Registration Dossier

Administrative data

Description of key information

Acute oral toxicity was assessed in:

1) an OECD 423 study for a read-across substance, Phosphoric acid, 2-ethylhexl ester, the LD50 was 2500 mg/kg bw - Category 5 acute toxicity (GHS);

2) an OECD 401 (equivalent study) for a read-across substance, phosphoric acid ester (linear C8), the LD50was greater than 2000 mg/kg bw - Category 5 acute toxicity (GHS).

Acute inhalation and dermal toxicity studies were waived on the basis of skin corrosivity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
30 June 2011 and 26 July 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Female Wistar (RccHan#:WIST) strain rats were supplied by Harlan Labo
ratories UK Ltd., Oxon, UK.- Age at study initiation: Eight to twelve weeks of age- Weight at study
initiation: 158 - 183 g - Fasting period before study: Overnight fast immediately before dosing and for
approximately three to four hours after dosing- Housing: The animals were housed in groups of three
in suspended solid floor polypropylene cages furnished with woodflakes.- Diet (e.g. ad libitum): Food
(2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed
throughout the study.- Water (e.g. ad libitum): Free access to mains drinking water was allowed throu
ghout the study.- Acclimation period: At least five days.ENVIRONMENTAL CONDITIONS- Tempera
ture (°C): Set to achieve limits of 19 to 25°C - Humidity (%): Set to achieve limits of 30 to 70%- Air
changes (per hr): At least fifteen changes per hour - Photoperiod (hrs dark / hrs light): lighting was
controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours
darkness.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE- Concentration in vehicle: 30 mg/ml or 200 mg/mlMAXIMUM DOSE VOLUME APPLIED:
10 ml/kgDOSAGE PREPARATION: The test item was freshly prepared, as required, as a solution at t
he appropriate concentration in distilled water. The test item was formulated within two hours of being
applied to the test system. It is assumed that the formulation was stable for this duration. CLASS
METHOD (if applicable)- Rationale for the selection of the starting dose: Using available information
on the toxicity of the test item, 300 mg/kg was chosen as the starting dose.
Doses:
300 mg/kg and 2000 mg/kg
No. of animals per sex per dose:
3 females at 300 mg/kg. 6 females at 2000 mg/kg
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 ½, 1, 2 and 4 hours after
dosing and subsequently once daily for up to fourteen days. Individual bodyweights were recor
ded prior to dosing and seven and fourteen days after treatment or at death.- Necropsy of survivors
performed: yes; At the end of the observation period the surviving animals were killed by cervical
dislocation. All animals were subjected to gross pathological examination. This consisted of an
external examination and opening of the abdominal and thoracic cavities for examination of major
organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
2 500 mg/kg bw
Based on:
test mat.
Mortality:
Individual mortality data are given in Table 1.One animal treated at a dose level of 2000 mg/kg was
found dead two days after dosing.
Clinical signs:
Individual clinical observations are given in Table 2 and Table 3.Signs of systemic toxicity noted in
one animal treated at a dose level of 2000 mg/kg were increased salivation, red/brown staining ar
ound the snout and noisy respiration. There were no other signs of systemic toxicity noted.
Body weight:
Individual bodyweights and weekly bodyweight changes are given in Table 4 and Table 5.The s
urviving animals showed expected gains in bodyweight over the study period.
Gross pathology:
Individual necropsy findings are given in Table 6 and Table 7.Abnormalities noted at necropsy of the
animal that died during the study were patchy pallor of the liver, dark spleen, dark kidneys and h
aemorrhage of the gastric mucosa. No other abnormalities were noted at necropsy of animals that we
re killed at the end of the study.

