Reaction mass of butyl diphenyl phosphate and dibutyl phenyl phosphate and tributyl phosphate

Endpoint summary

Description of key information

Acute toxicity information is available for the oral, inhalation and dermal route. The inhalation study received a K2 Klimisch score while all other studies were categorised K4. All studies indicated that no classification for acute toxicity is warranted.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

1979

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: The study protocol is poorly documented.

Justification for type of information:

Acryloid HF-422 (70.8% dibutylphenylphosphate and 29.2% n-butylmethacrylate polymer) is considered a suitable RA test substance based on the present % of DBPP.

Reason / purpose for cross-reference:

read-across source

Remarks:

RA RSS and orignal RSS are identical

Qualifier:

no guideline followed

Principles of method if other than guideline:

Acute oral toxicity test. A single oral dose was administered to rats. Animals were observed until 14 days after administration of the test substance. Mortalities, body weights and clinical observations were recorded.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Doses:

500, 1500, 2500, 3500, 5000 mg/kg

No. of animals per sex per dose:

5 males and 5 females

Control animals:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 307 mg/kg bw

95% CL:

3 568 - 6 423

One animal at the 2500 mg/kg dose and one at the 5000 mg/kg dose exhibited alopecia. One animal at the 2500 mg/kg dose, two at the 2500 mg/kg dose, two at the 3500 mg/kg dose, and 8 at the 5000 mg/kg dose were hypoactive. Bloody appearing urine was seen in one animal at the 3500 mg/kg dose and in 2 at the 5000 mg/kg dose. One animal at the 3500 mg/kg dose and one at the 5000 mg/kg dose had ptosis. Ataxia was seen in one animal at the 3500 mg/kg dose and in 5 animals at the 5000 mg/kg dose. Excessive lacrimation was observed in one animal at the 3500 mg/kg dose and in 4 animals at the 5000 mg/kg dose.

Gross necropsy: 20 animals were necropsied at terminal sacrifice. One had very pale lungs. One had very pale colored kidneys. One had unilateral hydronephrosis and white sediment in the same kidney. The remaining 17 animals were not remarkable.

Dose	Body weight (Gm)			Mortalities / dosed
mg/kg	Day 0 M/F	Day 7 M/F	Day 14 M/F	Male	Female	Combined
500	176/173	251/213	300/228	0/5	0/5	0/10
1500	171/171	244/218	293/227	0/5	0/5	0/10
2500	178/178	246/222	297/242	0/5	1/5	1/10
3500	178/168	245/203	307/221	0/5	2/5	2/10
5000	172/171	215/ -	281/ -	2/5	5/5	7/10

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: No guideline followed. Very concise report. Dose descriptor not appropriate for risk assessment.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Introduction of measured single doses of the undiluted test substance into the stomachs of healthy animals by means of a rubber catheter attached to a hypodermic syringe. Animals receiving a lethal dose were autopsied and macroscopic examination made of the viscera.

GLP compliance:

no

Test type:

other: not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Experiment also included New Zealand White rabbits, males and females.

Rats weighed 160 to 240 grams.
Rabbits weighed 1,7 to 2,2 kilograms

Route of administration:

other: catheter into stomach

Vehicle:

unchanged (no vehicle)

Doses:

Rats: 0,3 - 0,6 - 0,9 - 1,2 - 1,6 - 2,0 - 2,2 - 2,4 - 2,6 - 2,7 - 2,8 - 3,0 - 3,5 - 4,0 - 5,0 - 6,0 mg/kg
Rabbits: 0,3 - 0,6 - 1,2 - 1,5 - 2,0 - 2,2 - 2,4 - 2,5 - 3,5 - 4,5 mg/kg

No. of animals per sex per dose:

1 animal per dose, random sex

Control animals:

not specified

Sex:

male/female

Dose descriptor:

other: Minimum Lethal Dose

Effect level:

2.2 - 2.6 mL/kg bw

Based on:

test mat.

