on a the NOAEL for benzoic acid to 500 mg/kg /day. Read-across from data on benzoic acid is considered especially relevant as exposure to sucrose benzoate would not lead to systemic exposure to sucrose benzoate but benzoic acid and sucrose (see toxicokinetic section). Thus, the use of an oral NOAEL of 500 mg/kg bw/d for sucrose benzoate for subchronic exposure is to be considered as a conservative approach.

Executive summary:

There is no data on sucrose benzoate. Therefore data on benzoic acid is used. For benzoic acid/ benzoate a large number of subacute and subchronic oral toxicity studies have been performed in various mammalian species, although in general they do not meet current standards with regard to study design and reporting. EFSA (2016) set a NOAEL for benzoic acid to 500 mg/kg /day based on the study by Kieckebusch and Lang (1960).

For inducing systemic effects from repeated exposure the substance has to be absorbed in order to reach the inner organs. Therefore, read-across to data on benzoic acid is considered especially relevant as exposure to sucrose benzoate would not lead to systemic exposure to sucrose benzoate but benzoic acid and sucrose (see toxicokinetic section). Thus, the use of an oral NOAEL of 500 mg/kg bw/d for sucrose benzoate for subchronic exposure is to be considered as a conservative approach, since the oral absorption of sucrose benzoate is considered lower than for benzoic acid, because full hydrolysis of sucrose benzoate has to occur in the gastrointestinal tract before absorption of benzoic acid/benzoate can take place. 

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1960

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

The study, Kieckebusch et al. 1960, is referenced in RAC opinion (2012)

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study, Kieckebusch et al. 1960, is referenced in RAC opinion (2012)

GLP compliance:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Route of administration:

oral: feed

Details on oral exposure:

Not available

Duration of treatment / exposure:

3. generations

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

250 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

mortality

Key result

Critical effects observed:

no

In summary, it may be concluded that a dose of 500 mg/kg bw/d, as identified as

safe in rodents for subchronic exposure, neither affected survival nor produced clinical

signs of benzoic acid poisoning when exposure time was extended. However, it was indicated in the RAC-background document that the

available chronic toxicity data is not suitable to establish a NOAEL for target organ (liver, kidneys, brain) toxicity.

Conclusions:

The NOAEL of benzoic acid in the study was 500 mg/kg/day

Executive summary:

Repeated dose exposure to benzoic acid was investigated in male and female rats. The rats were exposed during 16 weeks to 0, 250 or 500 mg/kg/day benzoic acid through feeding. Gross and histopathology was performed after subchronic exposure and body weight was reported for an initial 12/8 wks (M/F) only. The top dose of 10,000 ppm, corresponding to approx. 500 mg/kg bw/d, neither reduced lifetime survival nor produced overt clinical symptoms of benzoic acid poisoning.

Reference 3

Endpoint:

sub-chronic toxicity: oral

Type of information:

other: Expert opinion

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

The assessment was considered to be valid by the EFSA Panel,

Dose descriptor:

NOAEL

Effect level:

ca. 500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

mortality

Key result

Critical effects observed:

no

Conclusions:

Based on a four generation study in rats, EFSA set a NOAEL for both the parental animals and the offspring, of 500 mg benzoic acid/kg bw per day, which was the highest dose tested.

Executive summary:

The toxicity of oral exposure to benzoic acid was evaluated by EFSA (2016). EFSA also refered to the multi-generation toxicity study on benzoic acid by Kieckebusch and Land (1960) which also included limited investigations into the chronic toxicity of benzoic acid. The study was performed on three groups of male and female rats, which were pair fed for 8 weeks on a standard rat diet, prepared as a feed mix with either 0, 0.5 or 1% benzoic acid (Kieckebusch and Lang, 1960). The rats were fed ad libitum over four generations resulting in an approximate intake of benzoic acid of 0, 250 or 500 mg/kg bw per day. Two generations were fed for their whole lifespan, the third and fourth generations were autopsied after 16 weeks. No treatment-related effects were observed on growth, fertility, lactation throughout all four generations and lifespan (for the first two generations). On the contrary, ad libitum ingestion of the 0.5% benzoic acid feed mix resulted in a significantly longer lifespan in the first and second generation of the rats, based on statistical analysis of the two generations combined. In the third generation, autopsied at 16 weeks, no treatment-related effects were reported on organ weights and histopathological findings in organs.

