Registration Dossier

Administrative data

Description of key information

Oral (WoE), rat: LD50 >2000 mg/kg bw (RA from CAS 131459-39-7, CAS 67762-53-2 and CAS 146289-36-3)

Inhalation (WoE), rat: LC50 >5.1 mg/L air (RA from CAS 67762-53-2 and CAS 68424-31-7)

Dermal (WoE), rat: LD50 >2000 mg/kg bw (RA from CAS 71010-76-9 and CAS 131459-39-7)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
other: Sprague-Dawley CD (Crl:CD® (SD) IGS BR)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: 234 - 237g (males), 215 - 220g (females)
- Housing: in groups of up to 3 by sex in solid-floor polypropylene cages
- Diet: rat and mouse Diet No.1, Special Diets Services Limited, Witham, Essex, UK, ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 21
- Humidity (%): 37 - 67
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2.09 mL/kg

DOSAGE PREPARATION: The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.

CLASS METHOD
- Rationale for the selection of the starting dose: The available information suggested the starting dose.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed for death or overt signs of toxicity 0.5; 1; 2 and 4 hours after dosing and subsequently once daily; individual body weights were determined prior to dosing, on day 7 and day 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 14-day observation period.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy and histopathological examination revealed no substance-related finding.

Table 1: Bodyweight gain

Dose level   Bodyweight [g] at Day
mg/kg bw female 0 7 14
2000 1-0 220 259 280
1-1 217 251 258
1-2 215 249 272
male      
2-0 235 307 348
2-1 237 300 343
2-2 234 298 343
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
other: Wistar TNO
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Weight at study initiation: mean 190 g (male), 160 g (female)
- Fasting period before study: 16 hours
- Housing: 5 animals per cage: Makrolon type-3 with standard soft wood bedding
- Diet: pelleted maintenance diet 1324 (Altromin GmbH), ad libitum
- Water: community tap water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 25
- Humidity (%): 45 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: arachidis oil, DAB9
Details on oral exposure:
VEHICLE
- Amount of vehicle: 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weighing one day before application, on day 2, 7 and 14 after application, animals were checked for mortality/viability two times daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, other: macroscopic examination of the cranial, thoracic and visceral cavities
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 14-day observation period.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy and histopathological examination revealed no substance-related findings.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
other: Albino Rats (Outbred). Stock: Sprague-Dawley-derived (CD) [Crl: CD (SD) IGS BR]
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, New York, USA
- Age at study initiation: 9 - 12 weeks
- Weight at study initiation: 279 - 318 g (males), 204 - 219 g (females)
- Fasting period before study: animals were fasted overnight prior administration
- Housing: 2 to 6 animals of the same sex per cage (during acclimation) und individual (during study) per cages. Cages were suspended, stainless cages with wire mesh bottoms.
- Diet: certified Rodent Diet, No. 5002 (PMI Nutrition International, Inc., St. Louis, MO), ad libitum
- Water: automatic watering system, Municipal water supply (Elizabethtown Water Company), ad libitum
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 – 26
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2 mL/kg bw



Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
other: not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were checked for viability daily. Each animal was examined (general condition, skin and fur, eyes nose, oral cavity, abdomen and external genitalia as well as evaluations of respiration and palpation for tissue masses) approximately 1, 2, and 4 hours after dosing and daily thereafter for 14 days. Individual body weights were determined on day 0 (at the time of fasting), day 1 (just prior to dosing; weights were used for calculation of doses), day 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, food consumption, macroscopic post-mortem examination.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity related to the administration of the test substance were observed up to the end of the 14-day observation period. However alopecia extremities on snout was seen in a single animal on day 9 through day 15 after the dose administration. This finding was not considered to be related to the administration of the test substance.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy revealed no substance-related findings.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
07. Dec. - 23. Dec. 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study with acceptable restrictions (no analytical purity reported)
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
no analytical purity reported
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
no analytical purity reported
GLP compliance:
yes (incl. QA statement)
Remarks:
Safepharm Laboratories Limited, Derby, UK
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: Sprague-Dawley CD (Crl:CD® (SD) IGS BR)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: 234 - 237g (males), 215 - 220g (females)
- Housing: in groups of up to 3 by sex in solid-floor polypropylene cages
- Diet: rat and mouse Diet No.1, Special Diets Services Limited, Witham, Essex, UK, ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 21
- Humidity (%): 37 - 67
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2.09 mL/kg

DOSAGE PREPARATION: The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.

