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Administrative data

Description of key information

Acute oral toxicity: LD50 (rat, females) = 3980 mg/kg bw; OECD Guideline 401; GLP
Acute inhalation toxicity: no relevant route of exposure
Acute dermal toxicity: LD50 (rat, male/female) > 2000 mg/kg bw; OECD Guideline 402; GLP

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:
1984-03-20 to 1984-04-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted May 12, 1981
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Methacrylate de Benzyle (MABz)
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 4 – 6 weeks
- Weight at study initiation: 101 – 196 g (males), 100 – 169 g (females)
- Fasting period before study: over night before study initiation, up to 2 h after administration
- Housing: in groups of 5 animals in polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): standard laboratory rodent diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 4°C
- Humidity (%): 45 – 60%
- Air changes (per hr): ca. 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
no vehicle used

MAXIMUM DOSE VOLUME APPLIED:
7.77 mL/kg bw
Doses:
range finding study: 5000, 8000 mg/kg bw
main study: 4000, 5040, 6350, 8000 mg/kg bw
No. of animals per sex per dose:
range finding study: 2
main study: 5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 5 days (range finding study), 14 days (main study)
- Frequency of observations and weighing: Animals were observed 0.5, 1, 2, 3, 4 and 5 hours following dosing and then at least once daily for 14 days. Mortalities and evidence of overt toxicity were recorded at each observation. In addition individual bodyweights were recorded on days 0, 7 and 14.
- Necropsy of survivors performed: Surviving animals were killed on day 14. All animals that died during the study and those killed on day 14 were subjected to a macroscopic post mortem examination.
- Other examinations performed: -
Statistics:
LD50 and 95% confidence intervals were calculated according to Litchfield JT and Wilcoxon F (1949) J. Pharmac, Exp.Ther.96,99
Preliminary study:
1/4 animals dead at 5000 mg/kg bw
4/4 animals dead at 8000 mg/kg bw
Sex:
female
Dose descriptor:
LD50
Effect level:
3 980 mg/kg bw
Based on:
test mat.
95% CL:
2 760 - 5 730
Sex:
male
Dose descriptor:
LD50
Effect level:
4 820 mg/kg bw
Based on:
test mat.
95% CL:
3 950 - 5 880
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4 450 mg/kg bw
Based on:
test mat.
95% CL:
3 620 - 5 470
Mortality:
- 4000 mg/kg bw: 1/5 males, 3/5 females dead
- 5040 mg/kg bw: 3/5 males, 4/5 females dead
- 6350 mg/kg bw: 4/5 males, 4/5 females dead
- 8000 mg/kg bw: 5/5 males, 5/5 females dead
Clinical signs:
- pilo-erection, hunched posture, decreased respiratory rate and lethargy was observed on all treatment groups shortly after dosing
- ptosis was observed in all animals of the 8000 mg/kg dose group
- ataxia, pallor of the extremi ties, body tremors, convulsions, loss of the righting reflex, increased lacrimation, abdominal discomfort and hind limb paralysis mainly prior to death in some rats.
- survivors had recovered on day 9
Body weight:
- reduced body weight gains in females at all dose levels in the first week; normal body weight gains in second week
- reduced body weight gains in males from 5040 mg/kg bw and higher; normal body weight gains in second week
Gross pathology:
- gross pathology of surviving animals revealed no abnormalities
- necropsy of the dead animals revealed haemorrhage of the lungs, pallor of the liver, spleen and kidneys and haemorrhage or inflammation of the glandular region of the stomach and/or small intestine
Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: other: CLP, EU GHS (Regulation (EC) No 1272/2008)
Conclusions:
The acute oral LD50 of BNMA in rat is 4820 mg/kg bw (95% C.I. 3950 – 5880) in males and 3980 mg/kg bw (95% C.I. 2760 – 5730) in females. The combined oral LD50 is 4450 mg/kg bw (95% C.I. 6320 – 5470).
Executive summary:

In an acute oral toxicity study according to OECD guideline 401 (adopted May 12, 1981), groups of fasted, 4 to 6 weeks old, Sprague Dawley rats (5/sex) were given a single oral dose of BNMA at doses of 4000, 5040, 6350 and 8000 mg/kg bw and observed for 14 days.

