Registration Dossier

Diss Factsheets

Administrative data

Description of key information

- LD50 oral = 500 mg/kg bw in rats
- LC50 > 5.32 mg/L for 4 h in rats

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:
10 June - 01 July 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well conducted and well described study in accordance with GLP and OECD Guideline 423 without any deviation.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: 8 weeks
- Weight at study initiation: 190-211 g
- Fasting period before study: Food was removed at Day 1 and then redistributed 4 h after the test item administration.
- Housing: Animals were housed by group of three in solid-bottomed clear polycarbonate cages with stainless steel mesh lids.
- Diet: Food, ad libitum
- Water: Drinking water (tap-water from public distribution system), ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-23 °C
- Humidity: 41-70 %
- Air changes: At least ten changes per hour
- Photoperiod: 12 h dark / 12 h light
Route of administration:
oral: gavage
Vehicle:
DMSO
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 and 200 mg/mL

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
Doses:
300 and 2000 mg/kg bw
No. of animals per sex per dose:
- 3 females/dose (2000 mg/kg bw)
- 6 females/dose (300 mg/kg bw)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical signs and mortality: Animals were observed frequently during the hours following administration of the test item, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day.
Bodyweight: The animals were weighed on Day 0 (just before administering the test item) then on Days 2, 7 and 14.
- Necropsy of survivors performed: Yes; On Day 14, the animals were anaesthetised with sodium pentobarbital and administration continued to fatal levels and macroscopic examination was performed.
Statistics:
None
Sex:
female
Dose descriptor:
LD50
Effect level:
500 mg/kg bw
Based on:
test mat.
Remarks on result:
other: All animals were died at 2000 mg/kg bw. No mortality was observed at 300 mg/kg bw.
Mortality:
- All three treated rats were died at 2000 mg/kg bw between 3 and 6 h after the test item administration.
- No mortality was observed at 300 mg/kg bw.
Clinical signs:
- At 2000 mg/kg bw, mortalities were preceded by a decrease of the spontaneous activity (3/3) associated with a decrease of muscle tone (2/2), a decrease or an absence of Preyer's and righting reflex (3/3) and a piloerection (2/2).
- At 300 mg/kg bw, from 30 minutes after the test item administration, a decrease of the spontaneous activity (6/6) associated with a decrease of righting reflex (5/6) and a piloerection (5/6). The animals recovered a normal activity between the 3rd and the 4th day of the test.
Body weight:
- Body weight evolution of the animals remained normal throughout the study.
Gross pathology:
- Macroscopical examination of the animals treated at 2000 mg/kg bw which died during the test revealed a white thickening layer at the level of the corpus.
- No macroscopic abnormalities were observed at 300 mg/kg bw.
Other findings:
None

None

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the oral LD50 for ZnDMA is 500 mg/kg bw in female rats therefore it is classified as R22 "harmful if swallowed" according to the Annex VI to the Directive 67/548/EEC and classified to "category 4" according to the CLP Regulation (EC) N° (1272-2008).
Executive summary:

In an acute oral toxicity study performed according to OECD Guideline 423 and in compliance with GLP, groups of Sprague Dawley rats were given a single oral (gavage) dose of ZnDMA at 2000 mg/kg bw (3 females) followed by 300 mg/kg bw (6 females). Animals were then observed for mortality, clinical signs and bodyweights for 14 days and were all sacrificed for macroscopic examination.

All three treated rats were died at 2000 mg/kg bw between 3 and 6 h after the test item administration. No mortality was observed at 300 mg/kg bw. At 2000 mg/kg bw, mortalities were preceded by a decrease of the spontaneous activity (3/3) associated with a decrease of muscle tone (2/2), a decrease or an absence of Preyer's and righting reflex (3/3) and a piloerection (2/2). At 300 mg/kg bw, from 30 minutes after the test item administration, a decrease of the spontaneous activity (6/6) associated with a decrease of righting reflex (5/6) and a piloerection (5/6). The animals recovered a normal activity between the 3rd and the 4th day of the test. Body weight evolution of the animals remained normal throughout the study. Macroscopical examination of the animals treated at 2000 mg/kg bw which died during the test revealed a white thickening layer at the level of the corpus. No macroscopic abnormalities were observed at 300 mg/kg bw. In this study, the oral LD50 of test item was considered to be 500 mg/kg bw in female rats.

