Registration Dossier

Administrative data

Description of key information

Oral (OECD 401), mouse: LD50=472 mg/kg bw 
Dermal: Data waiving according to Column 2 of REACH Annex VIII, Section 8.5.2
Inhalation (similar to OECD 403), rat, 6h exposure: LC50=28.1 mg/m³ (=0.0281 mg/L)

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:
30 Jan 1991 - 27 Feb 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(1981)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
The Department of Health and Social Security of the Government of the United Kingdom
Test type:
standard acute method
Limit test:
no
Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Chales River (UK) Ltd., Manston, Kent, U. K.- Age at study initiation: approximately 5-8 weeks- Weight at study initiation: 26-30 g (males), 20-24 g (females)- Fasting period before study: 2-4 hours prior to gavage and 2 hours after gavage- Housing: in groups of 5 by sex in solid-floor polypropylene cages with sawdust bedding- Diet (ad libitum): Rat and Mouse Expanded Diet No. 1, Special Diet Services Limited, Witham, Essex, U. K.- Water (ad libitum)- Acclimation period: at least 5 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 17-24- Humidity (%): 34-84- Air changes (per hr): 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: 0.83 ml/kg bw for the high dose groupDOSAGE PREPARATION: The volumes for each dose group were determined according to the specific gravity of the test material and the animals' fasted body weight at the time of dosing.
Doses:
500, 707, and 1000 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: 0.5, 1, 2, and 4 hours post-dosing, and subsequently once daily until study termination- Frequency of weighing: on days 0, 7 and 14, or at death- Necropsy of survivors performed: yes- Other examinations performed: careful examination of gastro-intestinal tract for signs of corrosion
Sex:
male/female
Dose descriptor:
LD50
Effect level:
472 mg/kg bw
Based on:
test mat.
95% CL:
234 - 953
Remarks on result:
other: Deaths are supposed to be contributed to irritation or corrosion of gastro-intestinal tract rather than systemic toxicity.
Sex:
male
Dose descriptor:
LD50
Effect level:
149 mg/kg bw
Based on:
test mat.
95% CL:
5 - 4 757
Sex:
female
Dose descriptor:
LD50
Effect level:
841 mg/kg bw
Based on:
test mat.
95% CL:
707 - 1 000
Mortality:
All animals treated at a dose level of 1000 mg/kg bw died the day of dosing or one or two days after dosing. One male and one female were killed in extremis on day 3. All males treated at a dose level of 707 mg/kg bw died. The deaths occured between one and four days after dosing. Four males died at a dose level of 500 mg/kg bw. Two of these animals died within 30 min of dosing and the other two animals died one or three days after dosing. Three females treated at a dose level of 500 mg/kg bw died one day after dosing.
Clinical signs:
Common signs of toxicity noted in all dose groups were hunched posture, lethargy, ptosis, laboured respiration, ataxia, and piloerection. Additional signs of loss of righting reflex were noted in animals treated with 707 and 1000 mg/kg bw. Isolated signs of toxicity noted were distended abdomen in animals treated with 500 mg/kg bw and decreased respiratory rate, dehydration, pallor of the extremities, and hypothermia in animals treated with 1000 mg/kg bw. All surviving animals appeared normal nine days after treatment and for the remainder of the study period.
Body weight:
Surviving animals showed little or no gain in body weight during the study except for one male treated with 500 mg/kg bw and one female treated with 707 mg/kg bw. These animals showed a loss in body weight during the first week of the study.
Gross pathology:
Abnormalities generally seen at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver and dark kidneys. Commonly noted effects on the gastro-intestinal tract were haemorrhage of the small intestines and gastric mucosa. Haemorrhage of the large intestine was noted in one male treated with 500 mg/kg bw and one male and two females treated with 1000 mg/kg bw; sloughing of the non-glandular epithelium was noted in three males treated with 500 mg/kg bw and one male and two females treated with 1000 mg/kg bw. No abnormalities were in one male and two females treated with 500 mg/kg bw and all females treated with 707 mg/kg bw that were killed at the ned of the study. A necropsy was not performed on one male that died after a dose of 707 mg/kg bw. This omission was due to an oversight but was considered not to affect the purpose or integrity of the study.
Interpretation of results:
other: CLP/EU GHS Category 4 (H302) according to Regulation (EC) No 1272/2008
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
472 mg/kg bw
Quality of whole database:
The study was conducted according to the OECD TG 401 (1981) and in compliance with GLP (RL1).