Table 1: Mortality Data

Dose Level mg/kg

Sex

Number of Animals Treated

Deaths During Day of Dosing
(Hours)

Deaths During Period After Dosing
(Days)

Deaths

½

1

2

4

1

2

3

4

5

6

7

8-14

300

Female

3

0

0

0

0

0

0

0

0

0

0

0

0

0/3

2000

Female

3

0

0

0

0

0

0

0

0

0

0

0

0

0/3

Female

3

0

0

0

0

0

1

0

0

0

0

0

0

1/3

Table 2: Individual Clinical Observations - 300 mg/kg

Dose Level mg/kg

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

300

1-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0


0= No signs of systemic toxicity

Table 3: Individual Clinical Observations - 2000 mg/kg

Dose Level mg/kg

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

2-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-1

Female

SSs

SSs

S

Rn

Rn

Rn

Rn

0

0

0

0

0

0

0

0

0

0

0

2-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-1

Female

0

0

0

0

0

X

 

 

 

 

 

 

 

 

 

 

 

 

3-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0


0= No signs of systemic toxicity           

Rn = Noisy respiration

S = Increased salivation

Ss = Red/brown staining around the snout

X = Animal dead

Table 4: Individual Bodyweights and Weekly Bodyweight Changes - 300 mg/kg

Dose Level

mg/kg

Animal Number
and Sex

Bodyweight (g) at Day

Bodyweight Gain (g) During Week

0

7

14

1

2

300

1-0 Female

177

203

210

26

7

1-1 Female

158

173

180

15

7

1-2 Female

183

210

220

27

10

Table 5: Individual Bodyweights and Weekly Bodyweight Changes - 2000 mg/kg

Dose Level

mg/kg

Animal Number
and Sex

Bodyweight (g) at Day

Bodyweight (g) at Death

Bodyweight Gain (g) During Week

0

7

14

1

2

2000

2-0 Female

177

182

193

 

5

11

2-1 Female

171

174

189

 

3

15

2-2 Female

169

177

191

 

8

14

3-0 Female

162

177

183

 

15

6

3-1 Female

158

-

-

150

-

-

3-2 Female

168

174

180

 

6

6

Table 6: Individual Necropsy Findings - 300 mg/kg

Dose Level

mg/kg

Animal Number and Sex

Time of Death

Macroscopic Observations

300

1-0 Female

Killed Day 14

No abnormalities detected

1-1 Female

Killed Day 14

No abnormalities detected

1-2 Female

Killed Day 14

No abnormalities detected

Table 7: Individual Necropsy Findings - 2000 mg/kg

Dose Level

mg/kg

Animal Number and Sex

Time of Death

Macroscopic Observations

2000

2-0 Female

Killed Day 14

No abnormalities detected

2-1 Female

Killed Day 14

No abnormalities detected

2-2 Female

Killed Day 14

No abnormalities detected

3-0 Female

Killed Day 14

No abnormalities detected

3-1 Female

Found Dead Day 2

Liver: patchy pallor

Spleen: dark

Kidneys: dark

Gastric mucosa: haemorrhagic

3-2 Female

Killed Day 14

No abnormalities detected

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was approx imately 2500 mg/kg bodyweight (Globally Harmonised Classification System - Category 5, >2000 -5000 mg/kg bodyweight).
Executive summary:

Introduction.

The study was performed to assess the acute oral toxicity of the test item following a single oral

administration in the Wistar strain rat. The method was designed to be compatible with the following:

- OECD Guidelines for the Testing of Chemicals No. 423 “Acute Oral Toxicity – Acute Toxic Class

Method” (adopted 17 December 2001) - Method B1 tris Acute Toxicity (Oral) of CommissionRegulation (EC) No. 440/2008

Method.

A group of three fasted females was treated with the test item 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

a dose level 2000 mg/kg bodyweight. Dosing was performed sequentially. The test item was administered orally as a solution in distilled water. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality.

One animal treated at a dose level of 2000 mg/kg was found dead two days after dosing.

Clinical Observations.

Signs of systemic toxicity noted in one animal treated at a dose level of 2000 mg/kg were increased salivation, red/brown staining around the snout and noisy respiration. There were no other signs of systemic toxicity noted.

Bodyweight.