CLASS METHOD
- Rationale for the selection of the starting dose: The available information suggested the starting dose.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed for death or overt signs of toxicity 0.5; 1; 2 and 4 hours after dosing and subsequently once daily; individual body weights were determined prior to dosing, on day 7 and day 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 14-day observation period.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy and histopathological examination revealed no substance-related finding.

Table 1: Bodyweight gain

Dose level   Bodyweight [g] at Day
mg/kg bw female 0 7 14
2000 1-0 220 259 280
1-1 217 251 258
1-2 215 249 272
male      
2-0 235 307 348
2-1 237 300 343
2-2 234 298 343
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
08. Jan. - 29. Jan. 1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see "remarks"
Remarks:
GLP-Guideline study. According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (Dec 2012)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar TNO
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Weight at study initiation: mean 190 g (male), 160 g (female)
- Fasting period before study: 16 hours
- Housing: 5 animals per cage: Makrolon type-3 with standard soft wood bedding
- Diet: pelleted maintenance diet 1324 (Altromin GmbH), ad libitum
- Water: community tap water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 25
- Humidity (%): 45 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: arachidis oil, DAB9
Details on oral exposure:
VEHICLE
- Amount of vehicle: 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weighing one day before application, on day 2, 7 and 14 after application, animals were checked for mortality/viability two times daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, other: macroscopic examination of the cranial, thoracic and visceral cavities
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 14-day observation period.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy and histopathological examination revealed no substance-related findings.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
7 Dec - 23 Dec 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions (no analytical purity reported)
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
adopted in 1992
Deviations:
yes
Remarks:
no analytical purity reported
GLP compliance:
no
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
other: Albino Rats (Outbred). Stock: Sprague-Dawley-derived (CD) [Crl: CD (SD) IGS BR]
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, New York, USA
- Age at study initiation: 9 - 12 weeks
- Weight at study initiation: 279 - 318 g (males), 204 - 219 g (females)
- Fasting period before study: animals were fasted overnight prior administration
- Housing: 2 to 6 animals of the same sex per cage (during acclimation) und individual (during study) per cages. Cages were suspended, stainless cages with wire mesh bottoms.
- Diet: certified Rodent Diet, No. 5002 (PMI Nutrition International, Inc., St. Louis, MO), ad libitum
- Water: automatic watering system, Municipal water supply (Elizabethtown Water Company), ad libitum
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 – 26
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2 mL/kg bw



Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
other: not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were checked for viability daily. Each animal was examined (general condition, skin and fur, eyes nose, oral cavity, abdomen and external genitalia as well as evaluations of respiration and palpation for tissue masses) approximately 1, 2, and 4 hours after dosing and daily thereafter for 14 days. Individual body weights were determined on day 0 (at the time of fasting), day 1 (just prior to dosing; weights were used for calculation of doses), day 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, food consumption, macroscopic post-mortem examination.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity related to the administration of the test substance were observed up to the end of the 14-day observation period. However alopecia extremities on snout was seen in a single animal on day 9 through day 15 after the dose administration. This finding was not considered to be related to the administration of the test substance.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy revealed no substance-related findings.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products, similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
other: Sprague-Dawley CD®
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Klingston, NY, USA
- Age at study initiation: approximately 9 weeks (control group); approximately 10 weeks (test group)
- Weight at study initiation: 332 g (control group, males only); 358 g (test group, male) and 247 (test group, female)
- Fasting: feed was not provided during the exposure
- Housing: animals were group-housed in suspended, stainless steel, wire mesh cages during the acclimation period and individually-housed during all other non-exposure period.
- Diet: certified Rodent Diet, # 5002 meal, ad libitum
- Water: ad libitum
- Acclimation period: The control group animals were acclimated for 12 days. The test group animals were acclimated for 19 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23
- Humidity (%): 18 - 30
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: cast aluminium and alloy exposure chamber with polycarbonate nose-only tubes housed within 10 m³ Harford glass and stainless steel exposure chamber.
- Exposure chamber volume: 40 L
- Method of holding animals in test chamber: animals were placed in polycarbonate tubes attached to the chambers.
- Source and rate of air: 20 L/min
- System of generating particulates/aerosols: Approximately 110 mL of test material were placed into a nebulizer. House-supply air was delivered from a regulator and backpressure gauge, via ¼” tubing, to a plastic Y tube which split the airflow into the generation and dilution systems. The generation air (7.0 Lpm) was directed, via ¼” tubing, through a flowmeter regulated by a metering valve, and a backpressure gauge, to the nebulizer. The test material-laden airstream was directed through a flowmeter regulated by a metering valve, into the dilution port at the top of the nose-only exposure chamber.
- Method of particle size determination: In the control group the particle size distribution measurements were performed each hour of exposure for the chamber and room air using a TSI Aerodynamic Particle Sizer. The samples were drawn for 20 seconds at a rate of 5.0 Lpm. The mass median aerodynamic diameter, geometric standard deviation and in the test group samples for particle size distribution assessment were drawn each hour of exposure using a cascade impactor. The samples were drawn for one minute at a flowrate of 1.00 Lpm. The mass median aerodynamic diameter, geometric standard deviation and percent of particles ≤1.0, ≤4.0 and ≤10 microns were calculated based on the amount of material collected on the seven impactor stages and a final filter stage using a graphical analysis of an assumed lognormal distribution.
- Temperature, humidity, pressure in air chamber: 21°C (average), 23% (average)

TEST ATMOSPHERE
- Brief description of analytical method used: Sample concentration (mg/L) was determined gravimetrically on a total formulation basis. A drop of the test material was placed on a weighed filter, weighed immediately and again after drying overnight. This was done in triplicate. The resultant data were used to determine the fraction of solids in the test material. During the exposure, the filter was weighed before and immediately after sampling (wet weight). The exposure concentration (mg/L) was calculated on both a “wet” and “dry” basis by dividing the appropriate net weight (mg) by the volume of air sampled (liters). For the test group, only exposure levels were calculated on a formulation by dividing the exposure concentration on a “dry” basis (mg/L) by the fraction of solids.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.18/2.03
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetric
Duration of exposure:
4 h
Concentrations:
5.50 mg/L (analytical concentration)
6.6 mg/L (nominal concentration)
No. of animals per sex per dose:
10 (air control)
10 (males, test group)
5 (females, test group)
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days (5 males were sacrificed on Day 3)
- Frequency of observations and weighing: on day 1 all animals were observed individually immediately prior to the exposures, as a group at approximately 15 minute intervals during the first hour of each exposure, and hourly for the reminder exposure periods. All surviving animals were observed individually upon removal from the chambers (30 min after each exposure termination) and every hour for two hours post-exposure. Detailed physical observations (general condition, skin and fur, eyes, nose, oral cavity, abdomen and external genitalia as well as evaluations of respiration and palpation for tissue masses) were recorded at each interval. From day 2 to 15 detailed observations were recorded once daily. Individual body weights were recorded on day 1 (just prior to exposure), on Day 3 (just before sacrifice). Animal sacrificed on Day 15 were weighed on day 8 and 15 (just prior sacrifice)
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology, gross pathology.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
5.5 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality occurred during the study period.