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:
comparable to guideline study with acceptable restrictions
Remarks:
The study predates the appropriate OECD test guideline and GLP. However, the study was conducted similar to the OECD test guideline 403 with acceptable restrictions. The restrictions were that no details were given on the test material purity and the animals were kept in groups during whole-body inhalation exposure.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
(no details on test material purity given, the animals were kept in groups during whole-body inhalation exposure)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Age at study initiation: 7-9 weeksNo further details are given in the study report.
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION- Exposure apparatus: For the 6 hour exposure experiment 4 cages (9" x 9" x 14", with 5 animals each sex per cage) were closely grouped in the center of the chamber on the top shelf. Since this apparatus was too large for the target concentrations tested in the 1 hour exposure experiment a much smaller Rochester-type inhalation chamber was used. This is why the experiment was run twice with two cages with 5 males each, and two cages with 5 females each, respectively, placed on the top shelf of the exposure chamber.- Exposure chamber volume: 4.3 m³ (6 h exposure), 0.15 m³ (1 h exposure)- Method of holding animals in test chamber: in cages, grouped to 5 animals each sex per cage- System of generating vapour: Air was passed through a perforated plate distillation column (15 plates) while liquid test material was continously recirculated from the flask below the column to the top of the column, so that each plate in the column had a small layer of liquid on it. Each stage of the column, once steady state operation was reached, exhibited a good frothing action, and it was thus assumed that air leaving the column was saturated with the test item. Calculations from vapour pressure data supplied by Thermal Lab showed that, at 23 °C saturated air contains 250 ppm of the test compound. Air exiting from the distillation column was immediately diluted into the main air flow into the chamber, at a dilution factor appropriate for the given exposure. Any deviations from the target concentrations noted during analysis of the chamber atmosphere were corrected as soon as possible by appropriate adjustment of the air flowing through the distillation column. TEST ATMOSPHERE- Brief description of analytical method used: Analytical verification of the test atmosphere during the 6h exposure experiment was determined by placing a line, which sampled chamber air, with its opening in the center of the group of four cages; presumably what was then measured was the concentration of the test material in the air just before it reached the rats, since the air flow in the chamber was from top to bottom. The analysis of the chamber air was made at least once every half hour, and as often as every 3 min during start-up. During the 1 hour exposure experiments the line for sampling chamber air was placed with its opening between the two cages, just at the top of the cages; presumably what was then measured was the concentration of the test material in the air just before it reached the rats. Analyses were made every 2 min throughout each exposure. The analysis of the test item was determined by using gas chromatography. - Samples taken from breathing zone: no
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gas chromatography
Duration of exposure:
>= 1 - <= 6 h
Remarks on duration:
Two experiments were carried out, whereas in the first experiment the exposure duration was 6 hours and in the second expriment 1 hour.
Concentrations:
6 h exposure experiment (males and females): 7, 4, and 2 ppm (nominal, equal to 0.0443, 0.0253, and 0.0127 mg/L); 6.82, 3.96, and 2.03 ppm (time weighted average based on analytical analysis)1 h exposure experiment (males): 40, 20, and 10 ppm (nominal, equal to 0.2533, 0.1267, and 0.0633 mg/L); 36.32 ± 2.48, 20.39 ± 0.78, and 9.74 ± 0.56 ppm (time weighted average based on analytical analysis)1 h exposure experiment (females): 40, 20, and 10 ppm (nominal, equal to 0.2533, 0.1267, and 0.0633 mg/L); 36.57 ± 1.67, 19.77 ± 1.09, and 9.71 ± 0.42 ppm (time weighted average based on analytical analysis)The values in mg/L were calculated on the basis of c (mg/L) = (((155.1513 g/mol / 24.5 L) x concentration in ppm) / 1000)
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days- Frequency of weighing: just prior to exposure, and approx. 3 times/week thereafter- Necropsy of survivors performed: yes (gross pathology)
Sex:
male
Dose descriptor:
LC50
Effect level:
24.2 ppm
Based on:
test mat.
95% CL:
17.8 - 33.4
Exp. duration:
1 h
Sex:
male
Dose descriptor:
LC50
Effect level:
0.153 mg/L air
Based on:
test mat.
95% CL:
0.113 - 0.211
Exp. duration:
1 h
Sex:
female
Dose descriptor:
LC50
Effect level:
ca. 36 ppm
Based on:
test mat.
Exp. duration:
1 h
Remarks on result:
other: insufficient data for statistical treatment
Sex:
female
Dose descriptor:
LC50
Effect level:
0.228 mg/L air
Based on:
test mat.
Exp. duration:
1 h
Remarks on result:
other: insufficiant data for statistical treatment
Sex:
male
Dose descriptor:
LC50
Effect level:
4.44 ppm
Based on:
test mat.
95% CL:
3.21 - 6.53
Exp. duration:
6 h
Sex:
male
Dose descriptor:
LC50
Effect level:
