Registration Dossier

Administrative data

Description of key information

- Acute toxicity: oral: OECD 401, Sprague-Dawley rats, hunched posture, no other effects, LD50 > 2000 mg/kg bw;
- Acute toxicity: dermal: OECD 402, Sprague-Dawley rats, no systemic signs of toxicity, skin reactions, LD50> 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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1998-07-07 - 1998-12-29
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented guideline study in compliance with GLP (conducted with a read-across substance)
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
The Department of Health of the Government of the United Kingdom
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate, Kent, UK
- Age at study initiation: eight to twelve weeks
- Weight at study initiation: 204 to 222g (males); 204 to 215g (females)
- Housing: housed in groups of up to five by sex in solid-floor polypropylene cages furnished with woodflakes
- Diet/Water (e.g. ad libitum): free access to mains drinking water and food (except overnight fast before dosing and 3-4 h after dosing); Rat and
Mouse Expanded Diet No. 1, Special Diets Services Limited, Witham, Essex, UK
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 23
- Humidity (%): 50 to 62
- Air changes (per hr): fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg
Doses:
2000 mg/kg (Range-finding Study); 2000 mg/kg (Main Study)
No. of animals per sex per dose:
1 male/ 1 female (Range-finding Study)
5 males / 5 females (Main Study)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 5 days (Range-finding Study); 14 days (Main Study)
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after dosing and subsequently once daily for 5 (Range-finding Study) or 14 days (Main Study).
- Necropsy of survivors performed: yes (Main Study)
-Others: Individual bodyweights were recorded on the day of dosing to allow calculation of individual treatment volumes (Range-finding Study). Individual bodyweights were recorded prior to dosing on day 0 and on days 7 and 14.
Statistics:
not applied
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
Hunched posture was noted in all animals during the day of dosing and persisted in all females and one male one day after dosing.
Body weight:
All animals showed an expected gain in bodyweight during the study.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
Other observations were not performed.

Experimental Preparation

For the purpose of the study the test material was freshly prepared, as required, as a solution at the appropriate concentration in arachis oil BP. Preparation

was aided by the use of a vortex mixer and by heating the formulation in a warming bath at approximately 80 °C. The formulation was allowed to cool

prior to dosing. Determination by analysis of the concentration, homogeneity and stability of the test material preparations was not appropriate because it was not specified

in the Study Plan and is not a requirement of the Test Guideline.

Procedure

All animals were dosed once only by gavage using a metal cannula attached to a graduated syringe. The volume administered to each animal was

calculated according to its fasted bodyweight at the time of dosing.

Table 1. Individual Clinical Observations and Mortality Data in the Range-finding Study

Dose Level mg/kg Animal Number and Sex Effects Noted After Dosing (Hours) Effects Noted During Period After Dosing (Days)
 1/2 1 2 4 1 2 3 4 5
2000 1-0 Male 0 0 0 0 0 0 0 0 0
2-0 Female 0 0 0 0 0 0 0 0 0

0 = no signs of systemic toxicity

Table 2. Individual Clinical Observations and Mortality Data in the Main Study

Dose Level mg/kg Animal Number and Sex Effects Noted After Dosing (Hours) Effects Noted During Period After Dosing (Days)
1/2 1 2 4 1 2 3 4 5 6 7 8 9 I 10 11 12 13 14
2000 3-0 Male H H H H 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3-1 Male H H H H H 0 0 0 0 0 0 0 o o 0 0 0 i0
3-2 Male 0 0 H H 0 0 0 0 0 0 0 0 0 o 0 0 0 0
3-3 Male 0 0 H H 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3-4 Male H H H H 0 0 0 0 0 0 0 0 0 0 0 0 0 0
4-0 Female H H H H H 0 0 0 0 0 0 0 0 0 0 0 0 o
4-1 Female 0 0 0 H H 0 0 0 0 0 0 0 0 0 0 0 0 0
4-2 Female H H H H H 0 0 0 0 0 0 0 0 0 0 0 0 0
4-3 Female H H H H H 0 0 0 0 0 0 0 0 0 0 0 0 0
4-4 Female H H H H H 0 0 0 0 0 0 0 0 0 0 0 0 0