Clinical signs:
other: Test group: nasal discharge was noted as only sign of toxicity. Wet fur was noted as well but was considered an artefact of the nose-only exposure regimen. A few incidences of chromodacryorrhea were also noted to a comparable degree to the Group II animal
Body weight:
The test group females lost weight during the first week after the test material exposure, but gained weight during the second week after exposure. In all other animals no effect on body weight was noted.
Gross pathology:
Necropsy examination revealed no substance-related findings.

Other findings:
- Histopathology: There were no test material related microscopic findings. At the end of each of the post-exposure observation periods, incidental findings occurred with comparable incidence and severity in rats from the control and test groups or they occurred sporadically. The have been seen of this strain and age used in similar studies conducted in the study facility.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
other: Alpk:APfSD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Alderly Park, Cheshire, UK
- Age at study initiation: approx. 7 weeks
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Source and rate of air: dried and filtered air
- System of generating aerosols: glass concentric jet atomiser
- Method of particle size determination: Marple Cascade Impactor
- Temperature, humidity, pressure in air chamber: 20 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetrically
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.51 µm/2.51
Analytical verification of test atmosphere concentrations:
yes
Remarks:
particulate concentrations of the test atmospheres close to the animals breathing zone were measured gravimetrically
Duration of exposure:
4 h
Concentrations:
5.0 mg/L (nominal)
5.10 mg/L (analytical)
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: animals were observed for gross clinical abnormalities during exposure and were checked daily thereafter. A detailed examination was conducted after exposure on day 1 and on consecutive days, up to and including day 15. Individual body weights were recorded on Day 1 and Days 2, 3, 8 and day 15.
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.1 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality occurred during the study period.
Clinical signs:
other: Some clinical signs were noticed, which consisted of hunched position, chromodacryorrhea, piloerection, staining around nose and wet fur. These signs however occurred during or just after exposure and were clearly consistent with the use of restraint for
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy and histopathological examination revealed no substance-related findings.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions (no analytical purity reported)
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
adopted in 1996
Deviations:
yes
Remarks:
no analytical purity reported
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Sprague-Dawley CD®
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Klingston, NY, USA
- Age at study initiation: approximately 9 weeks (control group); approximately 10 weeks (test group)
- Weight at study initiation: 332 g (control group, males only); 358 g (test group, male) and 247 (test group, female)
- Fasting: feed was not provided during the exposure
- Housing: animals were group-housed in suspended, stainless steel, wire mesh cages during the acclimation period and individually-housed during all other non-exposure period.
- Diet: certified Rodent Diet, # 5002 meal, ad libitum
- Water: ad libitum
- Acclimation period: The control group animals were acclimated for 12 days. The test group animals were acclimated for 19 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23
- Humidity (%): 18 - 30
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: cast aluminium and alloy exposure chamber with polycarbonate nose-only tubes housed within 10 m³ Harford glass and stainless steel exposure chamber.
- Exposure chamber volume: 40 L
- Method of holding animals in test chamber: animals were placed in polycarbonate tubes attached to the chambers.
- Source and rate of air: 20 L/min
- System of generating particulates/aerosols: Approximately 110 mL of test material were placed into a nebulizer. House-supply air was delivered from a regulator and backpressure gauge, via ¼” tubing, to a plastic Y tube which split the airflow into the generation and dilution systems. The generation air (7.0 Lpm) was directed, via ¼” tubing, through a flowmeter regulated by a metering valve, and a backpressure gauge, to the nebulizer. The test material-laden airstream was directed through a flowmeter regulated by a metering valve, into the dilution port at the top of the nose-only exposure chamber.
- Method of particle size determination: In the control group the particle size distribution measurements were performed each hour of exposure for the chamber and room air using a TSI Aerodynamic Particle Sizer. The samples were drawn for 20 seconds at a rate of 5.0 Lpm. The mass median aerodynamic diameter, geometric standard deviation and in the test group samples for particle size distribution assessment were drawn each hour of exposure using a cascade impactor. The samples were drawn for one minute at a flowrate of 1.00 Lpm. The mass median aerodynamic diameter, geometric standard deviation and percent of particles ≤1.0, ≤4.0 and ≤10 microns were calculated based on the amount of material collected on the seven impactor stages and a final filter stage using a graphical analysis of an assumed lognormal distribution.
- Temperature, humidity, pressure in air chamber: 21°C (average), 23% (average)