0.028 mg/L air
Based on:
test mat.
95% CL:
0.02 - 0.041
Exp. duration:
6 h
Sex:
female
Dose descriptor:
LC50
Effect level:
5.27 ppm
Based on:
test mat.
95% CL:
3.98 - 7.99
Exp. duration:
6 h
Sex:
female
Dose descriptor:
LC50
Effect level:
0.033 mg/L air
Based on:
test mat.
95% CL:
0.025 - 0.051
Exp. duration:
6 h
Mortality:
6 h exposure experiment: 7 ppm: Of 10 male rats exposed, 2 died between 24 and 32 hours post exposure, 4 died between 32 and 48 hours post exposure. A seventh rat was found to be clearly moribund 72 hours post exposure and was sacrificed. The remaining 3 rats survived 14 days until sacrifice and necropsy. Of the 10 females, 4 died between 24 and 32 hours post exposure, 3 more by 48 hours post exposure. The remaining 3 rats survived 14 days until sacrifice. 4 ppm: Of the 10 males exposed, 6 died between 32 and 48 hours post-exposure. Of the 10 female rats exposed, 3 died between 24 and 32 hours post-exposure, the rest surviving until sacrifice. 2 ppm: None of the rats, either male or female, died post exposure up to sacrifice 14 days later. 1h exposure experiment: 40 ppm: Of the 10 males exposed, 2 died within 24 hours post exposure, 2 more died within 100 hours post exposure. 4 more males dying in the 11th and 13th day post exposure due to rapid weight loss. Of the 10 females, 2 died 4 days post exposure, 3 more died in the 11th and 12th days post exposure. 20 ppm: 4 of 10 males died on the 10th and 11th days post exposure after their rapid weight loss from day 7 on.
Clinical signs:
6 h exposure experiment: 7 ppm: During exposure, all rats showed progressively increased signs of eye and nasal irritation and respiratory difficulties. Just after exposure there were signs of eye irritation, and dried dark red-brown exudate on the noses; respiratory difficulties appeared to have diminished, only slight rales being observable in a few rats. 16 hours later there was evidence of severe respiratory distress in all animals exposed. 4 ppm: Signs of the rats post-exposure were essentially the same as in the 7 ppm exposure, but slightly less pronounced. The surviving females showered severe weight loss, whereas 6 of the 7 rats regained weight and were at normal levels at sacrifice, but the seventh female showed essentially monotonous weight loss to sacrifice. 2 ppm: Signs in the rats during exposure were slight, and just after 30 min venting period post-exposure they appeared normal. 1h exposure experiment: 40 ppm: Signs in the animals developed much more quickly than in the 6 hour exposure experiment. During exposures, all rats showed signs of eye and nasal irritation and respiratory difficulties. After exposure and a 30 min venting period, both male and female rats, showed diminished signs of respiratory difficulties, but did show laboured breathing, stains on their noses, and appeared lethargic. The two male rats surviving to necropsy at day 14 post exposure showed laboured breathing and were extremely lethargic. The five surviving females did not show abnormal signs.20 ppm: Signs during and post exposure were similar to those seen in rats exposed to 40 ppm, but to lesser extent. The females apparently tolerated the exposure better than the males. Five of the six survivors showed laboured breathing and extreme lethargy, the sixth, however, appeared normal. At the end of the 14 days all females appeared normal. 10 ppm: Signs during exposure were slight; females showed no signs post exposure, only few males showed slight stains on the noses.
Body weight:
6 h exposure experiment: 7 ppm: The surviving 3 male rats showed severe and monotonous weight loss until sacrifice. One of the 3 surviving females showed essentially monotonous weight loss, whereas the two others, after severe weight loss, eventually began to gain weight and reached normal weight levels.4 ppm: The surviving males showed essentially monotonous weight loss until sacrifice14 days later, but appeared to be stabilising at that time, with 2 rats showing weight gains just prior to sacrifice. 2 ppm: All animals suffered a severe initial weight loss (more severe in males than in females), but then began to gain weight and had reached normal levels by sacrifice. 1h exposure experiment: 40 ppm: The six male survivors, after having shown severe initial weight losses, appeared to be stabilised in weight after 1 week post exposure, but shortly thereafter lost weight rapidly and steadily, within 4 more dying in the 11th and 13th day post exposure. The two rats surviving to necropsy at day 14 post exposure continued to lose weight. The five surviving females appeared to have stabilised in weight prior to necropsy. 20 ppm: The 10 males exposed showed severe weight losses, then appeared to stabilise at about 7 days post exposure, but then 9 of 10 lost weight rapidly, 4 of them died on days 10 and 11. Five of the six survivors continued to lose weight rapidly throughout the 14 day post exposure period, the sixth , however, was gaining weight. The 10 females showed severe temporary weight losses, but 4-5 days post exposure their weights stabilised, and at the end of the 14 days all their weights were near normal. 10 ppm: All males and most of the females showed weight losses post exposure, but in only one male and one female was the loss severe, and all rats of both sex were gaining weight and apparently in normal condition 14 days post exposure.

