Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Original tests performed according to an international guideline under GLP.
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH:
Studies performed with various alkyl lactate, which can be considered as a valid analogues of C12-15 alkyl lactates.

2. SOURCE AND TARGET CHEMICAL(S):
ethyl lactate, n-butyl lactate, isobutyl lactate, and 2-ethylhexyl lactate

3. ANALOGUE APPROACH JUSTIFICATION
Effects observed were restricted to local effects in the respiratory tract, which comply with the potential for irritation of respiratory tract due to eventual exposure to the UVCB under registration.
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
inhalation
Type of inhalation exposure:
nose only
Details on inhalation exposure:
Ethyl, n-butyl, and isobutyl-L-lactates were vapor studies, whereas 2-ethylhexyl-L-lactate was evaluated in an aerosol study and in a supplemental study comparing vapor and aerosol exposure.
Duration of treatment / exposure:
6 h
Frequency of treatment:
5 days a week
Remarks:
Doses / Concentrations:
ethyl-L-lactate: 0, 150, 600, or 2500 mg/m3 and 0, 25, 75, or 200 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
isobutyl-L-lactate: 0, 100, 200, 400, or 800 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
n- butyl- L-lactate: 0, 75, 200, or 600 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
2-ethylhexyl-L-lactate: 0, 75, 200, 600, or 1800 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
ethyl, isobutyl, and the primary 2-ethylhexyl studies: 5 males and 5 females;
n-butyl and the supplemental 2-ethylhexyl study: 6 males
Clinical signs:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Main histopathological changes were observed in the nasal cavity (epithelial degeneration, hyperplasia, metaplasia, and inflammatory changes) larynx and trachea (slight epithelial hyperplasia and squamous metaplasia), and lungs (septal fibrosis).
Details on results:
2-Ethylhexyl-L-lactate appeared to be the most reactive in causing irritation of the nasal airways. In general, the local toxicity NOECs of alkyl lactate are lower than the systemic NOECs. This is probably mainly related to the activity of free lactic acid generated by enzymatic hydrolysis of the alkyl lactates.
Dose descriptor:
NOAEC
Effect level:
200 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
ethyl, n-butyl, and isobutyl lactates
Sex:
male/female
Basis for effect level:
other: Local effects: hyperplasia of the nasal respiratory epithelium, including hyperplasia of goblet cells.
Key result
Dose descriptor:
NOAEC
Effect level:
600 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
butyl- L-lactate
Sex:
male
Basis for effect level:
other: Systemic toxicity
Key result
Dose descriptor:
NOAEC
Effect level:
200 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
butyl- L-lactate
Sex:
male
Basis for effect level:
other: Local effects
Dose descriptor:
NOAEC
Effect level:
800 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
isobutyl-L-lactate
Sex:
male/female
Basis for effect level:
other: Systemic toxicity
Dose descriptor:
NOAEC
Effect level:
200 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
isobutyl-L-lactate
Sex:
male/female
Basis for effect level:
other: Local effects
Dose descriptor:
NOAEC
Effect level:
600 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
2-ethylhexyl-L-lactate
Sex:
male/female
Basis for effect level:
other: Systemic toxicity
Dose descriptor:
NOAEC
Based on:
test mat.
Remarks:
2-ethylhexyl-L-lactate
Sex:
male/female
Basis for effect level:
other: Local effects (nasal epithelium)
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Dose descriptor:
LOAEC
Effect level:
75 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
2-ethylhexyl-L-lactate (aerosol or vapor)
Sex:
male/female
Basis for effect level:
other: Local effects: slight focal hyperplasia of the nasal respiratory epithelium, including hyperplasia of goblet cells.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
600 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Based on tests with shorter chain alkyl lactates.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Original tests performed according to an international guideline under GLP.
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH:
Studies performed with various alkyl lactate, which can be considered as a valid analogues of C12-15 alkyl lactates.

