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Administrative data

Description of key information

PETMP is moderately toxic via the oral route and non-toxic via inhalation.

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:
2002-08-20 through 2002-09-03
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Bantin & Kingman, Hull, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 167-215 g
- Fasting period before study: yes
- Housing: in groups of three in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days


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


IN-LIFE DATES: From: 2002-08-20 To: 2002-09-02
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30, 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: Arachis oil BP was used because the test material did not dissolve in distilled water.
- Purity: BP grade

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Information from the sponsor suggested a starting dose of 300 mg/kg.
Doses:
300, 2000 mg/kg bw
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity %, 1, 2 and 4 hours after dosing
and subsequently once daily for up to fourteen days. Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment or at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology
Statistics:
not applicable for ATC method
Sex:
female
Dose descriptor:
LD50
Effect level:
> 1 000 - < 2 000 mg/kg bw
Remarks on result:
other: Estimated using the ATC flowchart
Mortality:
Two animals treated with 2000 mg/kg were found dead four hours or two days after dosing. One animal treated with 2000 mg/kg was killed in extremis one day after dosing. There were no deaths noted in animals treated with 300 mg/kg.
Clinical signs:
other: Signs of systemic toxicity noted in animals treated with 2000 mg/kg were hunched posture, increased lachrymation, clonic andlor tonic convulsions, pilo-erection, ptosis, decreased respiratory rate, laboured respiration, loss of righting reflex, ataxia and
Gross pathology:
Abnormalities noted at necropsy of animals that died or were killed in extremis during the study were abnormally red lungs, dark liver, slight haemorrhage or sloughing of the gastric mucosa and slight haemorrhage of the non-glandular epithelium of the stomach. No abnormalities were noted at necropsy of animals that were killed at the end of the study.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
EU classification: Xn, R22: Harmful if swallowed.
EU-GHS classification: Warning, Acute Tox. 4, H302: Harmful if swallowed.
Executive summary:

The study was performed to assess the acute oral toxicity of the test material following a single oral administration in the Sprague-Dawley CD strain rat in accordance with OECD TG 423.


group of three fasted females was treated with the test material at a dose level of
300 mg/kg bodyweight. Based on the results from this dose level further groups of fasted females were treated at dose levels of 2000 and 300 mg/kg bodyweight. Dosing was performed sequentially.
The test material was administered orally as a solution in arachis oil BP. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.
Two animals treated with 2000 mg/kg were found dead four hours or two days after dosing. One animal treated with 2000 mg/kg was killed in extremis one day after dosing. There were no deaths noted in animals treated with 300 mg/kg.
Clinical Observations. Signs of systemic toxicity noted in animals treated with 2000 mg/kg were hunched posture, increased lachrymation, clonic and/or tonic convulsions, pilo-erection, ptosis, decreased respiratory rate, laboured respiration, loss of righting reflex, ataxia and hypothermia.
One animal treated with 2000 mg/mg was found comatose. Signs of systemic toxicity noted in animals treated with 300 mg/kg were hunched posture, increased lachrymation, clonic and/or tonic convulsions and pilo-erection. There were no signs of systemic toxicity noted in three animals treated with 300 mg/kg.
The surviving animals showed expected gains in bodyweight over the study period.


Abnormalities noted at necropsy of animals that died or were killed in extremis during the study were abnormally red lungs, dark liver, slight haemorrhage or sloughing of the gastric mucosa and slight haemorrhage of the non-glandular epithelium of the stomach. No abnormalities were noted at necropsy of animals that were killed at the end of the study.


The acute oral median lethal dose (LDso) of the test material in the female Sprague-Dawley CD strain rat was estimated to be in the range of 1000 - 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 000 mg/kg bw

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:
2008-03-06 through 2008-07-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
The humidity in the exposure chamber is lower than recommended by the guideline.
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
yes
Remarks:
The humidity in the exposure chamber is lower than recommended by the guideline.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
not specified
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan-Winkelmann GmbH, Borchen (Germany)
- Age at study initiation: approximately 2 months
- Weight at study initiation: 178-209 g (males); 172-196 g (females)
- Fasting period before study: no
- Housing: single housing, Makrolon cages, low-dust wood granulate bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-60
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2008-04-02 To: 2008-04-23
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglas exposure tubes applying a directed-flow nose-only exposure principle.
- Exposure chamber volume: 3.8 L
- Method of holding animals in test chamber: plexiglass tubes
- Source and rate of air: Compressed air was supplied by Boge compressors
- Method of conditioning air: Air was conditioned (i.e. freed from water, dust, and oil) automatically by a VIA compressed air dryer.
- System of generating particulates/aerosols: Under dynamic conditions the neat test article was atomized into a baffle (pre-separator) from which the substance was conveyed into the intake of the cylindrical inhalation chamber. Atomization was achieved by using two types of binary nozzles with conditioned compressed air (15 L/min; dispersion pressure approximately 600 kPa). The test substance was fed into the nozzle by a calibrated digital pump (Harvard PHD 2000).
- Method of particle size determination: The particle-size distribution was analyzed using a BERNER-TYPE AERAS low-pressure critical orifice cascade impactor
- Temperature, humidity, pressure in air chamber: < 5%-10%