6 h exposure experiment:

2 ppm: No grossly visible lesions were noted in any of the male rats. 5 of 10 females showed focal pneumonia in the lungs and one female showed focal atelectasis (collapse) in the lung. These minimal lesion were considered to be due to exposure to vapours of the test material since similar lesions were observed only infrequently in control animals.

4 ppm: In general, the rats that died had porphyrin-containing secretions on the facial regions adjacent to the eyes, nose, and/or mouth. This was considered to be an indication of irritation of the ocular and nasal mucous membranes. Corneal or conjunctival alterations indicative of eye irritation were observed in 4 of 6 males that died, but not in the females. Examination of the internal organs and tissues of rats that died revealed variable evidence of upper respiratory irritation such as inflammation of the nasal mucosa (rhinitis), and excess quantities of gaseous material in the gastrointestinal tract. Congestion of the lungs which was observed in some rats may have been indicative of an effect on this organ. Congestion of the liver and kidneys which was observed in rats that died was considered to be an agonal event and not a primary effect of treatment. All male rats killed at the end of the 14 day observation period had patchy areas of pneumonia usually accompanied by inflammatory exudate in the trachea and/or bronchi; decreased quantities of ingesta within the gastrointestinal tract; decreased deposits of adipose tissue, and a shrunken, atrophic appearance of the thymus. In the surviving females 2 out of 7 had focal pneumonia, 4 of 7 had decreased deposits of adipose tissue, and one had a shrunken, atrophic thymus. The focal pneumonia observed in the surviving rats was considered to be indicative of probable irritation to the lungs, whereas the observations of decreased deposits of adipose tissue and thymic atrophy were interpreted to be secondary effects related to stress incurred as a result of primary effects of the test material on the respiratory system.