Decreased respiratory rate, pilo-erection and lethargy was observed in all treatment groups shortly after dosing. Ptosis was observed in all animals of the 8000 mg/kg dose group. Ataxia, pallor of the extremities, body tremors, convulsions, loss of the righting reflex, increased lacrimation, abdominal discomfort and hind limb paralysis were mainly seen prior to death in some rats. Surviving animals had recovered on day 9.

Depressed bodyweight gains were recorded for female rats at all dose levels and male rats at 5040 mg/kg bw and above during the first week of observation only. Normal bodyweight gains were seen in all rats during Week 2. Gross pathology of surviving animals revealed no abnormalities. Necropsy of the dead animals revealed haemorrhage of the lungs, pallor of the liver, spleen and kidneys and haemorrhage or inflammation of the glandular region of the stomach and/or small intestine.

 

Oral LD50 Males = 4820 mg/kg bw (95% C.I. 3950 – 5880)

      Females = 3980 mg/kg bw (95% C.I. 2760 – 5730)

      Combined = 4450 mg/kg bw (95% C.I. 6320 – 5470)

GHS criteria not met

 

NOTE: Any of data in this dataset are disseminated by the European Union on a right-to-know basis and this is not a publication in the same sense as a book or an article in a journal. The right of ownership in any part of this information is reserved by the data owner(s). The use of this information for any other, e.g. commercial purpose is strictly reserved to the data owners and those persons or legal entities having paid the respective access fee for the intended purpose.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 000 mg/kg bw

Acute toxicity: via inhalation route

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:
2011-10-19 to 2011-12-27
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
With acceptable restrictions. GLP.
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
adopted 30 May 2008
Deviations:
yes
Remarks:
3 animals were subject to reduced exposure time ranging between >4 to 24 hours
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted 24th Feb, 1987
Deviations:
yes
Remarks:
3 animals were subject to reduced exposure time ranging between >4 to 24 hours
GLP compliance:
yes (incl. QA statement)
Remarks:
Certificate dated 6 April 2009
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): Benzyl methacrylate
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- WISTAR rats Crl:WI(Han) (full barrier)
- Age at study initiation: males: approx. 13 weeks, females: approx. 14 weeks
- Weight at study initiation: males: 250-267 g, females: 205-223 g
- Fasting period before study: no
- Housing: separate IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding, full barrier in air-conditioned room
- Diet (e.g. ad libitum): Altromin 1324 maintenance diet for rats and mice, ad libitum
- Water (e.g. ad libitum): tap water, sulphur acidified to a pH value of approx. 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals), ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 10/hr
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 2011-09-20 to 2011-11-10
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal area of the trunk
- % coverage: 10
- Type of wrap if used: gauze-dressing with non-irritating tape, fixed with additional dressing in suitable manner.

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): n/a (undiluted)
- Constant volume or concentration used: yes (single dose)

