Reaction products of phosphoryl trichloride and 2-methyloxirane

Endpoint summary

Description of key information

Key Studies:
OECD 401 (Stropp, Bayer AG, 1996): LD50 = 632 mg/kg bw (Acute Tox. 4)
OECD 403 (IRI 1990a): LC50 = > 7 mg/L (not classified)
OECD 402 (IRI 1989b): LD50 = > 2,000 mg/kg bw (not classified)

Hazards identified by EU Risk Assessment in May 2008
-TCPP is of moderate toxicity via the oral route of exposure, with LD50 values from the better quality studies ranging from 632 mg/kg up to 4200 mg/kg, with the majority of values determined to be 2000 mg/kg.
-TCPP is of low  toxicity via the inhalation route.
-There is no concern for acute delayed neurotoxicity for TCPP.
-TCPP is of low t oxicity via the dermal route of exposure.

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study.

Qualifier:

according to guideline

Guideline:

other: This study was conducted according to the methods of Annex V, Part B.1. (acute toxicity (oral), to Directive 67/548/EEC of the Council of the European Communities of June 27, 1967 (Official Journal of the European Communities L196/1 of August 16, 1967)

Principles of method if other than guideline:

This study was conducted according to the methods of Annex V, Part B.1. (acute toxicity (oral), to Directive 67/548/EEC of the Council of the European Communities of June 27, 1967 (Official Journal of the European Communities L196/1 of August 16, 1967) in the current version as amended for the seventeenth time by Directive 92/69/EEC of the Commission of the European Communities of July 31, 1992 (Official Journal of the European Communities L 383 A of December 29, 1992).

GLP compliance:

yes

Test type:

other: Acute oral toxicity

Limit test:

no

Specific details on test material used for the study:

Tris(2-chlorisopropyl)phosphat CAS-No. 13674-84-5
designation: tris(2-chloropropyl)phosphate
manufacturer: Bayer AG
Batch: 07026
CAS no: 13674-84-5
appeartance: colourleaa liquid
storage: room temperature
expiry date: 07 Feb 1998

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: corn oil

Doses:

200, 500 mg/kg (both sexes) 2000mg/kg females only

No. of animals per sex per dose:

5/sex/dose
only female rats received 2000 mg/kg bw.

Control animals:

not specified

Sex:

female

Dose descriptor:

LD50

Effect level:

632 mg/kg bw

Sex:

male

Dose descriptor:

LD50

Effect level:

> 500 - < 2 000 mg/kg bw

Mortality:

All animals in the female group 2000 mg/kg bw died after 3-6 hours.

Clinical signs:

other: other: In female rats after 2000 mg/kg bw following signs of intoxication were observed: Apathy, palmospasm, blood-crusted snout and lateral position. A single dose of 200 and 500 mg/kg bw was tolerated by male and female rats without any clinical signs.

Gross pathology:

At necropsy mottled reddened lungs were noticed in the animals which died during the observation period.
None of the animals sacrified at the end of the 14-day observation period showed any noticeable gross pathological findings.

RS-Freetext:
LD50 > 500 mg/kg (males); LD50 = 632 mg/kg (females)

RS-Freetext:
mortality: 0/5 at 200 and 500 mg/kg (both sexes), 5/5 at
2000 mg/kg (females); clinical signs observed only at 2000
mg/kg: apathy, palmospasm, blood-crusted snout and lateral
position; necropsy findings only at 2000 mg/kg: reddened
lungs

Executive summary:

Acute toxicological investigations in male and female Wistar rats were conducted after single oral administration of TCPP.

The LD50 was calculated as approximate 632 mg/kg body weight for female rats and was greater than 500 mg/kg and less than 2000 mg/kg bw for the male rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

632 mg/kg bw

Quality of whole database:

Data rich endpoint, with multiple reliable studies. The key study was chosen based on the lowest LD50 value.