Remarks on result:

other: rat

Sex:

male/female

Dose descriptor:

other: Minimum Lethal Dose

Effect level:

2.2 - 2.4 mL/kg bw

Based on:

test mat.

Remarks on result:

other: rabbit

Mortality:

All rats dosed 2.6 mL/kg and above died. One of 2 rats dosed 2.4 mL/kg died.

Clinical signs:

Mild diarrhea and temporary loss of appetite in all survivors, with exception of the rats and rabbits dosed 0,3 and 0,6 mL/kg.
All rats developed unsteadiness and lethargy within 2-3 hours after dosing at levels above 0,6 mL/kg.

Gross pathology:

gastroenteritis and blood in the urine

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Quality of whole database:

Three K4 studies are available.
No study was selected as key study since a weight-of-evidence approach was applied using the most relevant studies.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study, no internationally accepted protocol mentioned but test procedure is described in sufficient detail.

Justification for type of information:

Acryloid HF-422 (70.8% dibutylphenylphosphate and 29.2% n-butylmethacrylate polymer) is considered a suitable RA test substance based on the present % of DBPP.

Reason / purpose for cross-reference:

read-across source

Remarks:

RA RSS and original RSS are identical

Qualifier:

no guideline followed

Principles of method if other than guideline:

A sonic jet nebulizer was used to generate the test material atmosphere. The test material was metered under pressure through a small stainless steel capillary tube (0,030" I.D.) and 3 feet of 1/4" polyethylene tubing to an orifice where an air stream was directed at a right angle to the liquid flow. This orifice is a sonic jet and will produce either an aerosol or an aerosol-vapour mixture, depending upon the test material's vapour pressure.

A single 4-hour exposure was conducted using 5 animals of each sex. Nominal concentrations were determined hourly throughout the exposure and were maintained at approx. 4,15 mg/L of air. Animals were weighed just prior to the exposure, and on post-exposure days 2, 7, and 14. Gross observations for signs of toxicity were recorded during the exposure and twice daily during the 14-day post-exposure period. Gross necropsies were performed on all animals.

GLP compliance:

yes

Test type:

other: not specified

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 55 days (females), 60-75 days (males, according to protocol)
- Weight at study initiation: 172-220g (females), 200-300g (males, according to protocol)
- Fasting period before study: no data
- Housing: two per cage
- Diet: Purina Standard Laboratory Rodent Chow, ad libitum
- Water: ad libitum
- Acclimation period: according to standard procedures (not copied in study report)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 +/- 2°F
- Humidity (%): 35-60%
- Air changes (per hr): see other section
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

other: combination of aerosol and vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: sonic jet nebulizer (Laskin style)
- Exposure chamber volume: 300L
- Source and rate of air: room air, exposure chamber airflow was maintained at 70L/min, i.e. 14 air-changes per hour.
- System of generating particulates/aerosols: test material was metered under pressure through a small stainless steel capillary tube (0,030" I.D.) and 3 feet of 1/4" polyethylene tubing to an orifice where an air stream was directed at a right angle to the liquid flow.

TEST ATMOSPHERE
A nominal concentration will be determined 3 times during the run: at the beginning, after several hours and within 1 hour of termination. The presence of an aerosol in the chamber will be recorded.

VEHICLE
- Composition of vehicle: corn oil
- Concentration of test material in vehicle: 50.9% wt/wt
- Justification of choice of vehicle: use of vehichle was required due to the test material viscosity

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

4 h

Concentrations:

4,15 mg/L

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
* weighing: just prior to exposure + at days 2, 7 and 14
* observation: during the exposure + twice daily afterwards
- Necropsy of survivors performed: yes

Sex:

male/female

Dose descriptor:

LC0

Effect level:

4.15 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No deaths occurred during the exposure or during the 14-day post exposure period.

Clinical signs:

other: chromodacryorrhea around the nose durint the exposure in all animals.

Body weight:

No treatment effects were noted in the individual or mean body weights during the entire study period.