TEST ATMOSPHERE
- Brief description of analytical method used: Sample concentration (mg/L) was determined gravimetrically on a total formulation basis. A drop of the test material was placed on a weighed filter, weighed immediately and again after drying overnight. This was done in triplicate. The resultant data were used to determine the fraction of solids in the test material. During the exposure, the filter was weighed before and immediately after sampling (wet weight). The exposure concentration (mg/L) was calculated on both a “wet” and “dry” basis by dividing the appropriate net weight (mg) by the volume of air sampled (liters). For the test group, only exposure levels were calculated on a formulation by dividing the exposure concentration on a “dry” basis (mg/L) by the fraction of solids.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.18/2.03
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetric
Duration of exposure:
4 h
Concentrations:
5.50 mg/L (analytical concentration)
6.6 mg/L (nominal concentration)
No. of animals per sex per dose:
10 (air control)
10 (males, test group)
5 (females, test group)
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days (5 males were sacrificed on Day 3)
- Frequency of observations and weighing: on day 1 all animals were observed individually immediately prior to the exposures, as a group at approximately 15 minute intervals during the first hour of each exposure, and hourly for the reminder exposure periods. All surviving animals were observed individually upon removal from the chambers (30 min after each exposure termination) and every hour for two hours post-exposure. Detailed physical observations (general condition, skin and fur, eyes, nose, oral cavity, abdomen and external genitalia as well as evaluations of respiration and palpation for tissue masses) were recorded at each interval. From day 2 to 15 detailed observations were recorded once daily. Individual body weights were recorded on day 1 (just prior to exposure), on Day 3 (just before sacrifice). Animal sacrificed on Day 15 were weighed on day 8 and 15 (just prior sacrifice)
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology, gross pathology.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
5.5 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality occurred during the study period.

Clinical signs:
other: Test group: nasal discharge was noted as only sign of toxicity. Wet fur was noted as well but was considered an artefact of the nose-only exposure regimen. A few incidences of chromodacryorrhea were also noted to a comparable degree to the Group II animal
Body weight:
The test group females lost weight during the first week after the test material exposure, but gained weight during the second week after exposure. In all other animals no effect on body weight was noted.
Gross pathology:
Necropsy examination revealed no substance-related findings.