Under the test conditions, the oral LD50 for ZnDMA is 500 mg/kg bw in female rats therefore it is classified as R22 "harmful if swallowed" according to the Annex VI to the Directive 67/548/EEC and classified to "category 4" according to the CLP Regulation (EC) N° (1272-2008).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 mg/kg bw
Quality of whole database:
GLP and OECD guideline-compliant study with Klimisch score 1

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:
09-31 October 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study conducted according to OECD 436 Guideline with one deviation: one sample was greater than 20 % of the mean achieved atmosphere concentration.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
yes
Remarks:
one sample was greater than 20 % of the mean achieved atmosphere concentration
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: RccHan : WIST strain
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd, Oxon, UK.
- Age at study initiation: Approximately 8-12 weeks
- Weight at study initiation: 200-350 g
- Housing: Animals were housed in groups of up to three by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes.
- Diet: Food (Harlan 2014C Rodent Diet, Harlan Laboratories UK Ltd, Oxon, UK), ad libitum
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 30-70 %
- Air changes: 15/h
- Photoperiod: 12 h dark / 12 h light

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: SAG 410 Solid Aerosol Generator (TOPAS GmbH, Dresden, Germany)
- Exposure chamber volume: Approximately 30 litres (dimensions: 28 cm diameter x 50 cm high)
- Method of holding animals in test chamber: Each rat was individually held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber and sealed by means of a rubber ‘O’ ring.
- Source and rate of air: Compressed air at 60 L/min providing 120 air changes per hour.
- Method of particle size determination: Particle size of the generated atmosphere inside the exposure chamber was determined three times during the exposure period using a Marple Personal Cascade Impactor (Westech IS Ltd, Beds., UK).
- Treatment of exhaust air: The extract from the exposure chamber passed through a ‘scrubber’ trap and was connected with a high efficiency filter to a metered exhaust system.
- Temperature and humidity in air chamber: 19-20 ºC and 56-68 %; Temperature and relative humidity inside the exposure chamber were measured by an electronic thermometer/humidity meter (Hanna Instruments Ltd, Beds., UK) located in a vacant port in the animals’ breathing zone of the chamber and recorded every thirty minutes throughout the four-hour exposure period.

TEST ATMOSPHERE
- Samples taken from breathing zone: Yes

VEHICLE
- In order to facilitate aerosolisation and reduce particle size, the test item was ground using a small amount of diethyl ether in a Retsch Planetary Ball Mill (Retsch (UK) Ltd, Leeds, UK) the solvent was removed via evaporation prior to use.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: See table 7.2.2/1
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.69 / 2.66
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5 mg/mL (target concentration)
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: All animals were observed for clinical signs at hourly intervals during exposure, immediately on removal from the restraining tubes at the end of exposure, one hour after termination of exposure and subsequently once daily for up to 14 days.
- Frequency of weighing: Individual bodyweights were recorded on arrival, prior to treatment on the day of exposure and on Days 1, 3, 7 and 14 or at death.
- Necropsy of survivors performed: Yes, All animals, including the one that died during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded. The respiratory tract was subjected to a detailed macroscopic examination for signs of irritancy or local toxicity.
Statistics:
None
Preliminary study:
Not applicable
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.32 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: No mortality was observed in males and 1/3 female died during the study
Mortality:
No mortality was observed in males and 1/3 female died during the study.
Clinical signs:
other: - Upon removal from the chamber, all animals exhibited increased respiratory rate and ataxia and occasional instances of noisy respiration, which remained one hour post removal. - One day post exposure, all animals exhibited hunched posture, pilo-erection
Body weight:
- All animals exhibited bodyweight losses on the first day post-exposure.
- All animals exhibited bodyweight gains during the remainder of the recovery period, with the exception of one surviving female animal which showed no bodyweight gain from Days 1 to 3 post-exposure.
Gross pathology:
- No macroscopic abnormalities were detected at necropsy amongst the animals that survived until the end of the fourteen day recovery period.
- Macroscopic abnormalities such as dark patches in the lungs and gaseous distension in stomach were noted at necropsy in the animal that died during the course of the study.
Other findings:
None