Duration of exposure:
24 h (except for 3 test animals which unwrapped themselves overnight, leading to a shortened application period of 4 to 24 hours)
For the animals which unwrapped themselves, no signs of toxicity and significant dermal irritation were observed. As at the 4 h control observation the dressing was tight on all animals, it is very likely that the 3 animals unwrapped themselves clearly after the 4 h period. It can be expected that these animals have been exposed to the test item partially also by the oral route, while grooving, in addition to the dermal route.
It is concluded that the abbreviated exposure period has no effect on the overall result and the classification of the test item, and that a sufficient estimation of the dermal toxicity is ensured.
The validity of the study is not affected and according to animal welfare reasons it was decided not to repeat the study.
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 observation several times on day of dosing (at least once during first 30 minutes and with special attention given during the first 4 hours post-dose). Symptoms were recorded as soon as noticed. Thereafter, daily observations for clinical signs until end of observation period. All abnormalities were recorded. Animals were weighed on day 1 (prior to application of dose) and on day 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed:
-- In case of gross pathological changes, tissues were preserved for a possible histopathological evaluation.
-- The treated areas of skin were examined daily for signs of primary skin irritation. Signs of erythema and oedema were assessed using the scoring system laid down in OECD Guideline 404, adopted 24th April 2002.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
All animals survived until the end of the observation period of 14 days.
Clinical signs:
No signs of systemic toxicity were observed
Body weight:
A slight weight loss was recorded for 1 of 5 female animals during the first week, but 4 of 5 female animals showed weight gain during the second week and stagnation was recorded for 1 of 5 female animals. According to discussion by the study authors, the effects on weight development might be secondary to the dressing, and toxicological relevance of this finding cannot clearly be concluded. The male animals showed weight gain during the first and the second week of the observation.
Gross pathology:
With the exception of acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection, no specific gross pathological changes were recorded for any animal.
Other findings:
Signs of irritation:
- very slight erythema (grade 1, reversible within 8 days) was observed in 1/5 females on days 4, 5, and 7; this animal showed also eschar (up to day 10) and desquamation (up to day 12)
- eschar, desquamation and scratches were observed in one further female, without leading to scoring
- all effects were reversible within 13 days - females with reduced exposure time due to unwrapping showed either no effects or only non-scored eschar (day 5 to 7) or scratches (day 7)
- No skin irritation was observed at the males.
Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: CLP, EU GHS (Regulation (EC) No 1272/2008)
Conclusions:
The LD50-value for acute dermal toxicity of the test substance BNMA is > 2000 mg/kg bw.
Executive summary:

In an acute dermal toxicity study according to OECD guideline 402 (adopted 24th Feb, 1987), EU Method B.3 (adopted 30 May 2008), 5 male and 5 female young adult WISTAR Crl: WI(Han) rats were dermally exposed to BNMA (98.37%) for 24 hours under a semiocclusive dressing to approx. 10% of body surface area at doses of 2000 mg/kg bw. Animals then were observed for 14 days.

No animal died. Erythema grade 1 was observed in 1 of 5 female animals. Eschar and scratches were observed in 3 of 5 female animals. Desquamation was observed in 2 of 5 female animals. No signs of irritation were found for the male animals. All signs of irritation were reversible within the observation period. No clinical signs of systemic toxicity were observed. Weight gain was positive and within normal range, except for 3 female rats which temporarily lost weight in the first week. No macroscopic substance related pathologic organ findings were noted during necropsy.

Dermal LD50

Males > 2000  mg/kg bw

Females > 2000  mg/kg bw

Combined > 2000  mg/kg bw

NOTE: Any of data in this dataset are disseminated by the European Union on a right-to-know basis and this is not a publication in the same sense as a book or an article in a journal. The right of ownership in any part of this information is reserved by the data owner(s). The use of this information for any other, e.g. commercial purpose is strictly reserved to the data owners and those persons or legal entities having paid the respective access fee for the intended purpose.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Reliable (RL 1-2), relevant and adequate data are available for the acute oral and dermal toxicity of BNMA.

 

Acute oral toxicity

In an acute oral toxicity study according to OECD guideline 401 (adopted May 12, 1981), groups of fasted, 4 to 6 weeks old, Sprague Dawley rats (5/sex) were given a single oral dose of BNMAat doses of 4000, 5040, 6350 and 8000 mg/kg bw and observed for 14 days.

Decreased respiratory rate, pilo-erection and lethargy were observed in all treatment groups shortly after dosing. Ptosis was observed in all animals of the 8000 mg/kg dose group. Ataxia, pallor of the extremities, body tremors, convulsions, loss of the righting reflex, increased lacrimation, abdominal discomfort and hind limb paralysis were mainly seen prior to death in some rats. Surviving animals had recovered on day 9.