Other findings:
- Histopathology: There were no test material related microscopic findings. At the end of each of the post-exposure observation periods, incidental findings occurred with comparable incidence and severity in rats from the control and test groups or they occurred sporadically. The have been seen of this strain and age used in similar studies conducted in the study facility.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
22 Mar - 05 Apr 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions (only few data on test item and animal husbandry were given)
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
(No details on test material and limited data on animal husbandry)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Alpk:APfSD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Alderly Park, Cheshire, UK
- Age at study initiation: approx. 7 weeks
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Source and rate of air: dried and filtered air
- System of generating aerosols: glass concentric jet atomiser
- Method of particle size determination: Marple Cascade Impactor
- Temperature, humidity, pressure in air chamber: 20 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetrically
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.51 µm/2.51
Analytical verification of test atmosphere concentrations:
yes
Remarks:
particulate concentrations of the test atmospheres close to the animals breathing zone were measured gravimetrically
Duration of exposure:
4 h
Concentrations:
5.0 mg/L (nominal)
5.10 mg/L (analytical)
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: animals were observed for gross clinical abnormalities during exposure and were checked daily thereafter. A detailed examination was conducted after exposure on day 1 and on consecutive days, up to and including day 15. Individual body weights were recorded on Day 1 and Days 2, 3, 8 and day 15.
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.1 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality occurred during the study period.
Clinical signs:
other: Some clinical signs were noticed, which consisted of hunched position, chromodacryorrhea, piloerection, staining around nose and wet fur. These signs however occurred during or just after exposure and were clearly consistent with the use of restraint for
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy and histopathological examination revealed no substance-related findings.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products, similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, UK
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: males: 202 - 217 g (male) and 202 - 212 g (female)
- Housing: individually housed in suspended polypropylene cages for the time of exposure and in groups of five, by sex, for the reminder of the study.
- Diet: ad libitum, Rat and Mouse Expanded Diet No.1, Special Diets Services Limited, UK
- Water: ad libitum
- Acclimation period: minimum 5 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 21 (18 at one ocasion, this was not considered relevant for the study)
- Humidity (%): 47 - 67
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: back and flanks
- % coverage: approx. 10% of total body surface
- Type of wrap if used: gauze secured with self-adhesive bandage


REMOVAL OF TEST SUBSTANCE
- Washing: wiping with cotton wool moistened with distilled water
- Time after start of exposure: 24 h
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 0.5 h; 1 h; 2 h and 4 h after dosing and daily thereafter for 14 days. Weighing on Days 0, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: Skin reactions according to Draize Scoring System (1977)
Statistics:
Not required
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 14-day observation period.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy and histopathological examination revealed no substance-related findings.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan
- Age at study initiation: 9 - 10 weeks
- Weight at study initiation: 247 - 253 g (males), 217 - 239 g (females)
- Housing: animals were group housed by sex upon receipt and individually housed upon assignment to study in compliance with the National Research Council " Guide for the Care and Use of Laboratory Animals".
- Diet: Harlan Teklad Rodent Diet, ad libitum
- Water: Tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 22
- Humidity (%): 23 - 59
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
From: 9 Jan 2006
To: 23 Jan 2006
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: clipped skin of the dorsal area of the trunk
- Type of wrap if used: the treated skin site was covered with a gauze patch/dental dam, wrapped with an elastic bandage and secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing: residual test substance was removed with water
- Time after start of exposure: 24 h
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were recorded immediately after dosing and at approximately 1, 2.5 and 4 h after dosing and daily thereafter through Day 15. Animals were weighed prior to dosing on Day 1 and on Days 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: Mortality/morbidity (twice daily)
Statistics:
Body weights were summarized using descriptive statistics (mean and standard deviation).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 14-day observation period.
Body weight:
Body weight gains of all animals were within the normal ranges during the whole study period.
Gross pathology:
Necropsy revealed no substance-related findings.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
05 Jan - 19 Jan 1999
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study with acceptable restrictions (limited data on test substance)
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
limited data on test substance
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
limited data on test substance
GLP compliance:
yes (incl. QA statement)
Remarks:
Safepharm laboratories ltd., Derby, UK
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, UK
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: males: 202 - 217 g (male) and 202 - 212 g (female)
- Housing: individually housed in suspended polypropylene cages for the time of exposure and in groups of five, by sex, for the reminder of the study.
- Diet: ad libitum, Rat and Mouse Expanded Diet No.1, Special Diets Services Limited, UK
- Water: ad libitum
- Acclimation period: minimum 5 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 21 (18 at one ocasion, this was not considered relevant for the study)
- Humidity (%): 47 - 67
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: back and flanks
- % coverage: approx. 10% of total body surface
- Type of wrap if used: gauze secured with self-adhesive bandage


