Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 October 2015 to 05 November 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and OECD guideline compliant with no deviations

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report Date:
2015

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
2009
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
2014
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): Di-Pentaerythritol (2,2,2',2'-tetrakis(hydroxymethyl)-3,3'-oxydipropan-1-ol)
- Physical state: white crystalline solid
- Analytical purity: 97.9%
- Lot/batch No.: 615061008
- Expiration date of the lot/batch: 02 July 2017
- Storage condition of test material: room temperature in the dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Oxon, UK.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 200-350 g
- Housing: groups of up to five by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes (Datesand Ltd., Cheshire, UK) and provided with environmental enrichment items: wooden chew blocks and cardboard “fun tunnels” (Datesand Ltd., Cheshire, UK).
- Diet (e.g. ad libitum): Rodent 2014C Teklad Global Certified Diet (Envigo RMS (UK) Limited, Oxon, UK), ad libitum
- Water (e.g. ad libitum): mains drinking water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70%
- Air changes (per hr): at least 15/hour
- Photoperiod (hrs dark / hrs light): 12 hour cycle

IN-LIFE DATES: From: 13 October 2015 To: 05 November 2015

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
In order to facilitate aerosolisation and reduce particle size, the test item was ground using a Retsch Planetary Ball Mill (Retsch (UK) Ltd, Leeds, UK) prior to use. A dust atmosphere was produced from the test substance using a SAG 410 Solid Aerosol Generator (TOPAS GmbH, Dresden, Germany) located adjacent to the exposure chamber. The SAG 410 was connected to a metered compressed air supply. Compressed air was supplied by means of an oil free compressor and passed through a water trap and respiratory quality filters before it was introduced to the SAG 410. The cylindrical exposure chamber had a volume of approximately 30 liters (dimensions: 28 cm diameter x 50 cm high). The concentration within the chamber was controlled by adjusting the test substance feed rate from the SAG 410. The extract from the exposure chamber passed through a ‘scrubber’ trap and was connected with a high efficiency filter to a metered exhaust system. The chamber was maintained under negative pressure.

One day prior to the day of exposure, each rat was acclimatized (for approximately 2 hours) to a tapered polycarbonate restraining tube. During the exposure period, 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. Only the nose of each animal was exposed to the test atmosphere. Following an appropriate equilibration period a single group of ten rats (five males and five females) was exposed to an atmosphere of the test item for a period of four hours. A target
concentration of 5.0 mg/L was used for the exposure. As the mean achieved concentration was 101 % of target and no deaths occurred, no further levels were required.

The 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. Oxygen levels within the exposure chamber were measured by an electronic oxygen analyzer (Servomex (UK) Ltd, Crowborough, East Sussex) located in a port in the animals breathing zone during the four-hour exposure period. The test atmosphere was generated to contain at least 19% oxygen.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5.07 mg/L (achieved)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
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 fourteen days. Any evidence of overt toxicity was recorded at each observation. Individual body weights were recorded on arrival, prior to treatment on the day of exposure and on Days 1, 3, 7 and 14. At the end of the fourteen day observation period the animals were killed by intravenous overdose of sodium pentobarbitone. All animals 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.

Data evaluations included the relationship, if any, between the animals’ exposure to the test item and the incidence and severity of all abnormalities including behavioral and clinical observations, necropsy findings, body weight changes, mortality and any other toxicological effects. Using the mortality data obtained, an estimate of the acute inhalation median lethal concentration (LC50) of the test item was made.
Statistics:
Not required.

Results and discussion

Preliminary study:
Not applicable.
Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.07 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortalities occured.
Clinical signs:
Signs of hunched posture and pilo- erection are commonly seen in animals for short periods on removal from the chamber following 4-Hour inhalation studies. Wet fur is commonly recorded both during and for a short period after exposure. These observations are considered to be associated with the restraint procedure and, in isolation, are not indicative of toxicity. In addition to the observations considered to be due to the restraint procedure, decreased respiratory rate was noted in all animals during exposure, on removal from the chamber and one hour after removal. One day after exposure, all animals exhibited increased respiratory rate only. All animals recovered to appear normal on Day 2 post-exposure.
Body weight:
All animals exhibited body weight losses on the first day post-exposure. Body weight gains were noted in all animals during the remainder of the recovery period.
Gross pathology:
No macroscopic abnormalities were detected amongst animals at necropsy.
Other findings:
No other findings reported.

Any other information on results incl. tables

Exposure Chamber Concentration

Atmosphere Concentration

Mean Achieved (mg/L)

Standard Deviation

Nominal (mg/L)

5.07

0.17

14.4

Particle Size Distribution

Mean Achieved Atmosphere Concentration (mg/L)

Mean Mass Median Aerodynamic Diameter (µm)

Inhalable Fraction (% <4 µm)

Geometric Standard Deviation

5.07

1.73

74.9

3.50

The chamber flow rate was maintained at 60 L/min providing 120 air changes per hour. The theoretical chamber equilibration time (T99) was 3 minutes* (Silver, 1946).

 

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No deaths occurred in a group of ten rats exposed to a mean achieved atmosphere concentration of 5.07 mg/L for four hours. The acute 4 hr LC50 is therefore considered to be greater than 5.07 mg/L and classification is not required.
Executive summary:

The acute inhalation toxicity of dipentaerythritol was investigated in 5 male and 5 female RccHAN:WIST rats, according to OECD 403 (2009). The rats were exposed nose-only to a dust atmosphere for four-hours, followed by a 14-day observation period. The mean achieved atmosphere concentration was 5.07 mg/L (nominal 14.4 mg/L). The MMAD was determined to be 1.73 µm with a geometric standard deviation of 3.50, and the inhalable fraction (% <4 µm) was 74.9%. No deaths occurred. Common abnormalities noted during the study included decreased respiratory rate, increased respiratory rate, hunched posture, pilo-erection and wet fur. All animals recovered to appear normal on Day 2 post-exposure. All animals exhibited body weight losses on the first day post-exposure. All animals exhibited body weight gains during the remainder of the recovery period. No macroscopic abnormalities were detected at necropsy. No deaths occurred in a group of ten rats exposed to a mean achieved atmosphere concentration of 5.07 mg/L for four hours; the acute LC50 is therefore considered to be greater than 5.07 mg/L. Classification according to Regulation (EC) No 1272/2008 is not required.