Other findings:

occasional mottled liver in 2 females

A light aerosol mist was visible during the entire exposure and the calculated mean nominal concentration was 4,15 mg/L of air.

Conclusions:

The test substance, when administered by inhalation under the experimental conditions described above produced a low acute toxicity in male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

There is only one K2 study is available.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

1979

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: The study protocol is poorly documented.

Justification for type of information:

Acryloid HF-422 (70.8% dibutylphenylphosphate and 29.2% n-butylmethacrylate polymer) is considered a suitable RA test substance based on the present % of DBPP.

Reason / purpose for cross-reference:

read-across source

Remarks:

source RSS and RA RSS are identical

Qualifier:

no guideline followed

Principles of method if other than guideline:

Dermal toxicity test with rabbits. Survival and clinical observations were recorded. A gross pathology was conducted.

GLP compliance:

no

Limit test:

yes

Species:

rabbit

Strain:

other: New Zealand

Sex:

male/female

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Doses:

dosage: 2000 mg/kg bw

No. of animals per sex per dose:

10 animals: 5 males and 5 females

Control animals:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Mortality:
male: 0/5
female: 0/5

Clinical signs:

Six animals had dry and crusty skin in the treatment area. The remaining animals appeared normal.

Gross pathology:

Three animals had necrotic spots on their livers. One animal had white sediment in one kidney. Six animals were not remarkable.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1956

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: The study protocol is poorly documented.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Undiluted dibutyl phenyl phosphate was applied in varying amounts to the closely clipped intact skin of New Zealand white rabbits and the treated areas covered with plastic shields to retard evaporation. Observations were made for outward signs of toxicity and those animals succumbing were examined macroscopically.

GLP compliance:

not specified

Test type:

other: no data

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

no data

Type of coverage:

other: plastic shields, not further specified

Vehicle:

unchanged (no vehicle)

Duration of exposure:

no data

Doses:

2,0 - 3,2 - 4,2 - 5,0 - 6,0 and 7,5 (2 animals) g/kg

No. of animals per sex per dose:

1 animal of random sex per dose

Control animals:

not specified

Sex:

not specified

Dose descriptor:

other: Minimum Lethal Dose

Effect level:

5 000 - 7 500 mg/kg bw

Based on:

test mat.

Mortality:

All animals exposed to 7.5 g/kg died (2 males). The animal exposed to 5.0 g/kg died (1 female). However, the animal exposed to 6.0 g/kg (1 female) survived.

Clinical signs:

Succumbing animals became shaky and lethargic overnight.

Body weight:

Body weight loss was observed in the animals exposed to 2.0, 3.2 and 4.2 g/kg. Nevertheless, the animal exposed to 5.0 g/kg did not show any weight loss.

Other findings:

At autopsy, no specific abnormalities were observed macroscopically aside from pulmonary congestion, which is often observed in such instance.

Animal No. - Sex	Weight (kg)	Dose g/kg	Weight change 5 days after dosing (%)	Fate
1 - Female	2.3	2.0	- 3.5	Survived
2 - Male	2.6	3.2	- 8.0	Survived
3 - Male	2.2	4.2	- 5.0	Survived
4 - Female	2.1	5.0		Died -- 3 days
5 - Female	2.0	6.0	0.0	Survived
6 - Male	2.4	7.5		Died -- 2 days
7 - Male	2.4	7.5		Died -- 2 -3 days

Interpretation of results:

relatively harmless

Remarks:

Migrated information

Conclusions:

The minium lethal dose was found to be in the range of 5.0 to 7.5 g /kg.

Executive summary:

The minium lethal dose was found to be in the range of 5.0 to 7.5 g /kg. Survival time was 2 to 3 days. Body weight loss was observed in the animals exposed to 2.0, 3.2 and 4.2 g/kg. Nevertheless, the animal exposed to 5.0 g/kg did not show any weight loss.

