Registration Dossier

Administrative data

Description of key information

LD50 p.o. (rat ): 1336 mg/kg bw (BASF AG, 1979)

LD50 dermal (rat): > 400 - < 800 mg/kg (BASF AG, 1979)

LC50 (IRT, rat): > 0.06 mg/L (BASF AG, 1963)

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
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
- Source: WIGA
- Weight at study initiation: male: 190-220g; female: 160-190g
- Fasting period before study: 15-20 hours
- Diet: Herlian MRH-Haltung; H. Eggersmann KG

ENVIRONMENTAL CONDITIONS
no data
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
0.5 % aqueous carboxymethylcellulose formulation

DOSE (mg/kg) | 2150 | 1470 | 1000| 681 |
conentration % (w/v) | 21.5 | 14.7 | 10.0 | 6.81 |

MAXIMUM DOSE VOLUME APPLIED:
Dose volume: 10 ml/kg
Doses:
681, 1000, 1470, 2150 mg/kg bw
No. of animals per sex per dose:
10 (one exception: only 9 female animals for dose 1470 mg/kg bw)
Control animals:
no
Details on study design:
- Duration of observation period following administration: at least 14 days
- Frequency of observations: multiple observations after administration up to 5 hours afterwards; then daily (but not on weekends)
- Frequency of weighing: day 2-5, and also on day 7, 13 and 21
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, necropsies were performed on all animes that died or were sacrificed.
Sex:
male
Dose descriptor:
LD50
Effect level:
1 544 mg/kg bw
Sex:
female
Dose descriptor:
LD50
Effect level:
1 195 mg/kg bw
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 336 mg/kg bw
Mortality:
male: female: male/female
Dose: 681 (mg/kg bw) 1/10 (10%) 0/10 (0%) 1/20 (5%)
Dose: 1000 (mg/kg bw) 2/10 (20%) 3/10 (30%) 5/20 (25%)
Dose: 1470 (mg/kg bw) 5/10 (50%) 8/9 (88.9%) 13/19 (68.4%)
Dose: 2150 (mg/kg bw) 7/10 (70%) 9/10 (90%) 16/20 (80%)
Clinical signs:
Clinical signs (day 0 is day of application; no time specification in brackets: true for whole observation period)
2150 mg/kg bw: irregular breathing, apathy, gasping (day 0-3), tremor, spastic movement, ruffled fur, aggressiveness (day 15-20), diarrhea (day 0 and 1), exsiccosis, poor general condition
1470 mg/kg bw: irregular breathing (day 0-7), apathy (day 0-7), tremor (day 1 - 3), spastic movement (day 0 - 7), ruffled fur (day 1 - 6), diarrhea (day 3), exsiccosis (day 0 - 7), poor general condition (day 0 - 7)
1000 mg/kg bw: irregular breathing (day 0-7, 13), apathy (day 0-7), spastic movement, ruffled fur (day 1 - 6), exsiccosis (day 0 - 7), poor general condition (day 0 - 7)
681 mg/kg: bw: irregular breathing (day 0-4), apathy (day 0-4), spastic movement (day 0-1), ruffled fur (day 0 - 4), poor general condition (day 0-4)
Body weight:
Dose (mg/kg bw): 2150 1470 1000 681
mean weight male animals (g): day 2-5 205 206 199 213
day 7 283 208 208 221
day 13 223 233 248 262
day 21 277 - - -

Dose (mg/kg bw) 2150 1470 1000 681
mean weight female animals (g): day 2-5 174 152 158 172
day 7 169 176 160 177
day 13 131 167 180 197
day 21 148 - - -
Gross pathology:
animals that died:
Heart: acute dilatation of the vestiubules; acute congestive hyperanemia; Liver: peripheral lobus pattern; Stomach: severe vascular injection; partly reddened with extensive bleeding; intestine: vascular injection, atonic, hematinized and diarrheic content; in some cases substance-related malacia of the mucosa; in some cases prominent bleeding of areas of the mucosa; hydrothorax
sacrificed animals:
stomach: forestomach wall thickened, forestomach agglutination; in some cases so-called "button"-formation; in some cases diverticulum formation
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The LD50 in rats for butandioldiacrylate was 1336 mg/kg bw.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 336 mg/kg bw

