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Description of key information

Based on the study results, the acute oral LD50 of the test substance was determined to be >2000 mg/kg bw.


 


Based on the results of read across study, the acute dermal LD50 of the test substance is considered to be >2000 mg/kg bw.

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:
From 6 April, 2012 to 26 April, 2012
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
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No 8147, April 2011, including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: Wistar strain, Crl:WI (Han)
Sex:
female
Details on test animals or test system and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 8-9 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean (first group: 156 - 178 g; second group: 149 - 157 g).
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 h after administration of the test substance. Water was available ad libitum.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 d

ENVIRONMENTAL CONDITIONS
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approx 15 room air changes/h, and a 12-h light/12-h dark cycle.

IN-LIFE DATES: From 06 April 2012 to 26 April 2012
Route of administration:
oral: gavage
Details on oral exposure:
GAVAGE METHOD: Plastic feeding tubes.

Frequency: Single dosage, on Day 1.

VEHICLE Polyethylene glycol 400 (Merck, Darmstadt, Germany) (specific gravity 1.125).
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at NOTOX and on test substance data supplied by the sponsor.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 mL/kg) bw.

DOSAGE PREPARATION:
The formulations (w/w) were prepared using amber coloured glassware within 4 h prior to dosing. Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of the test substance and vehicle. No correction was made for purity of the test substance.
Doses:
2000 mg/kg bw

No. of animals per sex per dose:
6 (2 groups of three females in a stepwise manner)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of observations and weighing:
Mortality/Viability: Twice daily
Body weights: Days 1 (pre-administration), 8 and 15.
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.
- Necropsy of survivors performed: At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
- Other examinations performed: none.
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture and/or piloerection was noted in all animals on Day 1.
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
other: EU CLP criteria not met
Conclusions:
Under the study conditions, the oral LD50 value of the test substance in rats was considered to be > 2,000 mg/kg bw.
Executive summary:

A study was conducted to determine the acute oral toxicity of test substance, DPHA according to OECD Guideline 423, EU method B.1 tris, EPA OPPTS 870.1100 and Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF) Guidelines, in compliance with GLP. The test substance was administered by oral gavage to two groups of three female Wistar rats at 2,000 mg/kg bw. No mortality occurred. Hunched posture and/or piloerection were noted in all animals on Day 1. The body weight gain shown over the study period was similar to that expected of normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post-mortem examination. Under the study conditions, the oral LD50 value of the test substance in rats was considered to be > 2,000 mg/kg bw (Beerens-Heijnen, 2012).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The information requirements for this tonnage band is sufficiently met with the available data.

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:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From 14 Oct, 1980 to 28 Oct, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
KL2 due to RA
Justification for type of information:
Refer to section 13 of IUCLID for details on the read-across justification.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: 40 CFR Part 163.81-2 (Environmental Protection Agency, Pesticides Programs, Proposed Guidelines for Registering Pesticides in the U.S.; Hazard Evaluation: Humans and Domestic Animals. Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
not specified
Limit test:
yes
Species:
other: Albino rabbits
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Penn Dutch Laboratory animals, Denver, Pennsylvania
- Age at study initiation: Young adults
- Weight at study initiation: 2.2 to 2.8 kg (males), 2.5 to 2.9 kg (females)
- Housing: Individually housed
- Diet: Purina Rabbit Chow, ad libitum
- Water: Automatic watering system, ad libitum.Municipal water supply (Elizabethtown Water Co. )

ENVIRONMENTAL CONDITIONS
- Temperature: 60 to 66°F
- Photoperiod: 12 h light, 12 h dark