2. SOURCE AND TARGET CHEMICAL(S):
ethyl lactate, n-butyl lactate, isobutyl lactate, and 2-ethylhexyl lactate

3. ANALOGUE APPROACH JUSTIFICATION
Effects observed were restricted to local effects in the respiratory tract, which comply with the potential for irritation of respiratory tract due to eventual exposure to the UVCB under registration.
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
inhalation
Type of inhalation exposure:
nose only
Details on inhalation exposure:
Ethyl, n-butyl, and isobutyl-L-lactates were vapor studies, whereas 2-ethylhexyl-L-lactate was evaluated in an aerosol study and in a supplemental study comparing vapor and aerosol exposure.
Duration of treatment / exposure:
6 h
Frequency of treatment:
5 days a week
Remarks:
Doses / Concentrations:
ethyl-L-lactate: 0, 150, 600, or 2500 mg/m3 and 0, 25, 75, or 200 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
isobutyl-L-lactate: 0, 100, 200, 400, or 800 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
n- butyl- L-lactate: 0, 75, 200, or 600 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
2-ethylhexyl-L-lactate: 0, 75, 200, 600, or 1800 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
ethyl, isobutyl, and the primary 2-ethylhexyl studies: 5 males and 5 females;
n-butyl and the supplemental 2-ethylhexyl study: 6 males
Clinical signs:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Main histopathological changes were observed in the nasal cavity (epithelial degeneration, hyperplasia, metaplasia, and inflammatory changes) larynx and trachea (slight epithelial hyperplasia and squamous metaplasia), and lungs (septal fibrosis).
Details on results:
2-Ethylhexyl-L-lactate appeared to be the most reactive in causing irritation of the nasal airways. In general, the local toxicity NOECs of alkyl lactate are lower than the systemic NOECs. This is probably mainly related to the activity of free lactic acid generated by enzymatic hydrolysis of the alkyl lactates.
Dose descriptor:
NOAEC
Effect level:
200 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
ethyl, n-butyl, and isobutyl lactates
Sex:
male/female
Basis for effect level:
other: Local effects: hyperplasia of the nasal respiratory epithelium, including hyperplasia of goblet cells.
Key result
Dose descriptor:
NOAEC
Effect level:
600 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
butyl- L-lactate
Sex:
male
Basis for effect level:
other: Systemic toxicity
Key result
Dose descriptor:
NOAEC
Effect level:
200 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
butyl- L-lactate
Sex:
male
Basis for effect level:
other: Local effects
Dose descriptor:
NOAEC
Effect level:
800 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
isobutyl-L-lactate
Sex:
male/female
Basis for effect level:
other: Systemic toxicity
Dose descriptor:
NOAEC
Effect level:
200 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
isobutyl-L-lactate
Sex:
male/female
Basis for effect level:
other: Local effects
Dose descriptor:
NOAEC
Effect level:
600 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
2-ethylhexyl-L-lactate
Sex:
male/female
Basis for effect level:
other: Systemic toxicity
Dose descriptor:
NOAEC
Based on:
test mat.
Remarks:
2-ethylhexyl-L-lactate
Sex:
male/female
Basis for effect level:
other: Local effects (nasal epithelium)
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Dose descriptor:
LOAEC
Effect level:
75 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
2-ethylhexyl-L-lactate (aerosol or vapor)
Sex:
male/female
Basis for effect level:
other: Local effects: slight focal hyperplasia of the nasal respiratory epithelium, including hyperplasia of goblet cells.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
200 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Based on tests with shorter chain alkyl lactates.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Referenced study in summarizing report with limited details on test conditions.
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Study was performed with C16 alkyl lactate, which can be considered as a valid analogue of C12-15 alkyl lactates.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
25% solution of Cetyl Lactate in mineral oil.

3. ANALOGUE APPROACH JUSTIFICATION
Results of a study with C14 alkyl lactate performed in the same period gave a similar result.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Thirty day skin irritation test.
GLP compliance:
not specified
Limit test:
yes
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
Body weights: 2.0 to 3.0 kg
Type of coverage:
not specified
Vehicle:
other: mineral oil
Duration of treatment / exposure:
For 30 days, the solution was applied each morning to the back of each animal, after which the animals were restrained in stocks for four hours.
Dose / conc.:
500 mg/kg bw/day
Remarks:
Doses / Concentrations:
5 ml of a 25% solution corresponds with approx. 1250 mg. Considering an average body weight of 2.5 kg this corresponds with an estimated dose of 500 mg/kg bw.