Table 7.2.2/1: Particle Size Distribution

Cascade Impactor Data

Impactor Stage

Number

Cut Point

(μm)

Amount Collected (mg) per Sample Number

Mean Amount Collected (mg)

1

2

3

3

8.6

0.27

0.14

0.16

0.19

4

5.5

0.60

0.62

0.46

0.56

5

3.8

0.65

0.80

0.62

0.69

6

1.7

0.62

1.03

0.91

0.85

7

0.86

0.36

0.20

0.19

0.25

8

0.41

0.19

0.02

0.10

0.10

Back-up Filter

<0.41

0.22

0.23

0.23

0.23

Total Mean Amount of Test Item Collected

2.87

 

Calculation

Cut Point

(μm)

Log10

Cut Point

Mean Cumulative Amount Less Than Cut Point

mg

%

Probit

8.6

0.935

2.68

93.4

6.51

5.5

0.740

2.12

73.9

5.64

3.8

0.780

1.43

49.8

5.00

1.7

0.230

0.58

20.2

4.17

0.86

-0.066

0.33

11.5

3.80

0.41

-0.387

0.23

8.01

3.60

 

Results

 

Mean Mass Median Aerodynamic Diameter (MMAD) = 2.69 μm

Geometric Standard Deviation (GSD) = 2.66

Predicted amount less than 4 μm = 65.8%

 

Table 7.2.2/2: Mortality Data

Mean

Achieved

Atmosphere

Concentration

(mg/L)

Sex

Deaths

During

Exposure

Deaths

Post

Exposure

(1 Hour)

Deaths During Day of Observation

Total

Deaths

1

2

3

4

5

6

7

8-14

5.32

Male

0

0

0

0

0

0

0

0

0

0

1/6

Female

0

0

0

1

0

0

0

0

0

0

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the inhalation LC50 for Zinc dimethacrylate is higher than 5.32 mg/mL for 4 h in rats. It is therefore not classified according to the Annex VI to the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).
Executive summary:

In an acute inhalation toxicity study performed according to OECD Guideline 436, groups (3/sex/dose) of RccHan : WIST strain rats were exposed (nose only) to dust atmosphere of Zinc dimethacrylate at the concentration of 5.32 mg/mL (mean achieved) for 4 h. Animals were observed for mortality and signs of sensory irritation, airflow limitation and pulmonary irritation during the exposure period and continued the observation up to 14 days and necropsy was performed.

No mortality was observed in males and 1/3 female died on day 2. Common abnormalities noted during the study included increased respiratory rate, ataxia, hunched posture, pilo-erection, red/brown staining around the eyes and/or snout and wet fur. Frequent occurrences of sneezing and occasional instances of decreased respiratory rate and noisy respiration were also noted on the first days post exposure. The surviving animals recovered to appear normal from Days 8 to 9 post-exposure. All animals exhibited bodyweight losses on the first day post-exposure. All animals exhibited bodyweight gains during the remainder of the recovery period, with the exception of one surviving female animal which showed no bodyweight gain from Days 1 to 3 post-exposure. No macroscopic abnormalities were detected at necropsy amongst the animals that survived until the end of the 14 day recovery period. Macroscopic abnormalities such as dark patches in the lungs and gaseous distension in stomach were noted at necropsy in the animal that died during the course of the study. In this study, the combined inhalation LC50 of Zinc dimethacrylate was considered to be higher than 5.32 mg/mL for 4 h.