Depressed bodyweight gains were recorded for female rats at all dose levels and male rats at 5040 mg/kg bw and above during the first week of observation only. Normal bodyweight gains were seen in all rats during Week 2. Gross pathology of surviving animals revealed no abnormalities. Necropsy of the dead animals revealed haemorrhage of the lungs, pallor of the liver, spleen and kidneys and haemorrhage or inflammation of the glandular region of the stomach and/or small intestine.

Oral LD50 Males = 4820 mg/kg bw (95% C.I. 3950 – 5880)

Oral LD50 Females = 3980 mg/kg bw (95% C.I. 2760 – 5730)

Oral LD50 Combined = 4450 mg/kg bw (95% C.I. 6320 – 5470)

 

This finding is supported by another study:

In an acute oral toxicity study according to OECD guideline 401 (adopted May 12, 1981), groups of fasted, 7 to 10 weeks old Wistar rats, 3/sex were given a single oral dose of BNMA(100% a.i.)in PEG400 at doses of 1000 and 5000 mg/kg bw and observed for 14 days.

In the 1000 mg/kg dose group no mortality occurred. In the 5000 mg/kg dose group 2/3 females and 1/3 males died.

Sedation, dyspnea, curved body position and ruffled fur were observed; these symptoms were more pronounced at 5000 mg/kg. Additionally, ataxia was observed in the 5000 mg/kg dose group. The surviving rats recovered within 7 days. There was no effect on body weight gain. Gross pathology revealed no macroscopic organ changes.

Oral LD50 combined = 5000 mg/kg bw

              

Acute inhalative toxicity

A study on acute inhalation toxicity is unjustified in accordance to REACH regulation Annex VIII, column 2 due to exposure considerations as well as in accordance to REACH regulation Annex XI due to scientific considerations. The use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur. Furthermore, systemic toxicity relevant to humans did not appear in acute by oral or dermal exposure. Considering the exposure probability and the available information on the intrinsic toxic activity of the substance, an inhalative systemic toxicity risk to humans is unlikely and therefore, the conduct of an inhalative toxicity study is not scientifically necessary. Thus, also animal welfare is respected according to REACH intentions.

Acute dermal toxicity

In an acute dermal toxicity study according to OECD guideline 402 (adopted 24th Feb, 1987), EU Method B.3 (adopted 30 May 2008), 5 male and 5 female young adult WISTAR Crl: WI(Han) rats were dermally exposed to BNMA (98.37%) for 24 hours under a semiocclusive dressing to approx. 10% of body surface area at doses of 2000 mg/kg bw. Animals then were observed for 14 days.

No animal died. Erythema grade 1 was observed in 1 of 5 female animals. Eschar and scratches were observed in 3 of 5 female animals. Desquamation was observed in 2 of 5 female animals. No signs of irritation were found for the male animals. All signs of irritation were reversible within the observation period. No clinical signs of systemic toxicity were observed. Weight gain was positive and within normal range, except for 3 female rats which temporarily lost weight in the first week. No macroscopic substance related pathologic organ findings were noted during necropsy.

Dermal LD50Males > 2000  mg/kg bw

Dermal LD50Females > 2000 mg/kg bw

Dermal LD50Combined > 2000 mg/kg bw

Based on the available information, the acute toxicity of BNMA is low for oral and dermal routes of administration in rat. There are no data gaps in acute toxicity. Even though there is no information on acute inhalative toxicity, there is no reason to believe that the acute toxicity is higher for this route of exposure. Even though there is no information on acute toxicity in humans, there is no reason to believe that the low acute toxicity observed in experimental animals would not be relevant for human health.


Justification for selection of acute toxicity – oral endpoint
OECD guideline study, GLP

Justification for selection of acute toxicity – inhalation endpoint
Inhalation is no relevant route of exposure and testing by inhalation is not appropriate. Exposure of humans via inhalation is unlikely taking into account the possibility of exposure to aerosols, particles or droplets of an inhalable size.

Justification for selection of acute toxicity – dermal endpoint
OECD guideline study, GLP

Justification for classification or non-classification

Based on the available data, BNMA does not need to be classified for acute toxicity according to regulation (EC) 1272/2008. Thus, no labelling is required.

GHS criteria not met