No. of animals per sex per dose:
3
Observations and examinations performed and frequency:
Blood counts were made at the beginning of the experiment, at the end of the second week, when the last application was made, and one week after the last application.
Sections of skin were removed from test application sites and fixed in formalin for histological examination.
Body weights and weight gain were recorded weekly.
Clinical signs:
no effects observed
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Haematological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
Weight gains and blood counts were normal throughout the test period. No irritation as evidenced by erythema and edema was found following any of the applications. Scarified areas showed normal healing, and histological examination of the skin showed a normal picture. It was concluded that no irritation occurred upon daily application of a 25% solution of Cetyl Lactate for 30 days.
Key result
Dose descriptor:
NOEL
Effect level:
>= 500 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Dermal irritation, clinical signs, body weights, haematology and histopathology.
Critical effects observed:
not specified
Conclusions:
No irritation occurred upon daily application of a 25% solution of Cetyl Lactate for 30 days.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Low (not assignable).

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Referenced study in summarizing report with limited details on test conditions.
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Study was performed with C16 alkyl lactate, which can be considered as a valid analogue of C12-15 alkyl lactates.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
25% solution of Cetyl Lactate in mineral oil.

3. ANALOGUE APPROACH JUSTIFICATION
Results of a study with C14 alkyl lactate performed in the same period gave a similar result.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Thirty day skin irritation test.
GLP compliance:
not specified
Limit test:
yes
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
Body weights: 2.0 to 3.0 kg
Type of coverage:
not specified
Vehicle:
other: mineral oil
Duration of treatment / exposure:
For 30 days, the solution was applied each morning to the back of each animal, after which the animals were restrained in stocks for four hours.
Dose / conc.:
500 mg/kg bw/day
Remarks:
Doses / Concentrations:
5 ml of a 25% solution corresponds with approx. 1250 mg. Considering an average body weight of 2.5 kg this corresponds with an estimated dose of 500 mg/kg bw.

No. of animals per sex per dose:
3
Observations and examinations performed and frequency:
Blood counts were made at the beginning of the experiment, at the end of the second week, when the last application was made, and one week after the last application.
Sections of skin were removed from test application sites and fixed in formalin for histological examination.
Body weights and weight gain were recorded weekly.
Clinical signs:
no effects observed
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Haematological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
Weight gains and blood counts were normal throughout the test period. No irritation as evidenced by erythema and edema was found following any of the applications. Scarified areas showed normal healing, and histological examination of the skin showed a normal picture. It was concluded that no irritation occurred upon daily application of a 25% solution of Cetyl Lactate for 30 days.
Key result
Dose descriptor:
NOEL
Effect level:
>= 500 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Dermal irritation, clinical signs, body weights, haematology and histopathology.
Critical effects observed:
not specified
Conclusions:
No irritation occurred upon daily application of a 25% solution of Cetyl Lactate for 30 days.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rat
Quality of whole database:
Low (not assignable).

Additional information

Justification for classification or non-classification

The effect concentration for an analogue of alkyl lactates ( 2-ethylhexyl-L-lactate) was above the classification limt of 0.2 mg/L (> 200 mg/m³) for inhalatory exposure of aerosol or mist. Local effects of repeated inhalatory exposure to a concentration of 200 mg/m³ of butyl lactate included slight focal hyperplasia of the nasal respiratory epithelium, including hyperplasia of goblet cells. Due to the longer carbon chain, the predicted NOAEC for C12 -C15 lactates would be significantly higher. In case of dermal exposure, the effect concentration for an analogue of alkyl lactates (Cetyl lactate) was above the classification limt of 200 mg/kg bw/d (> 500 mg/kg bw/d).