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Administrative data

Description of key information

oral LD50 >5000 mg/kg, (Argus et al, 1986).
dermal LD50 >2010 mg/kg, (Taberski et al., 1986).
inhalation LC50 >2000 mg/m3, 4 hour, (Taberski et al., 1986). 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
6 February 1986 to 20 February 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Groups of 5 male and 5 female young adult Sprague Dawley rats.
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
The test article was dissolved in 1% carboxy methylcellulose and a volume of 50 ml/kg was administered.
Doses:
0, 100, 500, 1000, 2500, or 5000 mg/kg CGA154281
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
The animals were observed for 14 days and deaths, clinical signs and body weights were recorded.
Statistics:
Not reported.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: based on 20% mortality in males (only) at 5000 mg/kg
Mortality:
One male dosed with 5000 mg/kg died on day 4.
Clinical signs:
Signs of systemic toxicity were observed at dose levels > 500 mg/kg and included hypoactivity, perineal staining, soft feces, and squinting. At dose levels > 2500 mg/kg, chromodacryorrhea, staining around the mouth and few feces were noted additionally. All surviving rats recovered within 5 days.
Body weight:
Body weight development was comparable between all groups, except of top dose animals (5000 mg/kg), for which a slightly decreased body weight gain was recorded during week 1.
Gross pathology:
At necropsy, no treatment-related findings were observed.

There were no clinical findings at 100 mg/kg. Clinical signs of toxicity were apparent at doses of 500 mg/kg or greater. At the high dose 5000 mg/kg one of five males died (20% mortality). There were no other deaths.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the results of this study, the LD50 was determined to be greater than 5000 mg/kg.
Executive summary:

Single oral doses of 100, 500, 1000, 2500 or 5000 mg/kg of benoxacor (CGA154281) were administered by gavage to groups of 5 male and 5 female rats. There were no clinical signs at 100 mg/kg. Signs of toxicity were apparent at doses of 500 mg/kg or greater. One of five males died at the 5000 mg/kg dose level. There were no other mortalities. The median lethal dose was greater than 5000 mg/kg in both sexes. Benoxacor was considered to be of low toxicity when given as a single oral dose to rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
One reliable study is available.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 February 1986 to 6 March 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Two groups of 8 to 10 week old Sprague Dawley rats (5 animals/sex).
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
The test material was supplied as a powder and tested as received. The test atmosphere was generated using a Teost Air Mill fed via a revolving disc driven by a Sage motor. The chamber concentration was controlled by adjusting generator conditions.

The gravimetric chamber concentrationd of the test substance was determined hourly from samples collected by means of an
open-faced filter placed near the breathing zone of the animals. The nominal chamber concentratione was also calculated. Particle size analyses were conducted on hourly samples taken from the chamber using a Sierra cascade impactor. The mass median diameter and its geometric standard deviation were derived from a log-normal plot of cumulative mass of test substance deposited on each successive stage of the impactor against the stage's effective cut-off size diameter.

The hourly gravimetric chamber concentrations for Group 2 ranged from 1.9 to 2.1 mg/L with a 4-hour average value of 2.0 mg/L.

The hourly mass median diameter (MMD) and geometric standard deviation for the test atmosphere ranged from from 7.2 to 13.0 µm. (geometric SD = 2.2 to 2.6). Approximately 51% of the particles collected had an equivalent aerodynamic diameter of less than or equal to 9 µm.

Animals were exposed to control air or to 2000 mg/m3 CGA 154281 for 4 consecutive hours.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
measured every hour and ranged from 1.9 to 2.1 mg/L.
Duration of exposure:
4 h
Concentrations:
2000 mg/m3
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
14 days observation period with observations of mortality, clinical signs and bodyweight. Gross pathology examination of animals at termination.
Statistics:
Not applicable.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2 000 mg/m³ air (analytical)
Exp. duration:
4 h
Remarks on result:
other: based on 100% survival at the highest dose tested
Mortality:
No mortality was observed during the 14-day observation period.
Clinical signs:
Control animals were asymptomatic. In treated animals lacrimation, chromodacryorrhea, rhinorrhea, chromorhinorrhea, red stains around the facial area, salivation, dehydration, anorexia and few feces were observed. All rats recovered within 7 days.
Body weight:
Body weight gain was comparable between the groups.
Gross pathology:
At necropsy, no treatment-related findings were recorded. Mean lung weights of treated animals were comparable to the control values.