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:

1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study performed to GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Qualifier:

according to guideline

Guideline:

OECD Guideline 433 draft (Acute Inhalation Toxicity: Fixed Concentration Procedure) (not officially approved)

GLP compliance:

yes

Test type:

fixed concentration procedure

Limit test:

yes

Specific details on test material used for the study:

Colourless liquid
received 20 November 1989
stored in dark at ambient temperature
Acid value 0.01 mg KOH/g
water contnet = 0.04%
colour H.U.= 10
Det. Index at 25C: 1.463

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles RiverUk Ltd, Margate
- Age at study initiation: not given
- Weight at study initiation: 111-139g
- Fasting period before study: none
- Housing:1-2 rats per cage, polypropylene with steel mesh lids and bottoms
- Diet (e.g. ad libitum): Rat and Mouse (modified) No1 Diet SQC expanded ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period:at least 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-23C
- Humidity (%): 36-68%
- Air changes (per hr): not given
- Photoperiod (hrs dark / hrs light): 12hr light dark cycle


IN-LIFE DATES: From:20 Feb 1990 To:10 MArch 1990

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Mass median aerodynamic diameter (MMAD):

4.6 µm

Geometric standard deviation (GSD):

3.3

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:cylindrical aluminium exposure chamber
- Exposure chamber volume: 41.5 litres
- Method of holding animals in test chamber: polycarbonte restraint tubes
- Source and rate of air: hydrovane compressors 8 litres/min
- Method of conditioning air:
- System of generating particulates/aerosols:sage syringe pump continuous metering of substance through a glass concentric jet atomiser.
- Method of particle size determination: Marple cascade impactor in breathing zone of animals 2l/min sampling rate
- Treatment of exhaust air:high efficiency filter to a metered vaccum system
- Temperature, humidity, pressure in air chamber: 18-19C, RH for three groups 38-72%, 38-80%, 71-90%


TEST ATMOSPHERE
- Brief description of analytical method used: gravimetric method sorbent(silica) gel sampling tubes
- Samples taken from breathing zone: yes


VEHICLE
- Composition of vehicle (if applicable):
- Concentration of test material in vehicle (if applicable):
- Justification of choice of vehicle:
- Lot/batch no. (if required):
- Purity:


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: 42% <3.5µm
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): MMAD 4.6µm/ GSD 3.3µm


CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration:

Analytical verification of test atmosphere concentrations:

yes

Remarks:

measured gravimetric concentration

Duration of exposure:

4 h

Concentrations:

3.8 mg/L dose rangefinding
7.19 mg/L main study

No. of animals per sex per dose:

2 groups of 2 male and 2 female Sprague-Dawley rats were exposed to a measured gravimetric concentration of TCPP of up to 3.80 mg/L by snout only inhalation, in a dose range finding study, for a period of 4 hours. A further group of 5 female and 5 male Sprague-Dawley rats were exposed to a concentration of TCPP of 7.19 mg/L, also for 4 hours. This was based on the results obtained with the concentration used in the range-finding study.

Control animals:

not specified

Details on study design:

All animals were observed continuously for clinical signs throughout the exposure period, for the first 1-2 hours post-dosing and thereafter once daily during the subsequent 3 day (dose range finding study) or 14 day (main study) observation period. All rats were weighed immediately before dosing and on days 1 and 3 post exposure for the dose ranging finding study and on days 2, 3, 4, 7, 10 and 14 post exposure for the main study. At the end of the study, all animals were subjected to a macroscopic post mortem exam.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 7 mg/L air

Exp. duration:

4 h

Mortality:

There were no deaths during the study.

Clinical signs:

other: No unusual clinical observations were recorded during the exposure period. All animals appeared slightly unkempt and had red staining around the snout and eyes immediately after dosing. No abnormalities were observed during the subsequent 14-day observati

Body weight:

There was no effect on body weight.

Gross pathology:

No abnormalities were observed at post mortem.

Other findings:

lung/bodyweight ratios observed were considered to be within normal limits.

The acute inhalation LC50 is taken to be greater than 7 mg/L from this study.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation LC50 is taken to be greater than 7 mg/L from this study.

Executive summary:

2 groups of 2 male and 2 female Sprague-Dawley rats were exposed to a measured gravimetric concentration of TCPP of up to 3.80 mg/L by snout only inhalation, in a dose range finding study, for a period of 4 hours. A further group of 5 female and 5 male Sprague-Dawley rats were exposed to a concentration of TCPP of 7.19 mg/L, also for 4 hours. This was based on the results obtained with the concentration used in the range-finding study. The acute inhalation LC50 is taken to be greater than 7 mg/L from this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 7 mg/L air

Physical form:

inhalation: aerosol

Quality of whole database:

Two reliable studies available, meeting data requirements under Annex VIII of REACH.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study performed to Guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

Received 30 Novemeber 1988
colourless liquid
stored in dark at ambient temperature
specific gravity 1.29