H = hunched posture; 0 = no signs of systemic toxicity

Table 3. Individual Bodyweights and weekly Bodyweight Changes in the Main Study

Dose Level mg/kg Animal Number and Sex Bodyweight (g) at Day Bodyweight Gain (g) During Week
0 7 14 1 2
2000 3-0 Male 216 267 314 51 47
3-1 Male 204 240 274 36 34
3-2 Male 222 263 305 41 42
3-3 Male 221 282 330 61 48
3-4 Male 210 250 297 40 47
4-0 Female 215 238 260 23 22
4-1 Female 210 233 251 23 18
4-2 Female 206 230 252 24 22
4-3 Female 204 223 231 19 8
4-4 Female 215 228 231 13 3

Table 4. Individual Necropsy Findings in the Main Study

Dose Level mg/kg Animal Number and Sex Time of Death Macroscopic Observations
2000 3-0 Male Killed Day 14 No abnormalities detected
3-1 Male Killed Day 14 No abnormalities detected
3-2 Male Killed Day 14 No abnormalities detected
3-3 Male Killed Day 14 No abnormalities detected
3-4 Male Killed Day 14 No abnormalities detected
4-0 Female Killed Day 14 No abnormalities detected
4-1 Female Killed Day 14 No abnormalities detected
4-2 Female Killed Day 14 No abnormalities detected
4-3 Female Killed Day 14 No abnormalities detected
4-4 Female Killed Day 14 No abnormalities detected

Evaluation of Data

Data evaluations included the relationship, if any, between the animals' exposure to the test material and the incidence and severity of all abnormalities

including behavioural and clinical observations, gross lesions, bodyweight changes, mortality and any other toxicological effects.

Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test material was made.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. According to Regulation (EC) No 1272/2008, the test substance is not classified as acutely toxic by oral route of exposure.
Executive summary:

A OECD Guideline 401 study was performed to assess the acute oral toxicity of phosphoric acid, mono- and di-(C8 -C10) ester, compds. with C12 -14 amine in the Sprague-Dawley CD strain rat in compliance with GLP. Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material as a solution in arachis oil BP at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were then killed and subjected to gross pathological examination.

There were no deaths. Hunched posture was noted in all animals up to one day after dosing. All animals showed an expected gain in bodyweight during the study. No abnormalities were noted at necropsy. The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study is GLP compliant and has Klimish score 2 (due to read-across).

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1998-07-07 - 1998-12-30
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented guideline study in compliance with GLP (conducted with a read-across substance)
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
The Department of Health of the Government of the United Kingdom
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent
- Age at study initiation: approximately eight to twelve weeks
- Weight at study initiation: 205 to 225 g (males); 201 to 234 g (females)
- Housing: housed individually in suspended polypropylene cages furnished with woodflakes during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study
- Diet/Water (e.g. ad libitum): free access to mains drinking water and food (Rat and Mouse Expanded Diet No.1, Special Diets Services Limited, Witham, Essex, UK)
- Acclimation period: five days
- Others: The animals were selected at random and given a number unique within the study by indelible ink-marking on the tail and a number written on a cage card.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 22 °C
- Humidity (%): 50 to 62 %
- Air changes (per hr): approximately fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- % coverage: 10
- Type of wrap if used: veterinary clippers

REMOVAL OF TEST SUBSTANCE
- Washing (if done): bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume or concentration used: yes
Duration of exposure:
24 h
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 males / 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual bodyweights were recorded prior to application of the test material on day 0 and on days 7 and days 14. The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.
- Necropsy of survivors performed: yes
Statistics:
not applied
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted during the study.
Body weight:
All animals showed an expected gain in bodyweight during the study.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
Dermal reaction
Signs of skin irritation noted in males were restricted to one animal and included crust formation five to seven days after dosing. Signs of skin irritation noted in females included very slight or well-defined erythema and crust formation one to seven days after dosing.

No effects after dosing were notes (0.5, 1, 2, 3 and 4 hours after dosing). Considering individual dermal reactions, crust formation was reported for one male animals on day 5, 6 and 7 after dosing. Furthermore, crust formation was reported for five females on day 4, 5, 6 and 7 after dosing.