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
The test was performed in principle as described in OECD test guideline 403. It demonstrates the toxicity of an atmosphere saturated with vapors of the volatile components of a test substance at 20 °C. Two groups of young adult laboratory rats (3 per sex per group; a total of 12 animals) were exposed sequentially to the vapors generated by bubbling 200 L/h air through a substance column of about 5 cm above a fritted glass disc in a glass cylinder for 8 h. The exposure was subsequently repeated in the same manner. No analytical determination of the atmosphere concentrations was performed. The nominal concentration was calculated as quotient of the amount of test substance weight loss during exposure, and the amount of air used during exposure. Group-wise documentation of clinical signs was performed over a 7 day study period. Body weight of groups was determined before the start of the study and at the end of the observation period.
GLP compliance:
no
Test type:
other: inhalation hazard test
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
Exposure:
12 rats for 8 hours; vapour temperature 20°C; concentration 0.06 mg/L;
Addtionally, rat were exposed to vapour generated at 100°C for 1h (6 rats), 3h (12 rats), and 8h (6 rats). Since a lot of substance was lost due to condensation in the pipes, no concentration estimate can be provided for these groups.
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
8 h
Concentrations:
0.06 mg/L;
No. of animals per sex per dose:
12 animals; 6 male and 6 female
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
Statistics:
no data
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 0.06 mg/L air (nominal)
Exp. duration:
8 h
Remarks on result:
other: no animals died when exposed to saturated vapour for 8 hours (20°C)
Mortality:
Mortality did not occur (0/12 died).
When exposed to a saturated atmosphere generated at 100°C (the animals were exposed at RT), 4/6 died when exposed for 1h, 8/12 when exposed for 3h, and 5/6 when exposed for 8h.
Clinical signs:
other: light mucosa irritation (20°C) The higher concentration achieved when generating the atmosphere at 100°C (despite the significant loss within the pipes) led to severe mucusal irritation, encrusted eyes and nose, dyspnoe, and attempts to escape
Body weight:
- Weight at study initiation: group 1 average weight of the 6 animals: 170.8 g
group 2 average weight of the 6 animals: 167.5 g
- Weight at the end of the study: group 1 average weight of the 6 animals: 164.6 g
group 2 average weight of the 6 animals: 164.3 g
Gross pathology:
nothing abnormal detected (20°C)
Interpretation of results:
study cannot be used for classification
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
60 mg/m³

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
only 3 animals / sex used in highest dose
GLP compliance:
no
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:
rats: SPF-breed; supplyling company: WIGA, Sulzfeld
diet: Herlian MRH-concentrated feed; suppyling company: H. Eggersmann, Rinteln/Weser; ad libitum
water: ad libitum
Type of coverage:
occlusive
Vehicle:
olive oil
Details on dermal exposure:
TEST SITE
- Area of exposure: ~49 cm2
- Type of wrap if used: inert foil; fixed with adhesive tape

REMOVAL OF TEST SUBSTANCE
- Washing: warm water or water/lutrol mixture; drying using tissue paper
- Time after start of exposure: 24 h

TEST MATERIAL
- Concentration: 50% for concentration 400 mg/kg(in olive oil); for all other concentrations the undeluted test substance was applied.
Duration of exposure:
24 h
Doses:
400, 800, 1250, 2000 mg/kg bw
No. of animals per sex per dose:
5 male and 5 female (exception was dose group 2000 mg/kg bw: 3 male and 3 female)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Weighing: one time at the beginning
- Necropsy of survivors performed: yes
- Fur was removed by shaving 15-24 hours before the beginning of the test. Only animals with healthy und undamaged skin were used for the test .
- Other examinations performed: clinical signs, necropsy
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 400 - < 800 mg/kg bw
Mortality:
see table below
Clinical signs:
Resorptive Symptoms of poisoning: unsteady breathing; apathy; staggering; ruffled fur
local irritation: 24 h following application significant primary irritations can be detected, which turns into necrosis on day 4.
Body weight:
average body weight:
males: 223g
females: 188g
Gross pathology:
animals that died:
heart: acute dilatation (right side); acute congestive hyperemia;
lung: in some cases acute inflation of medium grade
surviving animals:
no abnormality detected

Mortality

 Dose (mg/kg bw)  conc. (%) # animals

 died within

1 h

 died within

24 h

 died within

48 h

 died within

7 d

 died within

14 d

 2000  100  3 male  0/3  0/3  0/3  2/3  2/3
     3 female  0/3  3/3  3/3  3/3  3/3
 1250  100  5 male  0/5  5/5  5/5  5/5  5/5
     5 female  0/5  5/5  5/5  5/5  5/5
 800  100  5 male  0/5  5/5  5/5  5/5  5/5
     5 female  0/5  5/5  5/5  5/5  5/5
 400  50  5 male  0/5  0/5  0/5  0/5  0/5
     5 female  0/5  1/5  1/5  1/5  1/5
               
Interpretation of results:
Category 3 based on GHS criteria
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
Value:
400 mg/kg bw