The assessment of reproductive parameters was considered to be valid by the EFSA Panel, and provided a NOAEL, for both the parental animals and the offspring over four generations, of 500 mg benzoic acid/kg bw per day, the highest dose tested.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

old data 1960 and no guideline followed, however, by EFSA (2016) considered acceptable for NOAEL setting for benzoic acid

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

repeated dose toxicity: inhalation, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Justification for type of information:

The study described in this section is a key study in the RAC (2012) opinion on benzoic acid with the reference Rop, D. A., IRDC Report no: 163-676 (1981)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

no

Remarks:

Study was performed before 1. of June 2008

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation: dust

Type of inhalation exposure:

not specified

Vehicle:

other: no vehicle, exposure to particles of the substance

Mass median aerodynamic diameter (MMAD):

4.7 µm

Details on inhalation exposure:

5 d/wk, 6 h/d for 4 weeks

Dose / conc.:

0 mg/L air

Remarks:

Controls

Dose / conc.:

0.025 mg/L air

Dose / conc.:

0.25 mg/L air

Dose / conc.:

1.2 mg/L air

No. of animals per sex per dose:

10

Observations and examinations performed and frequency:

Evaluation of survival, body weight and organ weight and microscopic examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Evaluation of survival, body weight and organ weight demonstrated significant systemic toxicity including 2/20 mortalities at the top dose of 1.2 mg/L. A reddish discharge around the nares was observed at doses ≥ 0.25 mg/L.

Mortality:

mortality observed, treatment-related

Description (incidence):

2/20 mortalities at the top dose of 1.2 mg/L.

Body weight and weight changes:

effects observed, treatment-related

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Decrease in platelet count

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

decrease in liver and kidney weight

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Interstitial inflammation, lung fibrosis at all doses

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Compound-related microscopic lesions consisting of multifocal to generalised inflammatory cell infiltrates and interstitial fibrosis of the lung were observed. This was reported for all groups of benzoic acid treated animals with a concentration-dependent increase in intensity and incidence.

Key result

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

0.25 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

mortality

Key result

Dose descriptor:

LOAEL

Remarks:

systemic

Effect level:

1.2 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

mortality

Key result

Dose descriptor:

LOAEL

Remarks:

Local (pulmonary)

Effect level:

0.025 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

0.025 mg/L air

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

Inhalation toxicity of benzoic acid was evaluated in rats using fine benzoic acid dust with a mean aerodynamic particle diameter of 4.7 μm (Rop, 1981). Based on these results the RAC opinion concluded on a NOAEL and a LOAEL for systemic toxicity of 0.25 mg/L and 1.2 mg/L, respectively, and a LOAEL of 0.025 mg/L for local pulmonary toxicity.

Executive summary:

Inhalation toxicity of benzoic acid was evaluated in rats using fine benzoic acid dust with a mean aerodynamic particle diameter of 4.7 μm (Rop, 1981). Evaluation of survival, body weight and organ weight demonstrated significant systemic toxicity including 2/20 mortalities at the top dose of 1.2 mg/L. A reddish discharge around the nares was observed at doses ≥ 0.25 mg/L. In addition to systemic toxicity, compoundrelated microscopic lesions consisting of multifocal to generalised inflammatory cell infiltrates and interstitial fibrosis of the lung were observed. This was reported for all groups of benzoic acid treated animals with a concentration-dependent increase in intensity and incidence. The systemic effects observed at higher concentrations differed from those observed after oral exposure at higher concentrations (organ weight decrease, platelet decrease) and are thought to be secondary to local lung toxicity. Because the toxic effects observed in this study are attributed to the physico-chemical properties of these fine low-solubility particles, the study is not considered relevant for the evaluation of human health effects after repeated exposure to fluid benzoic acid formulations used in biocidal applications.