Table 1. Individual Bodyweights and weekly Bodyweight Changes

Dose Level mg/kg

Animal Number

and Sex

Bodyweight (g) at Day Bodyweight Gain (g) During Week
0 7 14 1 2
2000 1-0 Male 205 235 278 30 43
1-1 Male 225 251 290 26 39
1-2 Male 218 250 294 32 44
1-3 Male 216 252 312 36 60
1-4 Male 224 257 309 33 52
2-0 Female 201 205 223 4 18
2-1 Female 215 222 240 7 18
2-2 Female 234 238 256 4 18
2-3 Female 225 225 247 0 22
2-4 Female 212 219 231 7 12

For all treated animals and killed on day 14, no abnormalities during macroscopic observation were reported.

Evaluation of Data

Data evaluations included the relationship, if any, between the animal's exposure to the test material and the incidence and severity of all abnormalities

including behavioural and clinical observations, gross lesions, bodyweight changes, mortality and any other toxicological effects.

Using the mortality data obtained, an estimate of the acute dermal median lethal dose (LD50) of the test material was made.

Evaluation of Skin Reaction

Erythema and Eschar Formation Value

0 - No erythema

1 - Very slight erythema (barely perceptible)

2 - Well-defined erythema

3 - Moderate to severe erythema

4 - formation (injuries in depth)

5 - Severe erythema (beet redness) to slight eschar

Oedema Formation

0 - No oedema

1 - Very slight oedema (barely perceptible)

2 - Slight oedema (edges of area well-defined by definite raising)

3 - Moderate oedema (raised approximately 1 millimetre)

4 - Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure)

Any other skin reactions, if present were also recorded.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The acute dermal median lethal dose (LD50) of phosphoric acid, mono- and di-(C8-C10) ester, compds. with C12-14 amine in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. According to Regulation (EC) 1272/2008, the substance is not classified as acutely toxic by dermal route of exposure.
Executive summary:

A OECD Guideline 402 study was performed to assess the acute dermal toxicity of phosphoric acid, mono- and di-(C8 -C10) ester, compds. with C12-14 amine in the Sprague-Dawley CD strain rat in compliance with GLP. A group of ten animals (five males and five females) was given a single 24-hour, semi-occluded dermal application to intact skin at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of treatment and were then killed for gross pathological examination. There were no deaths. No signs of systemic toxicity were noted during the study. Signs of skin irritation noted during the study included very slight to well-defined erythema and crust formation. All animals showed an expected gain in bodyweight during the study. No abnormalities were noted at necropsy. The acute dermal median lethal dose (LD50) of the test material in the Sprague- Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study is GLP compliant and has Klimish score 2 (due to read-across).

Additional information

Acute toxicity: oral

An OECD Guideline 401 study was performed to assess the acute oral toxicity of the read-across substance (Phosphoric acid, mono- and di-(C8 -C10) ester, compds. with C12 -14 amine) in the Sprague-Dawley CD strain rat in compliance with GLP. Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material as a solution in arachis oil BP at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were then killed and subjected to gross pathological examination.

There were no deaths. Hunched posture was noted in all animals up to one day after dosing. All animals showed an expected gain in bodyweight during the study. No abnormalities were noted at necropsy. The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.

Acute toxicity:dermal

An OECD Guideline 402 study was performed to assess the acute dermal toxicity of the read-across substance (Phosphoric acid, mono- and di-(C8 -C10) ester, compds. with C12-14 amine) in the Sprague-Dawley CD strain rat in compliance with GLP. A group of ten animals (five males and five females) was given a single 24-hour, semi-occluded dermal application to intact skin at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of treatment and were then killed for gross pathological examination. There were no deaths. No signs of systemic toxicity were noted during the study. Signs of skin irritation noted during the study included very slight to well-defined erythema and crust formation. All animals showed an expected gain in bodyweight during the study. No abnormalities were noted at necropsy. The acute dermal median lethal dose (LD50) of the test material in the Sprague- Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.


Justification for selection of acute toxicity – oral endpoint
Only one study available (conducted with the read-across substance).

Justification for selection of acute toxicity – dermal endpoint
Only one study available (conducted with the read-across substance).

Justification for classification or non-classification

The read-across substance (Phosphoric acid, mono- and di-(C8 -C10) ester, compds. with C12 - 14 amine) had LD50 greater than 2000 mg/kg bw for acute oral and dermal toxicity. Inhalation is not a relevant route of exposure. Therefore, the target substance (Reaction products of diphosphorus pentaoxide and alcohol C7-9-iso, C8 rich, salted with 2-ethylhexylamine) does not meet the criteria for classification and labelling for oral, dermal or inhalatory toxicity in accordance with European Regulation (EC) No. 1272/2008.