TEST ATMOSPHERE
- Brief description of analytical method used: The test-substance concentration sampled by gravimetric analysis was eluted from the filter and then determined by HPLC. A sampling train was used to analyze volatilized test article in addition. No test article was found in the gass bubbler.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetric analysis / HPLC
Duration of exposure:
4 h
Concentrations:
Nominal: 2227.8, 6733.3 mg/m³
Analytical: 1382.6, 3152.8 mg/m³
Gravimetric: 1505.0, 3362.5 mg/m³
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The appearance and behavior of each rat were examined carefully several times on the day of exposure and at least once daily thereafter. Body weights were measured before exposure, on days 1, 3 and 7, and weekly thereafter. Individual weights are also recorded at death, if applicable.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: rectal temperatures
Statistics:
Necropsy: pair-wise Fisher test after the R X C chi-squared test.
Body weights: one-way ANOVA
LC50: maximum-likelihood method (Bliss)
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3 363 mg/m³ air (analytical)
Exp. duration:
4 h
Remarks on result:
other: No mortality at highest attainable concentration
Mortality:
Mortality did not occur up to the maximum technically attainable concentration.
Clinical signs:
other: Clinical signs suggestive of respiratory tract irritation (labored and irregular breathing patterns, bradypnea, muzzle area with red encrustations) occurred concentration-dependent and were essentially reversible within the first post-exposure week.
Body weight:
Comparisons between the control and the exposure groups revealed a consistent, concentration-dependent decrease in body weights
Gross pathology:
The macroscopic findings were essentially indistinguishable amongst exposure and control groups. In animals of group 3 skin areas with alopecia were observed.
Other findings:
Reflex measurements
A battery of reflex measurements was made on the first post-exposure day. In comparison to the rats of the control group, some rats of group 3 exhibited changes in reflexes

Rectal temperature
Significant decreases in body temperature in groups 2 and 3.

Target Concentration[mg/m³ air]

Toxicological results*

Duration of clinical signs

Time of death

Mortality
[%]

Rectal Temperature [°C]

Males

0

0/0/5

---

---

0

38.1

1500

0/5/5

0d - 10 d

---

0

33.8**

5000

0/5/5

0d - 10d

---

0

33.5**

Females

0

0/0/5

---

---

0

38.2

1500

0/5/5

0d - 12d

---

0

34.2**

5000

0/5/5

0d - 13d

---

0

32.5**

*first number = number of dead animals

 second number = number of animals with signs

 third number = number of animals used

** p < 0.01

 

Interpretation of results:
GHS criteria not met
Conclusions:
PETMP is not classified for acute inhalation toxicity because no mortality occurred at the maximum attainable concentration.
Executive summary:

A study on the acute inhalation toxicity of PETMP on rats was conducted in accordance wioth OECD TG 403. Two groups of rats were nose-onyl exposed to actual liquid aerosol at concentrations of 1505 and 3363 mg/m³ air.


Mortality did not occur up to the maximum technically attainable concentration.


Clinical signs suggestive of respiratory tract irritation (labored and irregular breathing patterns, bradypnea, muzzle area with red encrustations) occurred concentration-dependent and were essentially reversible within the first post-exposure week.


The 4 h LC50 was >3363 mg/m³

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
3 363 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral administration of PETMP to rats showed substance-related effects with an LD50 of 1000 - 2000 mg/kg bw obtained in females. After treatment with 2000 mg/kg, two animals were found dead 4 h or 2 d after dosing; one animal was killed in extremis one day after dosing. No deaths were noted in animals treated with 300 mg/kg.

Inhalation exposure (nose-only) to PETMP aerosol revealed a LC50 value of > 3363 mg/m³. No mortality was seen up to the maximum technically attainable concentration. Very detailed clinical observations allow the conclusion that the lowest concentration tested, 1505 mg/m³, was a LOAEC.

Acute dermal toxicity studies do not need to be performed according to the REACh regulation Annex VIII, Point 8.5.3 since inhalation exposure is the more likely route.


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

Justification for selection of acute toxicity – inhalation endpoint
OECD Guideline study, GLP

Justification for classification or non-classification

PETMP is classified as Acute Tox. 4 "Harmful if swallowed" according to EU and EU-GHS criteria.


PETMP is not classified for inhalation toxicity because no mortality occurred at the highest attainable concentration.

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