7 ppm: Most males and females that died had accumulations of prophyrin-containing secretions on the facial regions (eyes, nose, and/or mouth); decreased ingesta and/or increased quantities of gaseous material in the gastrointestinal tract; congestion of the livers, kidneys, and several had alterations of the cornea and/or conjunctiva. Of rats that survived the 14 day post exposure period: 3/3 males and 1/3 females had focal pneumonia and thymic atrophy, and 3/3 males and 2/3 females had decreased deposits of adipose tissue. Thus, the lesions in the rats exposed to 7 ppm were similar to those exposed to 4 ppm. The toxicological significance of the lesions was similar to that discussed above.

 

1h exposure experiment:

10 ppm: 4 males and 4 females were examined and had no lesions that could be attributed to the treatment with the test material.

20 ppm: 10 male and 3 females were subjected to gross pathologic examination. Focal cloudiness of the cornea of one eye was observed in the females that was considered to be possibly related to treatment. Males had lesions of the respiratory system, i. e. congestion of the nasal mucosa, focal pneumonia and failure of the lungs to collapse normally upon opening of the trachea and bronchi that were considered to be primary effects of treatment with the test material. Cloudiness or opacity of the cornea of one or both eyes was observed in 4/10 males and was also considered to be treatment related. In addition, decreased deposits of adipose tissue and/or dehydration of the tissues was observed in most of the males. These were considered to be secondary effects incurred as a result of the failure of the rats to consume normal quantities of food and water, which, in turn, can be attributed to the pneumonia observed in these rats.

40 ppm: Macroscopic evaluation of all 20 rats revealed a variety of grossly visible lesions that were indicative of irritation of the upper and lower respiratory passages. Lesions observed that were considered to be indicative of respiratory irritation were: exudative material around the external nares in 8/10 males and 4/10 females, congestion of the nasal turbinate mucosa in 7/10 males and 2/10 females, inflammatory exudate in the nasal passageways in 6/10 males and 2/10 females, focal pneumonia in 6/10 males and 3/10 females, failure of the lungs to collapse normally to opening the trachea and bronchi in 3/10 males and 3/10 females, areas of congestion and oedema of the lungs in 1/10 males, diffuse congestion of the lungs with focal atelectasis in 1/10 females, and distension of the stomach with air which is indicative of upper respiratory obstruction in 5/10 males and 2/10 females. Cloudiness of the cornea of one or both eyes was observed in 2/10 males which was considered to be a probable effect of treatment. A variety of other pathologic alterations such as dehydration, decreased deposits of adipose tissue, thymic atrophy, congestion of the abdominal viscera or liver, and a roughened appearance of the haircoat were observed which were considered to be secondary effects that were incurred as a result of inflammatory lesions of the respiratory system.

Interpretation of results:
other: CLP/EU GHS Category 1 (H330) according to Regulation (EC) No 1272/2008
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
28.1 mg/m³
Quality of whole database:
The study predates the appropriate OECD test guideline and GLP. However, the study was conducted similar to the OECD test guideline 403 with acceptable restrictions.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute toxicity: via oral route

In the available key study (SafePharm Laboratories, 1991a) the submission substance was investigated for acute oral toxicity according to the OECD test guideline 401, and in compliance with GLP. 5 CD-1 mice per sex per dose received the undiluted test item at doses of 500, 707, and 1000 mg/kg bw via gavage. All animals treated at a dose level of 1000 mg/kg bw died the day of dosing or one or two days after dosing. One male and one female were killed in extremis on day 3. All males treated at a dose level of 707 mg/kg bw died. The deaths occured between one and four days after dosing. Four males died at a dose level of 500 mg/kg bw. Two of these animals died within 30 min of dosing and the other two animals died one or three days after dosing. Three females treated at a dose level of 500 mg/kg bw died one day after dosing. Common signs of toxicity noted in all dose groups were hunched posture, lethargy, ptosis, laboured respiration, ataxia, and piloerection. Additional signs of loss of righting reflex were noted in animals treated with 707 and 1000 mg/kg bw. Isolated signs of toxicity noted were distended abdomen in animals treated with 500 mg/kg bw and decreased respiratory rate, dehydration, pallor of the extremities, and hypothermia in animals treated with 1000 mg/kg bw. All surviving animals appeared normal nine days after treatment and for the remainder of the study period. Surviving animals showed little or no gain in body weight during the study except for one male treated with 500 mg/kg bw and one female treated with 707 mg/kg bw. These animals showed a loss in body weight during the first week of the study. Abnormalities generally seen at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver and dark kidneys. Commonly noted effects on the gastro-intestinal tract were haemorrhage of the small intestines and gastric mucosa. Haemorrhage of the large intestine was noted in one male treated with 500 mg/kg bw and one male and two females treated with 1000 mg/kg bw; sloughing of the non-glandular epithelium was noted in three males treated with 500 mg/kg bw and one male and two females treated with 1000 mg/kg bw. No abnormalities were seen in one male and two females treated with 500 mg/kg bw and all females treated with 707 mg/kg bw that were killed at the end of the study. The LD50 calculated for males was 149 mg/kg bw, and for females xxx mg/kg bw. The combined LD50 is therefore 472 mg/kg bw. Since the deaths observed in this study are supposed to be contributed to irritation or corrosion of gastro-intestinal tract rather than systemic toxicity, the combined LD50 of 472 mg/kg bw (male/female) rather than the lower LD50 for males was used for assessment.