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
On the day before dosing (approx 18 h prior to dosing), the hair of each rabbit was closely clipped from the trunk with an electric clipper, so as to expose at least 10% of the body surface area. Just prior to dosing, the skin of all of the animals was abraded longitudinally every 2 or 3 cm over the area of exposure, deep enough to penetrate the stratum corneum, but not so deep as to disturb the dermis or produce bleeding. The test substance was applied directly onto the exposed skin of the animal, and spread evenly over the entire area. A layer of 8-ply gauze was then wrapped around the animal to cover the application site. The animal was then wrapped in an impervious plastic sleeve, designed to contain the test substance without leakage or undue pressure. The sleeve was secured with masking tape and Elizabethan collars were placed on all animals. Following approx 24 h of exposure, the wrappings were removed and the test site wiped free of excess test substance. After 30 min, dermal observations were made.
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
10 (six males, four females)
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: Approx 1, 2, and 4 h after dosing and daily thereafter for 14 d.
- Necropsy of survivors performed: Gross post mortem examinations were performed on all animals which died or were found dead during the study. All animals surviving at termination of the observation period (Day 14) were killed by an intravenous overdose of sodium pentobarbital and examined grossly. All abnormalities were recorded hut no tissues were saved.
- Other examinations performed: Clinical signs, body weight
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No
Clinical signs:
No
Body weight:
Most animals gained weight during the 14 d after dosing. However, one male and one female exhibited weight losses.
Other findings:
All animals exhibited well-defined to severe erythema with moderate or severe edema at 24 h. Two animals exhihited eschar at the dosing site
at terminal necropsy. Several animals exhibited nasal and/or oral or ocular discharge during the 14 d post-dose period. A single animal exhibited decreased food consumption and fecal staining of the abdomen at 24 h only.
Interpretation of results:
other: EU CLP criteria not met
Conclusions:
Under the study conditions, the dermal LD50 of the test substance was determined to be >2,000 mg/kg bw in rabbits.
Executive summary:

A study was conducted to determine the acute dermal toxicity of the read-across substance, PETIA in rabbits according to the EPA 40 CFR Part 163.81-2. A single dose of 2,000 mg/kg bw was administered at a dose volume of 1.7 mL/kg bw to ten rabbits (six males and four females). Following approximately 24 h of exposure, the wrappings were removed and the test site wiped free of excess test substance. After 30 min, dermal observations were made. No mortality occurred and most animals gained weight in the 14 d period after dosing although one male and one female exhibited weight loss. All animals showed well-defined to severe erythema with moderate or severe edema at 24 h. In two animals, eschar was seen at the dosing site at terminal necropsy. Several animals had nasal and/or oral or ocular discharge during the 14 d post-dose period. A single animal exhibited decreased food consumption and fecal staining of the abdomen at 24 h only. Under the study conditions, the dermal LD50 of the test substance was determined to be >2,000 mg/kg bw in rabbits (Auletta, 1980).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The information requirements for this tonnage band is sufficiently met with the available data.

Additional information

Oral


A study was conducted to determine the acute oral toxicity of test substance, DPHA according to OECD Guideline 423, EU method B.1 tris, EPA OPPTS 870.1100 and Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF) Guidelines, in compliance with GLP.The test substance was administered by oral gavage to two groups of three female Wistar rats at 2000 mg/kg bw. No mortality occurred. Hunched posture and/or piloerection were noted in all animals on Day 1. The body weight gain shown over the study period was similar to that expected of normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post-mortem examination. Under the study conditions, the oral LD50 value of the test substance in rats was considered to be > 2000 mg/kg bw (Beerens-Heijnen, 2012).


Dermal
A study was conducted to determine the acute dermal toxicity of the read-across substance, PETIA in rabbits according to the EPA 40 CFR Part 163.81-2.A single dose of 2000 mg/kg bw was administered at a dose volume of 1.7 mL/kg bw to ten rabbits (six males and four females). Following approximately 24 h of exposure, the wrappings were removed and the test site wiped free of excess test substance. After 30 min, dermal observations were made. No mortality occurred and most animals gained weight in the 14 d period after dosing although one male and one female exhibited weight loss. All animals showed well-defined to severe erythema with moderate or severe edema at 24 h. In two animals, eschar was seen at the dosing site at terminal necropsy. Several animals had nasal and/or oral or ocular discharge during the 14 d post-dose period. A single animal exhibited decreased food consumption and fecal staining of the abdomen at 24 h only.Under the study conditions, the dermal LD50 of the test substance was determined to be >2000 mg/kg bw in rabbits (Auletta, 1980).

Justification for classification or non-classification

The available data for DPHA and the read-across substance PETIA indicates a low potential for acute oral (LD50 > 2000 mg/kg bw) and dermal (LD50 > 2000 mg/kg bw) toxicity. The substance therefore does not meet the requirement for classification according to EU CLP (EC 1272/2008) criteria.