REMOVAL OF TEST SUBSTANCE
- Washing: wiping with cotton wool moistened with distilled water
- Time after start of exposure: 24 h
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 0.5 h; 1 h; 2 h and 4 h after dosing and daily thereafter for 14 days. Weighing on Days 0, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: Skin reactions according to Draize Scoring System (1977)
Statistics:
Not required
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 14-day observation period.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsy and histopathological examination revealed no substance-related findings.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study with acceptable restrictions (Lack of data on test material.)
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted in 1987
Deviations:
yes
Remarks:
(no data on test substance purity)
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
adopted in1992
Deviations:
yes
Remarks:
(no data on test substance purity)
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
adopted in 1998
Deviations:
yes
Remarks:
(no data on test substance purity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan
- Age at study initiation: 9 - 10 weeks
- Weight at study initiation: 247 - 253 g (males), 217 - 239 g (females)
- Housing: animals were group housed by sex upon receipt and individually housed upon assignment to study in compliance with the National Research Council " Guide for the Care and Use of Laboratory Animals".
- Diet: Harlan Teklad Rodent Diet, ad libitum
- Water: Tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 22
- Humidity (%): 23 - 59
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
From: 9 Jan 2006
To: 23 Jan 2006
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: clipped skin of the dorsal area of the trunk
- Type of wrap if used: the treated skin site was covered with a gauze patch/dental dam, wrapped with an elastic bandage and secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing: residual test substance was removed with water
- Time after start of exposure: 24 h
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were recorded immediately after dosing and at approximately 1, 2.5 and 4 h after dosing and daily thereafter through Day 15. Animals were weighed prior to dosing on Day 1 and on Days 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: Mortality/morbidity (twice daily)
Statistics:
Body weights were summarized using descriptive statistics (mean and standard deviation).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
No clinical signs of toxicity were observed up to the end of the 14-day observation period.
Body weight:
Body weight gains of all animals were within the normal ranges during the whole study period.
Gross pathology:
Necropsy revealed no substance-related findings.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products, similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Justification for read-across

There are no data available on acute toxicity of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid. In order to fulfil the standard information requirements set out in Annex VII and VIII, 8.5, and in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted. In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across) “to avoid the need to test every substance for every endpoint”. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13) and within Chapter 5.1 of the CSR.

 

Acute toxicity: oral

CAS 67762-53-2

An acute oral toxicity study performed equivalent or similar to OECD TG 420 with Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) is available (Zolyniene, 1999a). In this limit test groups of five fasted CD Sprague-Dawley rats of each sex were administered a single dose of 2000 mg/kg bw of the test substance via oral gavage. The animals were observed for 14 days after administration. No mortality occurred and body weight gain was normal during the study period. 1/10 animals showed alopecia extremities on snout which was not considered treatment-related. No further clinical signs of systemic toxicity were recorded in animals during the study period. Gross pathology revealed no abnormalities or substance-related findings. Thus, the acute oral LD50 value was considered to be greater than 2000 mg/kg bw.

 

CAS 146289-36-3

An acute oral toxicity study performed according to OECD TG 401 and in compliance with GLP with Isononanoic acid, mixed esters with 2-methylbutanoic acid, 3-methylbutanoic acid, pentaerythritol and valeric acid (CAS 146289-36-3) is available (Sterzel, 1991). In this limit test groups of five fasted Wistar rats of each sex were administered a single dose of 2000 mg/kg bw of the test substance via oral gavage. The animals were observed for 14 days after administration. No mortality occurred and body weight gain was normal during the study period. No clinical signs of toxicity were observed up to the end of the 14-day observation period. Necropsy and histopathological examination revealed no substance-related findings. Thus, the acute oral LD50 value was considered to be greater than 2000 mg/kg bw.

 

CAS 131459-39-7

An acute oral toxicity study performed equivalent or similar to OECD TG 423 with 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS 131459-39-7) is available (Allen, 1999a). In this limit test groups of three Sprague-Dawley CD rats of each sex were administered a single dose of 2000 mg/kg bw of the test substance via oral gavage. The animals were observed for 14 days after administration. No mortality occurred and body weight gain was normal during the study period. No clinical signs of toxicity were observed up to the end of the 14-day observation period. Necropsy and histopathological examination revealed no substance-related findings. Thus, the acute oral LD50 value was considered to be greater than 2000 mg/kg bw.