Based on these results the RAC opinion concluded on a NOAEL and a LOAEL for systemic toxicity of 0.25 mg/L and 1.2 mg/L, respectively, and a LOAEL of 0.025 mg/L for pulmonary toxicity.

Reference 2

Endpoint:

repeated dose toxicity: inhalation, other

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

No data exists on the repeated dose toxicity after inhalational exposure to sucrose benzoate. Therefore the conclusion is based on read-across from data on benzoic acid. As sucrose benzoate has a very low water solubility (3 mg/L) exposure to fine particles in the respirable size range may result in accumulation of particles in the lungs which may have a potential for particle related local effects and an inflammatory response. In addition to this slow hydrolysis of deposited sucrosebenzoate in lung tissue may liberate benzoic acid/benzoate with a potential for local tissue irritation and cytotoxic response. However, as no dose-response can be established a classification as STOT RE2 (H372; lungs, inhalation) is considered as the most appropriate classification for sucrose benzoate.

For more details please refer to the reas across justification attached in section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

Systemic

Effect level:

0.25 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

mortality

Key result

Dose descriptor:

LOAEL

Remarks:

Systemic

Effect level:

1.2 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

Key result

Dose descriptor:

LOAEL

Remarks:

Local (pulmonary)

Effect level:

0.025 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

0.025 mg/L air

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

No data exists on the repeated dose toxicity after inhalational exposure to sucrose benzoate. Therefore the conclusion is based on read across to benzoic acid. Inhalation toxicity of benzoic acid was evaluated in rats using fine benzoic acid dust with a mean aerodynamic particle diameter of 4.7 μm (Rop, 1981). Based on these results the RAC opinion concluded on a NOAEL and a LOAEL for systemic toxicity of 0.25 mg/L and 1.2 mg/L, repsectively, and a LOAEL of 0.025 mg/L for pulmonary toxicity. As sucrose benzoate has a very low water solubility (3 mg/L), exposure to fine particles in the respirable size range may result in accumulation of particles in the lungs which may have a potential for particle related local effects and an inflammatory response. In addition to this slow hydrolysis of deposited sucrosebenzoate in lung tissue may liberate benzoic acid/benzoate with a potential for local tissue irritation and cytotoxic response. However, as no dose-response can be established a classification as STOT RE2 (H372; lungs, inhalation) is considered as the most appropriate classification for sucrose benzoate.

Executive summary:

No data exists on the repeated dose toxicity after inhalational exposure to sucrose benzoate. Therefore the conclusion is based on read across to benzoic acid.

Inhalation toxicity of benzoic acid was evaluated in a rat study using exposure to fine benzoic acid dust with a mean aerodynamic particle diameter of 4.7 μm. Evaluation of survival, body weight and organ weight demonstrated significant systemic toxicity including 2/20 mortalities at the top dose of 1.2 mg/L. A reddish discharge around the nares was observed at doses ≥ 0.25 mg/L. The systemic effects observed at higher concentrations differed from those observed after oral exposure at higher concentrations (organ weight decrease, platelet decrease) and were thought to be secondary to local lung toxicity. In the lungs compound related microscopic lesions consisting of multifocal to generalised inflammatory cell infiltrates and interstitial fibrosis of the lung were observed. This was reported for all groups of benzoic acid treated animals with a concentration-dependent increase in intensity and incidence. The NOAEL and LOAEL for systemic toxicity was 0.25 mg/L and 1.2 mg/L, respectively, and the LOAEL was 0.025 mg/L for local pulmonary toxicity. Based on this study ECHA/RAC (2012) concluded to classify benzoic acid as STOT RE 1; (H372; lungs, inhalation) in relation to particle exposure (not considered relevant for aerosols with dissolved benzoic acid).