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
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 159-274g
- Fasting period before study: none
- Housing: polypropylene cages with mesh floors, max 5 animals per cage
- Diet (e.g. ad libitum): Expanded Rat& Mouse Maintenance Diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period:minimum 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22C
- Humidity (%): 48%
- Air changes (per hr): not given
- Photoperiod (hrs dark / hrs light ): 12 hr light/dark cycle


IN-LIFE DATES: From: 18 January 1989 To: 9 February 1989

Type of coverage:

other: Sleek non-irritating Tape, Smith& Nephew

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure:
- % coverage: upto at least 10%
- Type of wrap if used: Sleek Tape, Smith & Nephew


REMOVAL OF TEST SUBSTANCE
- Washing (if done): water dampened tissue
- Time after start of exposure:24 hrs


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 400, 1000, 1500, 2000 mg/kg
- Concentration (if solution):
- Constant volume or concentration used: no
- For solids, paste formed: yes/no


VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:

Duration of exposure:

24 hrs

Doses:

Rangefinding study 400, 1000, 1500, 2000 mg/kg
main study 2000 mg/kg

No. of animals per sex per dose:

2 per sex per dose rangefinding
5 per sex per dose main study

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:daily after exposure, animals weighed prior to dosing, day 7 and day 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.

Key result

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

nil

Clinical signs:

other: other: no clinical signs noted

Gross pathology:

nop abnormalities detected.

The median dermal lethal dose (LD50) of Tolgard TMCP in rats is greater than 2000 mg/kg

Interpretation of results:

GHS criteria not met

Conclusions:

The median dermal lethal dose (LD50) of Tolgard TMCP in rats is greater than 2000 mg/kg

Executive summary:

The acute dermal toxicity of Tolgard TMCP was investigated in rats.

A dose rangeing study in pairs of rats indicated that the LD50 value by the dermal route is greater than 2000 mg/kg bw. A main study dose level of 2000 mg/kg bw was selected accordingly.

In the main study, no deaths occured and no clinical signs were noted after 24h dermal administration, under occlusion, of Tolgard TMCP, at a dose level of 2000 mg/kg bw.

The medium Dermal Lethal Dose (LD50) of Tolgard TMCP in rats in this study is greater than 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

A single key study is available (OECD 402) that meets information requirements under Annex VIII of REACH.

Additional information

Hazards identified by EU Risk Assessment in May 2008:

"The inhalation exposure studies in animals were somewhat equivocal and in general lacking in detailed information. One study yielded an LC50 of > 7 mg/L/4hr. A limit test yielded an acute LC50 value of >4.6 mg/L/4hr. No deaths occurred at this concentration. Toxic signs observed in this study, and in 2 further poorly reported studies, included mild lethargy, matted fur, acute bodyweight depression and convulsions. From the studies, it appears that TCPP is more toxic when administered whole body as aerosol than by nose-only exposure. This suggests that some of the systemic toxicity observed when TCPP is administered whole body may result from dermal or oral uptake, rather than inhalation. Therefore, it is concluded that TCPP is of low toxicity via the inhalation route. Studies in rats indicated that TCPP is of moderate toxicity via the oral route of exposure, with LD50 values from the better quality studies ranging from 632 mg/kg up to 4200 mg/kg, with the majority of values determined to be 2000 mg/kg. Common clinical and macroscopic signs of toxicity observed on nearly all studies included depression, ataxia, hunched posture, lethargy, laboured respiration, increased salivation, partially closed eyelids, body tremors, pilo-erection, ptosis, haemorrhagic lungs and dark liver and/or kidneys. A NOAEL of 200 mg/kg can be identified for acute oral toxicity. This is taken from the Stropp 1996 study, in which no clinical signs of toxicity were observed in animals dosed with 200 mg/kg TCPP. In a delayed neurotoxicity study conducted in hens, TCPP showed moderate toxicity. The principle effects were reduced mean body weight and food consumption, feather loss and cessation of laying. There was no evidence of inhibited plasma acetylcholinesterase or brain neurotoxic esterase enzyme levels. Therefore, there is no concern for acute delayed neurotoxicity for TCPP.

Studies in rats and rabbits indicated that TCPP is of low toxicity via the dermal route of exposure with LD50values of >2000mg/kg. "

Justification for classification or non-classification

Based on the available data, the substance meets the criteria for classification as Acute Tox 4 (H302: Harmful if swallowed) in accordance with Regulation (EC) 1272/2008 (CLP), based on oral LD50 = 632 mg/kg bw (OECD 401/EU B.1). No further classification is required.