The data are further supported by a study conducted according to the OECD test guideline 401, and in compliance with GLP (SafePharm Laboratories, 1991b). 5 Sprague-Dawley rats per sex per dose received the undiluted test material at doses of 1000, 1581, and 2500 mg/kg bw. Deaths occured in 5/5 males and 5/5 females dosed at 2500 mg/kg bw, 4/5 males and 1/5 females at 1581 mg/kg bw, and 1/5 males and 0/5 females at 1000 mg/kg bw. Common signs of toxicity noted prior to death in animals treated at 2500 mg/kg bw were lethargy, hunched posture, ptosis, and ataxia. Additional or isolated signs of toxicity noted were decreased respiratory rate, laboured respiration, gasping respiration, increased salivation, loss of righting reflex and hypothermia. Signs of toxicity commonly noted prior to death in animals dosed at 1581 or 1000 mg/kg bw were decreased respiratory rate, hunched posture, lethargy, and ptosis. An isolated incident of red/brown stains around mouth was noted in one male dosed at 1000 mg/kg bw. Additional or isolated incidents of toxicity noted in animals treated with 1581 mg/kg bw were ataxia, tiptoe gait, and laboured respiration. The surviving animals showed increases in body weight over the study period. Abnormalities generally seen at necropsy of animals that died or were killed in extremis during the study were haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver and dark kidneys. Effects on the gastro-intestinal tract were haemorrhage of the small and large intestines and gastric mucosa, and haemorrhage or sloughing of the non-glandular epithelium of the stomach. White foci were noted on the non-glandular epithelium of the stomach of animals killed on day 14, after treatment at 1000 or 1581 mg/kg bw. Ulceration of the non-glandular epithelium of the stomach was also noted in one male treated with 1581 mg/kg bw. Abnormally red lungs, dark liver and dark kidneys were noted at necropsy of animals treated with 1000 mg/kg bw that were killed on day 14. Based on the outcome of the study the LD50 was determined to be 1541 mg/kg bw (male/female).

In conclusion, the test substance meets the criteria to be classified as harmful after single ingestion (Xn, R22 according to 67/584/EEC and Cat 4, H302 according to EC/1272/2008).

