Reaction mass of bis[4-(vinyloxy)butyl] hexane-1,6-diylbiscarbamate and 9,18-dioxo-3,8,19-trioxa-10,17-diazapentacos-1-en-25-yl [6-({[4-(vinyloxy)butoxy]carbonyl}amino)hexyl]carbamate

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03 October 2016 - 17 October 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The study was performed as a data requirement for a registration in China.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

September 2009

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

May 2008, including most recent amendments

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

August 1998

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147

Version / remarks:

November 2000; including the most recent partial revisions

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

d.d. 03 November 2015

Test type:

fixed concentration procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

420-990-1

EC Name:

-

Cas Number:

146421-65-0

Molecular formula:

C20H36N2O6

IUPAC Name:

4-(ethenyloxy)butyl N-[6-({[4-(ethenyloxy)butoxy]carbonyl}amino)hexyl]carbamate

Constituent 2

Reference substance name:

4-(ethenyloxy)butyl N-{6-[({[6-({[6-({[4-(ethenyloxy)butoxy]carbonyl}amino)hexyl]carbamoyl}oxy)hexyl]oxy}carbonyl)amino]hexyl}carbamate

Cas Number:

1516571-16-6

Molecular formula:

C34H62N4O10

IUPAC Name:

4-(ethenyloxy)butyl N-{6-[({[6-({[6-({[4-(ethenyloxy)butoxy]carbonyl}amino)hexyl]carbamoyl}oxy)hexyl]oxy}carbonyl)amino]hexyl}carbamate

Test material form:

solid: flakes

Details on test material:

Appearance: White flakes
Name as cited in test report: URALAC P 1920C
Test item storage: At room temperature

Test animals

Species:

rat

Strain:

other: Crl: WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 10-11 weeks old
- Weight at study initiation: males: 293-314 g; females: 193-211 g
- Fasting period before study: no
- Housing: Group housing of 5 animals in Makrolon cages (type IV; height 18 cm) containing sterilised sawdust as bedding material and paper as cage-enrichment
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum except during exposure to the test item
- Water: tap water ad libitum except during exposure to the test item
- Acclimation period: 5 days

Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.

ENVIRONMENTAL CONDITIONS (set to maintain)
- Temperature (°C): 18 - 24
- Humidity (%): 40-70
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

> 3.8 - < 5.2 µm

Geometric standard deviation (GSD):

1.8

Remark on MMAD/GSD:

The Mass Median Aerodynamic Diameter (MMAD) and geometric standard deviation (gsd) were determined twice during the exposure period. The MMAD was 5.2 μm (gsd 1.8) and 3.8 μm (gsd 1.8). The first measurement just felt outside the recommended range of 1 - 4 μm. There was no evidence for test item deposition in the upper airways due to this larger MMAD. Since the second measurement felt within the recommended range and since it is generally known that good distribution throughout the lung requires particles with an aerodynamic diameter between 1 and 5 μm, it can be assumed that sufficient deposition in the lower respiratory tract occurred during the exposure.

Details on inhalation exposure:

TEST ITEM PREPARATION:
Before use the test item was grinded with an automatic grinder (Retsch PM100 Planetary Ball Mill, Retsch GmbH, Haan, Germany) and additionally with a small automatic grinder. The test item was passed through a 250 μm steel mesh sieve before use.

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: exposure chamber based on the directed flow nose only inhalation chamber (Am. Ind. Hyg Assoc. J. 44(12): 923-928, 1983)
- Exposure chamber volume: ca. 150 mL
- Test chamber: polycarbonate restraining tubes
- Source and rate of air: at least 1 L/min (theoretical air flow in each animal port).
- System of generating aerosols: The test item was fed to a stream of pressurized air (mean air flow 11 L/min) by means of a spiral feeder (Randcastle Extrusion Systems, Cedar Grove, NJ, USA) and a micronizing jet mill (Bernstein, D.N., Aerosols, pp 721- 723, 1984). The aerosol was passed through a series of three cyclones, allowing larger particles to settle, before it entered the exposure chamber.
From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.
- Method of particle size determination: The particle size distribution was characterized twice during the exposure period. The samples were drawn (2 L/min) from the test atmosphere through a tube mounted in one of the free animal ports. The samples were collected with an 8 stage Marple personal cascade impactor containing fiber glass filters and a fiber glass back-up filter. Amounts of test item collected were measured gravimetrically. Subsequently the Mass Median Aerodynamic Diameter (MMAD) and the Geometric Standard Deviation (GSD) were determined.
- System stability: An indication of the stability of the test atmosphere was obtained from the concentration measurements, which were equally distributed over time.
- Temperature and humidity in air chamber: 21.1-21.6 °C and 54-60% respectively

