Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Oral and dermal toxicity studies were conducted to recognised training guidelines with GLP.

Inhalation study waived as only 10% of substance particles are capable of entering broncho-alveolar tract. As the substance shows no toxicity potential for oral/dermal, and no irritation potential for skin/eye, in the interests of animal welfare an inhalation study is regarded as not scientifically necessary.

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:
1987-05-04, 1987-06-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(1981)
Deviations:
yes
Remarks:
(Animals were sacrificed at day 18 instead of day 14. Only 2 doses were examined instead of at least 3.)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain as stated in the report: Tif: RAIf (SPF) hybrids of RII 1/Tif x RII 2/Tif
- Source: CIBA-GEIGY Ltd., Tierfarm, Sisseln, Switzerland
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: 173 - 230 g
- Fasting period: Overnight before application
- Housing: Groups of 5 in Macrolon cages type 4 with standardised soft wood bedding (Societe Parisienne des sciures, Pantin)
- Diet: Ad libitum, NAFAG No. 890, NAFAG AG, Gossau, SG (Switzerland)
- Water: Ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 15
- Air changes (per hr): appr. 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
other: carboxymethylcellulose and polysorbate 80
Details on oral exposure:
VEHICLE
- Amount of vehicle: 0.5 % carboxymethylcellulose and 0.1 % polysorbate 80 in distilled water

MAXIMUM DOSE VOLUME APPLIED
- 10 mL / kg body weight for the lower and 20 mL/kg body weight for the higher dose (due to low solubility of test substance, further details see additional informations)
Doses:
oral single application of 2000 and 5000 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: Mortality, signs and symptoms daily. Body weight at start, on day 7, and on day 14
- Necropsy of survivors performed: yes; The animals were sacrificed for necropsy on day 18 instead day 14 because of legal holidays.
Statistics:
From the body weights, the group means and their standard deviations were calculated.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality occurred.
Mortality:
None
Clinical signs:
other: Clinical signs were dyspnea, exophthalmus, ruffled fur and curved body position. All findings resolved by day 11 and were no longer observed at the end of the recovery period.
Gross pathology:
No deviations from normal morphology were found.
Other findings:
None

Table 1. Signs and symptoms*

Cbservations Exposure day: hours Days of post-exposure period
1 2 3 5 1 2 3 4 5 6 7 8 9 10 11 12 13 >13
2000 mg/kg bw
dyspnea XX XX XX XX X X X X X X X X X




exophthalmos X X X X X X X X X X







ruffled fur X X X X X X X X X X X X X X



body position- curved X X X X X X











5000 mg/kg bw
dyspnea X X X XX X X X X X X







exophthalmos X X X X X X











ruffled fur X X X X X X X X X X X X X X



body position- curved X X X X X X X










* X = slight; XX = moderate; XXX = marked

Table 2. Body weights and standard deviations.

Dose mg/kg Males Females
Day 1 Day 7 Day 14 Day 1 Day 7 Day 14
2000 193/ 4.4 260/ 8.8 312/ 9.8 175/ 2.2 209/ 3.0 224/ 4.8
5000 223/ 4.8 272/10.8 328/ 8.0 196/ 6.3 219/ 3.7 230/ 9.9
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the test, the acute oral LD50 of the test material to rats was found to be >5000 mg/kg bw.
Executive summary:

In this guideline (OECD 401) study conducted to GLP standards, the test material (EC 404-360-3) was determined to be practically nontoxic, with an acute oral LD50 > 5000 mg/kg bw. The test was conducted on male/female rats, administered by oral gavage with a vehicle of 0.5 % carboxymethylcellulose and 0.1 % polysorbate 80 in distilled water, at two different concentrations (2000 mg/kg bw and 5000 mg/kg bw). No mortality was observed, thus the test material is not classified as acutely toxic (oral) under CLP regulation 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study 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:
1988-07-26, 1988-09-26
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
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
- Strain as stated in the report: Tif: RAI f (SPF)
- Source: CIBA-GEIGY Ltd., Animal Production, Stein / Switzerland
- Age at study initiation: 7 to 8 weeks
- Weight at study initiation: 224 - 259
- Housing: Individually in Macrolon cages type 3, with standardized soft wood bedding (Société Parisienne des Sciures, Pantin)
- Diet: Ad libitum, NAFAG 890 Tox, NAFAG, Gossau/SG, Switzerland, Rat chow
- Water: Ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 10
- Air changes (per hr): appr. 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
semiocclusive
Vehicle:
peanut oil
Details on dermal exposure:
TEST SITE
- Area of exposure: Back
- % coverage: 10 %
- Type of wrap if used: gauze-lined semiocclusive dressing fastened around the trunk with an adhesive elastic bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): With lukewarm water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 mL/kg body weight
- Constant volume or concentration used: yes
- For solids, paste formed: yes
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 males and 5 females. Six male rats have been used, since a male rat was mistakenly applied in the female group. The treatment was repeated with the missing fifth female.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality, signs and symptoms daily; body weight at start, on day 7, and on day 14
- Necropsy of survivors performed: yes
Statistics:
From the body weights, the group means and their standard deviations were calculated.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
None
Clinical signs:
other: Piloerection, abnormal body positions, and dyspnea were seen, being common symptoms in acute dermal tests. The animals recovered within 7 to 9 days. See Table 1.
Gross pathology:
No deviations from normal morphology
Other findings:
None

Table 1. Observation of symptoms*

Observations Appl. day Days after application
1 2 3 4 5 6 7 8 9 >9
2000 mg/kg, males
piloerection + + + + + + + + +

hunched posture
+ + + +





ventr.recumbency + +








dyspnea + + + + +





2000 mg/kg, females
piloerection + + + + + + + + +

hunched posture
+ + + +





ventr.recumbency + +








dyspnea
+ + + +





* + = slight; ++ = moderate; +++ = severe

Table 2. Mean body weight and standard deviation

Group
 Appl.day Day 7 Day 14
Males 242 ± 3.2 272 ± 7.7 302 ± 16.1
Females 245 ± 13.9 260 ± 18.6 269 ±30.2
Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral toxicity LD50 to rats was determined to be >2000 mg/kg bw under the conditions of the test.
Executive summary:

In this guideline (OECD 402) study conducted to GLP standards, the test material (EC 404-360-3) was determined to be practically nontoxic, with an acute dermal LD50 > 2000 mg/kg bw. The test was conducted on rats (male/female) using a single dose of 2000 mg/kg bw and the test material was applied using a vehicle of peanut oil and held in place using a semiocclusive cover. As no mortalities occured the test material is not classified as acutely toxic (dermal) under CLP regulation 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

After single oral application of 2000 and 5000 mg/kg bw test article by gavage to male and female rats according to OECD 401 (1981) no mortality occurred. Dyspnea, exophthalmos, ruffled fur, and abnormal body position were seen. In both groups animals recovered within 11 days. Therefore, the LD50 is greater than 5000 mg/kg bw.

After dermal application of 2000 mg/kg bw test article to female and male rats for 24 h according to OECD 402 no mortality occurred. Clinical symptoms (piloerection, abnormal body positions, and dyspnea) of slight severity were seen. The animals recovered within 7 to 9 days. Therefore, the LD50 is greater than 2000 mg/kg bw for both sexes.

No experimental data for inhalative toxicity are available. However, gravimetric data are available which showed a mass median aerodynamic diameter of 55 µM when using the mass distribution method. Only 10 % of particles have a diameter below 20 µm (BASF KA-88/10 C; see chapter 4.5 of IUCLID). Therefore, the majority of generated particles is not expected to penetrate into the broncho-alveolar tract. Moreover, the substance showed neither a general toxic potential (LD 50 acute oral above 5000 mg/kg bw, LD 50 acute dermal above 2000 mg/kg bw), nor a irritating potential (skin and eye). Based on these data and with respect to animal welfare an acute inhalation study was not performed.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for acute oral or dermal toxicity under Regulation (EC) No. 1272/2008, as amended for the fifth time in Directive EC 944/2013.