Succumbing animals became shaky and lethargic overnight. All animals except the one treated with the lowest dose showed this condition to some extent. At autopsy, no specific abnormalities were observed macroscopically aside from pulmonary congestion, which is often observed in such instance.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Quality of whole database:

Two K4 studies are available. No key study was selected since a weight-of-evidence approach was applied.

Additional information

For acute toxicity via the oral route, a weight-of-evidence approach was applied. In the oldest study study report (Younger, 1953) a minimal lethal dose of 2.4 – 2.8 mg/kg for rats was observed. In another study report (Younger, 1956) an LD50 of 2620 mg/kg body weight for rats was calculated. In a third study (Branch, 1979), Acryloid HF-422, a formulation of 70.8% DBPP and 29.9 % n-butylmethacrylate polymer was tested on rats. An LD50 of 4307 mg/kg body weight was calculated in this study. This LD50 is probably an underestimation since the test material consisted of only 70.8% DBPP. An LD50 around 3049 mg/kg body weight would be a more realistic value taking into account the concentration of DBPP.

For acute toxicity via the inhalation route, read-across to Acryloid HF-422, a formulation of 70.8% DBPP and 29.2% n-butylmethacrylate polymer, was applied.

This endpoint was evaluated by a limit test in one study (Pounds, 1983). Ten Sprague-Dawley rats, five males and five females, were exposed during 4 h at a mean nominal concentration of 4.15 mg/l (mist). No deaths occurred during the exposure or during the 14-day post exposure period. During the entire study no effects on body weight were noted. Except for chromodacryorrhea around the nose (5M, 5F) during the exposure, no other clinical findings were noted. Gross postmortem findings were normal, except for 2 females with mottled livers.

Two acute dermal toxicity studies were available (Younger, 1956; Branch, 1979). However, both were ranked with a K4 Klimisch score and one of them used Acryloid HF-422, a formulation of 70.8% DBPP and 29.2% n-butylmethacrylate polymer, as a test substance (Branch, 1979). A weight of evidence approach was applied.

In the oldest study (Younger, 1956), concentrations ranged from 2000 until 7500 mg/kg bw were applied on the intact skin of New Zealand White rabbits. The minimum lethal dose was found to be in the range of 5000 until 7500 mg/kg bw. Until a dose of 4200 mg/kg bw the animals did not die but suffered from a slight weight loss (respectively -3.5, -8.0 and -5.0 % for a dose level of 2000, 3200 and 4200 mg/kg bw).

In the other study (Branch, 1979), a limit test was performed with Acryloid HF-422, a formulation of 70.8% DBPP and 29.2% n-butylmethacrylate polymer. Five male and five female New Zealand rabbits were treated with the undiluted test substance. No mortality was observed at a dose level of 2000 mg/kg bw Acryloid HF-422 (or ≈ 1416 mg/kg bw DBPP). A gross necropsy showed that three animals had necrotic spots on their livers and that one animal had white sediment in one kidney. The other six animals did not show remarkable symptoms.

Justification for classification or non-classification

Acute oral toxicity

The test substance has an oral ATE between 2400 and 3000 mg/kg body weight. According to the CLP Regulation (Annex I, Table 3.1.1), substances with an oral ATE higher than 2000 mg/kg body weight should not be classified for Acute toxicity via the oral route.

Acute inhalation toxicity

A limit test for inhalation toxicity was performed at a concentration of 4.15 mg/L (mist). According to the CLP Regulation (Annex I, Table 3.1.1) an ATE for dusts and mists between 1.0 and 5.0 mg/l should be classified as Category 4. Because no deaths occurred at 4.15 mg/l it is assumed that the LD50 will be higher than 5.0 mg/l. Consequently we concluded that the test substance should not be classified for Acute toxicity via the inhalation route.

Acute dermal toxicity

The minimum lethal dose was found to be in the range of 5000 to 7500 mg/kg body weight. According to the CLP Regulation (Annex I, Table 3.1.1), substances with an ATE higher than 2000 mg/kg body weight should not be classified for Acute toxicity via the dermal route.