TEST ATMOSPHERE
- Brief description of analytical method used: Samples were drawn from the test atmosphere through a tube mounted in one of the free animal ports of the middle section of the exposure chamber. Samples were drawn through a glass fiber filter. The collected amount of the test item in the air sample was measured gravimetrically. Sample volumes were measured by means of a dry gas meter. The time-weighted mean concentration with the standard deviation was calculated.
- Samples taken from breathing zone: Yes, the actual concentration was determined twenty-one times during the exposure period.
- The temperature and relative humidity were measured with a humidity and temperature indicator (E+E Elektronik, Engerwitzdorf, Austria) and were recorded after the animals were placed in the experimental set-up and at 30 minute intervals after initiation of the exposure.
CLASS METHOD
- Rationale for the selection of the starting concentration: Target concentrations were based on the cut off concentration values specified in the UN and EC classification guidelines.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5 mg/L

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:
- During exposure: 3 times
- After exposure:
Mortality: Twice daily
Clinical signs: On day 1, one and three hours after exposure and once daily thereafter until day 15
Body weights (individually): on day 1(pre-administration), 2, 4, 8 and 15.

- Necropsy of survivors performed: yes

Statistics:

No statistical analysis was performed.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4.7 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality occurred.

Clinical signs:

other: One male showed slow breathing during exposure. One male showed piloerection one hour after exposure. No further clinical signs were noted.

Body weight:

No abnormalities observed. Overall body weight gain in males and females was within the range expected for rats of this strain and age used in this type of study

Gross pathology:

No abnormalities were found at necropsy

Other findings:

- Actual exposure concentrations: The time-weighted mean actual concentration was 4.7 ± 0.13 mg/L. The nominal concentration (amount of test item used divided by the volume of pressurized air used) was 513 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 0.9%.

- Particle size: The Mass Median Aerodynamic Diameter (MMAD) and geometric standard deviation (gsd) were determined twice during the exposure period.(see table 1)

Any other information on results incl. tables

Table 1 Aerodynamic particle size distribution in the test atmosphere

Measurement 1:

Stage	Cut point (mm)		Mass sampled (mg)	Relative mass (%)	Cumulative mass (% of total sampled)
1	21.0		0.06	0.93	99.07
2	15.0		0.14	2.17	96.90
3	10.0		1.01	15.66	81.24
4	6.0		0.91	14.11	67.13
5	3.5		3.00	46.51	20.62
6	2.0		1.11	17.21	3.41
7	0.9		0.22	3.41	0.00
8	0.5		0.00	0.00	0.00
Back up	0.25		0.00	0.00	0.00
MMAD^1(μm):		5.2
gsd^2:		1.8

Measurement 2:

Stage	Cut point (mm)		Mass sampled (mg)	Relative mass (%)	Cumulative mass (% of total sampled)
1	21.0		0.05	0.63	99.37
2	15.0		0.00	0.00	99.37
3	10.0		0.42	5.26	94.11
4	6.0		2.08	26.07	68.05
5	3.5		3.56	44.61	23.43
6	2.0		1.20	15.04	8.40
7	0.9		0.36	4.51	3.88
8	0.5		0.12	1.50	2.38
Back up	0.25		0.19	2.38	0.00
MMAD^1(μm):		3.8
gsd^2:		1.8

¹ Mass Median Aerodynamic Diameter;² Geometric standard deviation

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Remarks:

Not class

Conclusions:

In an acute inhalation study, performed according to OECD guideline 403 and GLP principles, the LC50 of URALAC P 1920C in rats was found to exceed 5 mg/L. Based on these results, the test item is not classified according to GHS and Regulation (EC) No. 1272/2008.

Executive summary:

An acute inhalation study was performed according to OECD/EC guidelines and GLP principles. Five males and five females were exposed to an atmosphere with a time-weighted mean actual concentration of 4.7 ± 0.13 mg/L and observed for 14 days. No mortality occurred. One male showed slow breathing during exposure. One male showed piloerection one hour after exposure. No further clinical signs were noted, no unexpected effects on weight gain were observed and no abnormalities were seen at necropsy. These results show that the the LC50 of URALAC P 1920C in rats exceeds 5 mg/L.