Additional information

Acute Oral Toxicity

In an acute oral toxicity study similar to OECD 401, groups (10/sex) of Sprague-Dawley rats were administered with a single oral dose (gavage) of the test substance emulsified in CMC at concentrations of 681, 1000, 1470 and 2150 mg/kg bw. Animals were then observed for 14 days. One animal died at 681 mg/kg bw, 5 animals at 1000 mg/kg bw, 13 animals at 1470 mg/kg bw and 16 at 2150 mg/kg bw. Clinical signs that were observed at 2150 mg/kg bw, irregular breathing, apathy, gasping (day 0-3), tremor, spastic movement, ruffled fur, aggressiveness (day 15-20), diarrhea (day 0 and 1), exsiccosis, poor general condition. At1470 mg/kg bw, irregular breathing (day 0-7), apathy (day 0-7), tremor (day 1 - 3), spastic movement (day 0 - 7), ruffled fur (day 1 - 6), diarrhea (day 3), exsiccosis (day 0 - 7), poor general condition (day 0 - 7). At 1000 mg/kg bw: irregular breathing (day 0-7, 13), apathy (day 0-7), spastic movement, ruffled fur (day 1 - 6), exsiccosis (day 0 - 7), poor general condition (day 0 - 7). At 681 mg/kg: bw: irregular breathing (day 0-4), apathy (day 0-4), spastic movement (day 0-1), ruffled fur (day 0 - 4), poor general condition (day 0-4). Animals that died during the study showed acute dilatation of the vestiubules, acute congestive hyperanemia, peripheral lobus pattern (liver), severe vascular injection; partly reddened with extensive bleeding (stomach) vascular injection, atonic, hematinized and diarrheic content; in some cases substance-related malacia of the mucosa; in some cases prominent bleeding of areas of the mucosa, hydrothorax. In sacrificed animals the forestomach wall was thickened and forestomach agglutination was observed. In some cases so-called "button"-formation and diverticulum formation was described. An LD50 of 1336 mg/kg bw was determined for both male and female animals (BASF AG, 1979).

In an older study 5 rats per group were treated via gavage with app. 210, 420, 840, and 1690 mg/kg bw (aqueous emulsion with tragacanth) of the test substance. Animals were then observed for 7 days. All animals died at 1760 mg/kg bw and 3 animals died at 880 mg/kg bw. At 440 and 200 mg/kg no animals died. Clinical signs were temporarily staggering, mild apathy, piloerection. Animals that died showed sepsis (6 animals and focal pneumonia (1 animal). Sacrificed animal at 220 mg/kg showed no unusual findings. At 440 mg/kg slight agglutination of the stomach wall to the peritoneum (1 animal) and severe damage in the area of the forestomach were observed. At 880 mg/kg adhesion of the stomach wall with the peritoneum, perisplenitis, necrotisizing gastritis in the region of the forestomach (severe local damage) occured. An LD50 of approx. 740 mg/kg bw was determined for both male and female animals (BASF AG, 1963).

In a study with two rabbits per group, a single oral dose (gavage) of the test substance was administered at concentrations of app. 260, 530 and 2100 mg/kg bw. Animals were then observed for 7 days. All animals died at 2200 mg/kg, one animal died at 550 mg/kg bw and no animal died at 275 mg/kg bw. Clinical signs were atony, apathy, impairment of the hindlimbs and ataxia, lateral position and temporary inappetence. The animals that died, showed acute dilatation (heart), acute congestive hyperemia, sticky liver (clay-yellow colored) and pale kidney. An LD50 of approx. 550 mg/kg bw was determined (BASF AG, 1975).

Acute Inhalative Toxicity

In an inhalation hazard test, twelve rats (6 males and 6 females) were exposed for 8 hours to a saturated atmosphere (20°C) at a mean concentration of 0.06 mg/L. No mortality was observed. Animals showed light mucosa irritation. No pathological changes were observed at necropsy. The LC50 was > 0.06 mg/L (BASF AG,1963). In an additional test, saturated vapour concentration was generated while heating the liquid substance to 100°C. This led to severe local irritation and mortality in 4/6 rats after exposure for 1h. No concentration can be provided for this setting, since a significant, but undeterminable amount of test substance was lost in the pipes of the exposure apparatus. The maximum concentration calculated based on the vapour pressure at 100°C would have been 19mg/L.

Acute Dermal Toxicity

In an acute dermal toxicity study, goups of 10 rats (male and female) were administered doses of 400, 800 and 1250 mg/kg bw and 6 rats (male and female) with 2000 mg/kg bw. The undiluted substance (for 400 mg/kg bw the test substance was 50% in olive oil) was applied for 24 hours to the intact skin of rats under occlusive conditions. After 24 hours the skin was washed with warm water or water/lutrol mixture and dried with tissue paper. At the high dose (2000 mg/kg) 5/6 animals died within 7 days. All animals died within 24 hours at 1250 and 800 mg/kg bw and 1 animal died within 24 hours at 400 mg/kg bw. Resorptive symptoms of poisoning like unsteady breathing, apathy staggering and ruff fur were observed. Irritation was observed at the application site, which turned into necrosis by post-exposure day 4. The dermal LD50 was > 400 < 800 mg/kg bw (BASF AG, 1979).

Justification for classification or non-classification

Based on the results of the acute oral and dermal testing, the test item has to be classified as acute oral cat. 4 (H302) and acute dermal cat. 3 (H311) according to Regulation (EC) No 1272/2008 (CLP). Even though these concentration cannot be obtained by evaporation at room temperature, mortality occured at concentrations < 19mg/L. For conservative reasons, the substance is thus also classified for acute inhalation cat. 4.

The entry for acute oral toxicity in Table 3.1 of Annex VI of Regulation (EC) No 1272/2008 (CLP) confirms the proposed classification.