As sucrosebenzoate has a very low water solubility exposure to fine particles in the respirable size range may result in accumulation of particles in the lungs which may have a potential for particle related local effects and an inflammatory response. In addition to this slow hydrolysis of deposited sucrosebenzoate in lung tissue may liberate benzoic acid/benzoate with a potential for local tissue irritation and cytotoxic response. However, as no dose-response can be established a classification as STOT RE2 (H372; lungs, inhalation) is considered as the most appropriate classification for sucrose benzoate.

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

250 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

reliability score 2. Used by RAC for classification of benzoic acid

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Reference 1

Endpoint:

repeated dose toxicity: inhalation, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Justification for type of information:

The study described in this section is a key study in the RAC (2012) opinion on benzoic acid with the reference Rop, D. A., IRDC Report no: 163-676 (1981)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

no

Remarks:

Study was performed before 1. of June 2008

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation: dust

Type of inhalation exposure:

not specified

Vehicle:

other: no vehicle, exposure to particles of the substance

Mass median aerodynamic diameter (MMAD):

4.7 µm

Details on inhalation exposure:

5 d/wk, 6 h/d for 4 weeks

Dose / conc.:

0 mg/L air

Remarks:

Controls

Dose / conc.:

0.025 mg/L air

Dose / conc.:

0.25 mg/L air

Dose / conc.:

1.2 mg/L air

No. of animals per sex per dose:

10

Observations and examinations performed and frequency:

Evaluation of survival, body weight and organ weight and microscopic examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Evaluation of survival, body weight and organ weight demonstrated significant systemic toxicity including 2/20 mortalities at the top dose of 1.2 mg/L. A reddish discharge around the nares was observed at doses ≥ 0.25 mg/L.

Mortality:

mortality observed, treatment-related

Description (incidence):

2/20 mortalities at the top dose of 1.2 mg/L.

Body weight and weight changes:

effects observed, treatment-related

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Decrease in platelet count

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

decrease in liver and kidney weight

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Interstitial inflammation, lung fibrosis at all doses

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Compound-related microscopic lesions consisting of multifocal to generalised inflammatory cell infiltrates and interstitial fibrosis of the lung were observed. This was reported for all groups of benzoic acid treated animals with a concentration-dependent increase in intensity and incidence.

Key result

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

0.25 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

mortality

Key result

Dose descriptor:

LOAEL

Remarks:

systemic

Effect level:

1.2 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

mortality

Key result

Dose descriptor:

LOAEL

Remarks:

Local (pulmonary)

Effect level:

0.025 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

0.025 mg/L air

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

Inhalation toxicity of benzoic acid was evaluated in rats using fine benzoic acid dust with a mean aerodynamic particle diameter of 4.7 μm (Rop, 1981). Based on these results the RAC opinion concluded on a NOAEL and a LOAEL for systemic toxicity of 0.25 mg/L and 1.2 mg/L, respectively, and a LOAEL of 0.025 mg/L for local pulmonary toxicity.

Executive summary:

Inhalation toxicity of benzoic acid was evaluated in rats using fine benzoic acid dust with a mean aerodynamic particle diameter of 4.7 μm (Rop, 1981). Evaluation of survival, body weight and organ weight demonstrated significant systemic toxicity including 2/20 mortalities at the top dose of 1.2 mg/L. A reddish discharge around the nares was observed at doses ≥ 0.25 mg/L. In addition to systemic toxicity, compoundrelated microscopic lesions consisting of multifocal to generalised inflammatory cell infiltrates and interstitial fibrosis of the lung were observed. This was reported for all groups of benzoic acid treated animals with a concentration-dependent increase in intensity and incidence. The systemic effects observed at higher concentrations differed from those observed after oral exposure at higher concentrations (organ weight decrease, platelet decrease) and are thought to be secondary to local lung toxicity. Because the toxic effects observed in this study are attributed to the physico-chemical properties of these fine low-solubility particles, the study is not considered relevant for the evaluation of human health effects after repeated exposure to fluid benzoic acid formulations used in biocidal applications.