All rats survived treatment and only mild clinical signs were observed.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the results of the study the inhalation LC50 for a 4 hour exposure period was determined to be greater than 2000 mg/m3.
Executive summary:

Male and female rats were exposed, whole body, for 4 hours to an atmosphere containing benoxacor (CGA154281 Technical) at a concentration of 2.0 mg/L (MMD = 9.0 µm, GSD = 2.3). All rats survived treatment. Clinical signs were observed.

Based on the absence of signs of toxicity in the limit exposure conditions, benoxacor is considered to be of low acute inhalation toxicity and the median lethal dose was found to exceed 2 mg/L air.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
One reliable study is available.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 January 1986 to 27 January 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: H.A.R.E. Inc Hewitt NJ, USA
- Age at study initiation: 12-14 weeks
- Weight at study initiation: 2.5 to 3.5 kg
-
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period: 3 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): standard laboratory conditions
- Humidity (%): standard laboratory conditions
- Air changes (per hr): standard laboratory conditions
- Photoperiod (hrs dark / hrs light): standard laboratory conditions


IN-LIFE DATES: From: 13.01.1986 To: 27.01.1986
Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
The test material was moistened with water and applied to the shaved skin. It was covered by a gauze pad, which was held in place for 24 hours with a tape. Thereafter the material was removed with tap water. Collars prevented the rabbits from ingesting the test article.
Duration of exposure:
24 hours
Doses:
2010 mg/kg
No. of animals per sex per dose:
5 male and 5 female
Control animals:
no
Details on study design:
Two week observation period. Clinical signs and bodyweights recorded.
Statistics:
Not applicable.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 010 mg/kg bw
Remarks on result:
other: No notable effects on any parameters at limit dose level
Mortality:
No mortality was observed.
Clinical signs:
No signs of systemic toxicity were recorded; however, a slight erythema was noted in one male on test day two.
Body weight:
Body weight gain was normal during the observation period.
Gross pathology:
At necropsy, no remarkable findings were noted.

No notable clinical signs were observed. One male had a slight erythematous dermal response on day 2 but otherwise there were no changes indicative of derrmal irritation or systemic toxicity.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the results of this study, the dermal LD50 was determined to be greater than 2010 mg/kg.
Executive summary:

A single dose of 2010 mg benoxacor /kg bw was administered topically to a group of five male and five female NZW rabbits.

No notable clinical signs were observed. One male had a slight erythematous dermal response on day 2 but otherwise there were no changes indicative of dermal irritation or systemic toxicity. No mortalities occurred and the median lethal dose was found to exceed 2010 mg/kg bw. Benoxacor (CGA154281 Technical) was found to be of low toxicity when applied topically to rabbit skin on a single occasion.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
One reliable study is available.

Additional information

Guideline- and GLP-compliant acute toxicity studies are available for the test item administered by the oral, inhalation and dermal routes of exposure.

Acute oral toxicity data for benoxacor indicate an oral LD50 value in rats of >5000 mg/kg (Argus et al, 1986).

A four hour acute inhalation toxicity study in rats showed no acute inhalation toxicity at an exposure concentration of 2 mg/L (2000 mg/m3, Taberski et al., 1986). 

An acute dermal toxicity study gave an acute dermal LD50 value in rabbits of >2010 mg/kg (Taberski et al., 1986).


Justification for selection of acute toxicity – oral endpoint
The study is compliant with GLP and guidelines and demonstrated reliably the low oral acute toxicity of benoxacor with an LD50 >5000 mg/kg bw. One male animal died at the highest dose of 5000 mg/kg bw, whereas no mortality occurred at doses equal to or less than 2500 mg/kg bw.

Justification for selection of acute toxicity – inhalation endpoint
The study is compliant with GLP and guidelines and demonstrated reliably the low inhalation acute toxicity of benoxacor with an LC50 >2000 mg/m3.

Justification for selection of acute toxicity – dermal endpoint
The study is compliant with GLP and guidelines and demonstrated reliably the low dermal acute toxicity of benoxacor with an LD50 >2010 mg/kg bw.

Justification for classification or non-classification

Acute toxicity studies are available for the test item administered by the oral, inhalation and dermal routes of exposure. All the available studies are considered adequate and reliable for the purposes of risk assessment, classification and labelling. The three studies produced effect levels that are greater than the relevant cut-off values triggering classification via the different routes of exposure.

The results do not lead to classification according to Directive 67/548/EEC or according to Regulation (EC) No. 1272/2008 as amended by Commission Regulation (EU) No. 286/2011.