Acute toxicity: vial inhalation route

In the available key study (Dow Chemical U.S.A., 1978), the registered substance was investigated for acute inhalation toxicity in a study that predates the appropriate OECD test guideline and GLP. However, the study was performed according to a protocol that is similar to the OECD test guideline. 10 Fischer 344 rats per sex per dose were exposed to vapourised test material in a whole-body inhalation system for 1 and 6 h, respectively. The doses applied into the inhalation chamber were 40, 20, and 10 ppm (equal to 0.2533, 0.1267, and 0.0633 mg/L) for 1 h and 7, 4, and 2 ppm (equal to 0.0443, 0.0253, and 0.0127 mg/L) for the 6 h exposure duration. In the 6 h exposure experiment 2/10 male rats exposed to 7 ppm died between 24 and 32 h post exposure, and 4/10 died between 32 and 48 h post exposure. A 7th rat was found to be clearly moribund 72 h post exposure and was sacrificed. The remaining 3 rats survived 14 days until sacrifice and necropsy. Of the 10 females, 4 died between 24 and 32 hours post exposure, 3 more by 48 hours post exposure. The remaining 3 rats survived 14 days until sacrifice. At 4 ppm exposure 6/10 males died between 32 and 48 h post-exposure, and 3/10 female died between 24 and 32 h post-exposure. The remaining animals survived until sacrifice. None of the rats, either male or female, died following exposure to 2 ppm up to sacrifice 14 days later. 1 h exposure to 40 ppm revealed 2/10 males dying within 24 h post exposure. 2 more males died within 100 h post exposure and 4 more males died on the 11th and 13th day post exposure due to rapid weight loss. Of the 10 females, 2 died 4 days post exposure and 3 more died in the 11th and 12th days post exposure. At 20 ppm 4/10 males died on the 10th and 11th days post exposure after their rapid weight loss from day 7 on. In the 6 h exposure experiment all rats exposed to 7 ppm showed progressively increased signs of eye and nasal irritation and respiratory difficulties during treatment. Just after exposure there were signs of eye irritation, and dried dark red-brown exudate on the noses; respiratory difficulties appeared to have diminished, only slight rales being observable in a few rats. 16 h later there was evidence of severe respiratory distress in all animals exposed. At 4 ppm signs of the rats post-exposure were essentially the same as in the 7 ppm exposure, but slightly less pronounced. The surviving females showed severe weight loss, whereas 6 of the 7 rats regained weight and were at normal levels at sacrifice, but the seventh female showed essentially monotonous weight loss to sacrifice. Signs in the rats during exposure to 2 ppm were slight, and just after 30 min venting period post-exposure they appeared normal. Clinical signs in the animals treated with 40 ppm for 1 h developed much more quickly than in the 6 hour exposure experiment. During exposures, all rats showed signs of eye and nasal irritation and respiratory difficulties. After exposure and a 30 min venting period, both male and female rats, showed diminished signs of respiratory difficulties, but did show laboured breathing, stains on their noses, and appeared lethargic. The two male rats surviving to necropsy at day 14 post exposure showed laboured breathing and were extremely lethargic. The five surviving females did not show abnormal signs. Signs during and post exposure to 20 ppm were similar to those seen in rats exposed to 40 ppm, but to lesser extent. The females apparently tolerated the exposure better than the males. Five of the six survivors showed laboured breathing and extreme lethargy, the sixth, however, appeared normal. At the end of the 14 days all females appeared normal. Signs during exposure to 10 ppm were slight; females showed no signs post exposure and only few males showed slight stains on the noses. Generally severe body weight losses were observed for all animals in both experiments in all doses tested. Only in the 10 ppm dose group af the 1 h experiment body weights normalised in 9/10 animals each sex within the 14 day observation period. Gross pathology revealed generally effects on the respiratory tract, as well as irritating effects to the eyes. Secondary effects such as decreased deposits of adipose tissue were also observed and considered to be related to the severe body weight losses. No specific target organ toxicity except for irritating effects on the respiratory tract were observed. The LC50 was found to be 4.4 ppm (equal to 0.0281 mg/L).

Based on this data, the test substance meets the criteria to be classified as very toxic after inhalation (T+, R26 according to 67/584/EEC and Cat 1, H330 according to EC/1272/2008).

Acute toxicity: via dermal route

There are no data available to determine the acute dermal toxicity of the submission substance. However, in accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the dermal route (required in Section 8.5.2 of REACH Annex VIII) does not need to be conducted as reliable data via the oral and inhalation routes are available.


Justification for classification or non-classification

The available data are reliable and suitable for classification. Based on this data, the registered substance meets the criteria to be classified for actute oral toxicity (Xn, R22) and acute inhalation toxicity (T+, R26) according to 67/584/EEC and acute oral toxicity (Cat 4, H302) and acute inhalation toxicity (Cat 1, H330) according to EC/1272/2008.