The surviving animals showed expected gains in bodyweight over the study period.

Necropsy.

Abnormalities noted at necropsy of the animal that died during the study were patchy pallor of the liver,

dark spleen, dark kidneys and haemorrhage of the gastric mucosa. No other abnormalities were noted

at necropsy of animals that were killed at the end of the study.

Conclusion.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was

approximately 2500 mg/kg bodyweight (Globally Harmonised Classification System ‑ Category 5,

>2000 ‑ 5000 mg/kg bodyweight).

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across hypothesis proposed is that the organism is not exposed to common compounds but rather, because of structural similarity, that different compounds have similar toxicological and fate properties. In this case the ECHA Read-Across Assessment Framework (RAAF) Scenario 2 is used.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source: Phosphoric acid, 2-ethylhexyl ester [EC 235-741-0; CAS 12645-31-7]
Supporting Source: Phosphoric acid, mono and bis-linear butyl esters, potassium salts [EC 947-719-4]
Target: Phosphoric Acid, linear and branched Octyl Esters [EC not yet assigned; CAS not assigned]
3. ANALOGUE APPROACH JUSTIFICATION
The acute oral toxicity of two Source substances is very low with a range of LD50 values of greater than 2500 mg/kg bw to 20371 mg/kg bw. Structural and chemical similarities in these molecules and Target substance suggests that the Target may also be of very low oral systemic toxicity. The acute oral toxicity of the Target may be predicted to be in the region of greater than 2000 mg/kg bw.
4. DATA MATRIX
Please refer to attached justification.
Reason / purpose:
read-across source
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
2 500 mg/kg bw
Based on:
test mat.
Interpretation of results:
Category 5 based on GHS criteria
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2002-06-24
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
The test was essentially an OECD 401 design.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
Rats allowed free access to food (Altromin ®) and tap water.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Single dose, observed for seven days.
Doses:
2000 mg/kf/bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Post-dosing animals were observed during a seven day period for any adverse response to the single oral dose of 2000 mg/kg bw.
Statistics:
Not specified
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
None related to treatment
Clinical signs:
None reported
Body weight:
Not specified
Gross pathology:
Not specified
Other findings:
None reported
Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
The LD50 in the rat was greater than 2000 mg/kg bw
Executive summary:

Five male Fisher 344 rats were orally dosed with 2000 mg/kg bw of Hordaphos MDO (phosphoric acid ester - linear C8). The animals were allowed free access to food and water over an observation period of seven days. There were no treatment related deaths. The LD50 was determined to be greater than 2000 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across hypothesis proposed is that the organism is not exposed to common compounds but rather, because of structural similarity, that different compounds have similar toxicological and fate properties. In this case the ECHA Read-Across Assessment Framework (RAAF) Scenario 2 is used.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source: Phosphoric acid, 2-ethylhexyl ester [EC 235-741-0; CAS 12645-31-7]
Supporting Source: Phosphoric acid, mono and bis-linear butyl esters, potassium salts [EC 947-719-4]
Target: Phosphoric Acid, linear and branched Octyl Esters [EC not yet assigned; CAS not assigned]
3. ANALOGUE APPROACH JUSTIFICATION
The acute oral toxicity of two Source substances is very low with a range of LD50 values of greater than 2500 mg/kg bw to 20371 mg/kg bw. Structural and chemical similarities in these molecules and Target substance suggests that the Target may also be of very low oral systemic toxicity. The acute oral toxicity of the Target may be predicted to be in the region of greater than 2000 mg/kg bw.
4. DATA MATRIX
Please refer to attached justification.
Reason / purpose:
read-across source
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Interpretation of results:
Category 5 based on GHS criteria
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
2 500 mg/kg bw
Quality of whole database:
Adequate

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because the substance is classified as corrosive to the skin
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because the substance is classified as corrosive to the skin
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was approximately 2500 mg/kg bodyweight (Globally Harmonised Classification System - Category 5, >2000 -5000 mg/kg bodyweight).