Based on these results the RAC opinion concluded on a NOAEL and a LOAEL for systemic toxicity of 0.25 mg/L and 1.2 mg/L, respectively, and a LOAEL of 0.025 mg/L for pulmonary toxicity.

Reference 2

Endpoint:

repeated dose toxicity: inhalation, other

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

No data exists on the repeated dose toxicity after inhalational exposure to sucrose benzoate. Therefore the conclusion is based on read-across from data on benzoic acid. As sucrose benzoate has a very low water solubility (3 mg/L) exposure to fine particles in the respirable size range may result in accumulation of particles in the lungs which may have a potential for particle related local effects and an inflammatory response. In addition to this slow hydrolysis of deposited sucrosebenzoate in lung tissue may liberate benzoic acid/benzoate with a potential for local tissue irritation and cytotoxic response. However, as no dose-response can be established a classification as STOT RE2 (H372; lungs, inhalation) is considered as the most appropriate classification for sucrose benzoate.

For more details please refer to the reas across justification attached in section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

Systemic

Effect level:

0.25 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

mortality

Key result

Dose descriptor:

LOAEL

Remarks:

Systemic

Effect level:

1.2 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

Key result

Dose descriptor:

LOAEL

Remarks:

Local (pulmonary)

Effect level:

0.025 mg/L air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

0.025 mg/L air

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

No data exists on the repeated dose toxicity after inhalational exposure to sucrose benzoate. Therefore the conclusion is based on read across to benzoic acid. Inhalation toxicity of benzoic acid was evaluated in rats using fine benzoic acid dust with a mean aerodynamic particle diameter of 4.7 μm (Rop, 1981). Based on these results the RAC opinion concluded on a NOAEL and a LOAEL for systemic toxicity of 0.25 mg/L and 1.2 mg/L, repsectively, and a LOAEL of 0.025 mg/L for pulmonary toxicity. As sucrose benzoate has a very low water solubility (3 mg/L), exposure to fine particles in the respirable size range may result in accumulation of particles in the lungs which may have a potential for particle related local effects and an inflammatory response. In addition to this slow hydrolysis of deposited sucrosebenzoate in lung tissue may liberate benzoic acid/benzoate with a potential for local tissue irritation and cytotoxic response. However, as no dose-response can be established a classification as STOT RE2 (H372; lungs, inhalation) is considered as the most appropriate classification for sucrose benzoate.

Executive summary:

No data exists on the repeated dose toxicity after inhalational exposure to sucrose benzoate. Therefore the conclusion is based on read across to benzoic acid.

Inhalation toxicity of benzoic acid was evaluated in a rat study using exposure to fine benzoic acid dust with a mean aerodynamic particle diameter of 4.7 μm. Evaluation of survival, body weight and organ weight demonstrated significant systemic toxicity including 2/20 mortalities at the top dose of 1.2 mg/L. A reddish discharge around the nares was observed at doses ≥ 0.25 mg/L. The systemic effects observed at higher concentrations differed from those observed after oral exposure at higher concentrations (organ weight decrease, platelet decrease) and were thought to be secondary to local lung toxicity. In the lungs compound related microscopic lesions consisting of multifocal to generalised inflammatory cell infiltrates and interstitial fibrosis of the lung were observed. This was reported for all groups of benzoic acid treated animals with a concentration-dependent increase in intensity and incidence. The NOAEL and LOAEL for systemic toxicity was 0.25 mg/L and 1.2 mg/L, respectively, and the LOAEL was 0.025 mg/L for local pulmonary toxicity. Based on this study ECHA/RAC (2012) concluded to classify benzoic acid as STOT RE 1; (H372; lungs, inhalation) in relation to particle exposure (not considered relevant for aerosols with dissolved benzoic acid).