 

Under the test conditions, Zinc dimethacrylate inhalation LC50 is higher than 5.32 mg/mL for 4 h in rats, and is therefore not classified according to the Annex VI to the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 320 mg/m³
Quality of whole database:
GLP and OECD guideline-compliant study with Klimisch score 1

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In an acute oral toxicity study performed according to OECD Guideline 423 and in compliance with GLP, groups of Sprague Dawley rats were given a single oral (gavage) dose of zinc methacrylate at 2000 mg/kg bw (3 females) followed by 300 mg/kg bw (6 females). Animals were then observed for mortality, clinical signs and bodyweights for 14 days and were all sacrificed for macroscopic examination. All three treated rats were died at 2000 mg/kg bw between 3 and 6 h after the test item administration. No mortality was observed at 300 mg/kg bw. At 2000 mg/kg bw, mortalities were preceded by a decrease of the spontaneous activity (3/3) associated with a decrease of muscle tone (2/2), a decrease or an absence of Preyer's and righting reflex (3/3) and a piloerection (2/2). At 300 mg/kg bw, from 30 minutes after the test item administration, a decrease of the spontaneous activity (6/6) associated with a decrease of righting reflex (5/6) and a piloerection (5/6). The animals recovered a normal activity between the 3rd and the 4th day of the test. Body weight evolution of the animals remained normal throughout the study. Macroscopical examination of the animals treated at 2000 mg/kg bw which died during the test revealed a white thickening layer at the level of the corpus. No macroscopic abnormalities were observed at 300 mg/kg bw. In this study, the oral LD50 of test item was considered to be 500 mg/kg bw in female rats.

In a GLP-compliant acute inhalation toxicity study performed according to OECD Guideline 436 in wistar rats, 3 animals/sex were exposed (nose only) to a dust atmosphere of zinc methacrylate at the concentration of 5.32 mg/L (mean achieved) for 4 hr. One female was found dead on Day 2 post-dosing. All the other animals survived. Reversible common abnormalities after inhalation exposure to dust (increased respiratory rate, ataxia, hunched posture, pilo-erection, red/brown staining around the eyes) with frequent occurences of sneezing were observed on the first days post exposure and were totally reversed within 8 -9 days. Body weight loss was also observed on the first day post-exposure but was reversed within 24 hr with the exception of one surviving female that did not show any weight gain from Day 1 to 3 post exposure. No macroscopic abnormalities were detected at necropsy amongst the animals that survived until the end of the 14 day recovery period. Macroscopic abnormalities such as dark patches in the lungs and gaseous distension in stomach were noted at necropsy in the animal that died during the course of the study.

 

Justification for selection of acute toxicity – oral endpoint
Only one study available

Justification for selection of acute toxicity – inhalation endpoint
Only one study available

Justification for classification or non-classification

In an acute oral toxicity study performed according to OECD Guideline 423 and in compliance with GLP, the oral LD50 for zinc methacrylate was 500 mg/kg bw in female rats therefore it is classified as R22 "harmful if swallowed" according to the Annex VI to the Directive 67/548/EEC and classified to "category 4" according to the CLP Regulation (EC) No 1272-2008.

In a GLP-compliant acute inhalation toxicity study performed according to OECD Guideline 436 in wistar rats, LC50 is higher than 5.32 mg/L for 4 hr, therefore zinc methacrylate does not need to be classified for acute inhalation toxicity, according to the Annex VI to the Directive 67/548/EEC and to the CLP Regulation (EC) No 1272/2008.

Acute toxicity studies were provided for the oral and inhalation routes. In the acute toxicity study by oral route, all animals died at 2000 mg/kg bw but no death occured at 300 mg/kg bw therefore the LD50 was considered to be 500 mg/kg bw. Also, no acute toxicity was observed by inhalation. As, zinc methacrylate is not classified for skin irritation and that zinc and methacrylate compounds are known to be barely absorbed by dermal route, it is not expected to have acute systemic or local toxic effects via the dermal route. Thus, it should not be classified for acute dermal toxicity under the Directive 67/548/EEC and the CLP Regulation (EC) No 1272/2008.

Categories Display