 

Acute toxicity: inhalation

CAS 67762-53-2

An acute inhalation toxicity study performed equivalent or similar to OECD TG 403 and in compliance with GLP with Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) is available (Hoffman, 1999). In this limit test groups of 10 male and 5 female CD Sprague-Dawley rats were exposed to a single dose of 5.50 mg/L air (analytical concentration) test substance aerosol for 4 h via nose/head only inhalation. Five animals of each sex were observed for 14 days after test material exposure, whereas 5 males were sacrificed on Day 3. No mortality occurred during the entire study period and clinical signs of toxicity were limited to nasal discharge recorded in all animals of the test group. The test group females lost weight during the first week after the test material exposure, but gained weight during the second week after exposure. In all other animals no effect on body weight was observed. Necropsy examination revealed no substance-related findings. Thus, the acute inhalation LC50 value was considered to be greater than 5.50 mg/L air.

 

CAS 68424-31-7

An acute inhalation toxicity study performed equivalent or similar to OECD TG 403 with Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7) is available (Parr-Dobrzanski, 1994). In this limit test groups of 5 male and 5 female Alpk:APfSD rats were exposed to a single dose of 5.10 mg/L air (analytical concentration) test substance aerosol for 4 h via nose-only inhalation. The animals were observed for 14 days after administration. No mortality occurred during the entire study period and clinical signs of toxicity were limited to hunched position, chromodacryorrhea, piloerection, staining around nose and wet fur. These signs however occurred during or just after exposure and were clearly consistent with the use of restraint for exposure. No effect on body weight was noted during the study period and gross pathology revealed no abnormalities in any animal. Thus, the acute inhalation LC50 value was considered to be greater than 5.10 mg/L air.

 

Acute toxicity: dermal

CAS 71010-76-9

An acute dermal toxicity study was performed with Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9) equivalent or similar to OECD TG 402 and in compliance with GLP (Mallory, 2006). In this limit test five Sprague-Dawley rats of each sex were exposed to a single dose of 2000 mg/kg bw of the neat test substance for 24 h via semi-occlusive dressing and observed for 14 days post-application. No mortalities occurred and no systemic clinical signs of toxicity related to the administration of the test item were observed up to the end of the 14-day observation period. Furthermore, no effect on body weight development was recorded during the study period. Macroscopic examination at the end of the study revealed no treatment-related changes. Thus, the acute dermal LD50 value was considered to be greater than 2000 mg/kg bw.

 

CAS 131459-39-7

An acute dermal toxicity study was performed with 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS 131459-39-7) equivalent or similar to OECD TG 402 and in compliance with GLP (Allen, 1999b). In this limit test five Sprague-Dawley rats of each sex were exposed to a single dose of 2000 mg/kg bw of the neat test substance for 24 h via semi-occlusive dressing and observed for 14 days post-application. No mortalities occurred and no systemic clinical signs of toxicity related to the administration of the test item were observed up to the end of the 14-day observation period. Furthermore, no effect on body weight development was recorded during the study period. Macroscopic examination at the end of the study revealed no treatment-related changes. Neither erythema nor edema formation was observed in any animal during the entire study period. Thus, the acute dermal LD50 value was considered to be greater than 2000 mg/kg bw.

 

Overall conclusion for acute toxicity

Taken together, the available data on acute toxicity for the read-across analogue substances indicate a very low level of acute toxicity following the oral, inhalation and dermal route, as LD50 and LC50 values were greater than the currently applied limit values. Therefore, as the available data did not identify any hazard for acute toxicity, Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid is not considered to be hazardous following acute exposure.

Justification for classification or non-classification

Based on the analogue read-across approach, the available data on acute toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.