As sucrosebenzoate has a very low water solubility exposure to fine particles in the respirable size range may result in accumulation of particles in the lungs which may have a potential for particle related local effects and an inflammatory response. In addition to this slow hydrolysis of deposited sucrosebenzoate in lung tissue may liberate benzoic acid/benzoate with a potential for local tissue irritation and cytotoxic response. However, as no dose-response can be established a classification as STOT RE2 (H372; lungs, inhalation) is considered as the most appropriate classification for sucrose benzoate.

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

25 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

reliability score 2, used by RAC (2012) for classification of benzoic acid

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

repeated dose toxicity: dermal, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

The study is flagged as a critical study for SIDS endpoint in report on benzoates. Bibliographic source of article: Matthews E. J., Environm. Health Perspec. 101 [Suppl 2], 347-482 (1994)

Qualifier:

equivalent or similar to guideline

Guideline:

other: Not specified

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Type of coverage:

open

Vehicle:

not specified

Details on exposure:

Four male and four female rabbits were used in each treatment group and in the control group. The skin of one-half of the animals was abraded and the others left intact. Benzoic acid was applied 5 days a week for 3 weeks at dosage levels of 100, 500, 2500 mg/kg bw.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

21 days

Frequency of treatment:

Benzoic acid was applied 5 days a week for 3 weeks

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Controls

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

2 500 mg/kg bw/day (nominal)

No. of animals per sex per dose:

4

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

The rabbits were observed daily for signs of dermal irritation and changes in general behavior and appearance. Individual body weights were recorded weekly. Hematologic and biochemical studies were conducted once in the
pretest period and again at 21 days of the study. Gross and histopathology was performed on liver, kidneys, thyroid/parathyroid, heart, lung, ovaries, testes, adrenals as well as most gastrointestinal tract and neurological organs.

Sacrifice and pathology:

Gross and histopathology was performed on liver, kidneys, thyroid/parathyroid, heart, lung, ovaries, testes, adrenals as well as most gastrointestinal tract and neurological organs.

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Very slight dermal irritation was noted for one rabbit at the 2500 mg/kg dosage level.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Details on results:

Very slight dermal irritation was noted for one rabbit at the 2500 mg/kg dosage level. No compound-related effects were seen in general behavior and appearance, body weight, clinical laboratory tests, organ weights, or survival.

Key result

Dose descriptor:

NOAEL

Effect level:

2 500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

dermal irritation

Key result

Critical effects observed:

no

Conclusions:

The repeated dose toxicity of dermal exposure to benzoic acid was determined in New Zealand white rabbits in a 21 day study. No compound-related effects were seen in general behavior and appearance, body weight, clinical laboratory tests, organ weights, or survival. The NOAEL was set to 2500 mg/kg/day.

Executive summary:

The repeated dose toxicity of dermal exposure to benzoic acid was determined in New Zealand white rabbits. Four male and four female rabbits were used in each treatment group and in the control group. The skin of one-half of the animals was abraded and the others left intact. Benzoic acid was applied 5 days a week for 3 weeks at dosage levels of 100, 500, 2500 mg/kg bw. The rabbits were observed daily for signs of dermal irritation and changes in general behavior and appearance. Individual body weights were recorded weekly. Hematologic and biochemical studies were conducted once in the pretest period and again at 21 days of the study. Gross and histopathology was performed on liver, kidneys, thyroid/parathyroid, heart, lung, ovaries, testes, adrenals as well as most gastrointestinal tract and neurological organs. Result: Very slight dermal irritation was noted for one rabbit at the 2500 mg/kg dosage level. No compound-related effects were seen in general behavior and appearance, body weight, clinical laboratory tests, organ weights, or survival. The NOAEL was set to 2500 mg/kg/day.