Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Neurotoxicity
Administrative data
Description of key information
Delayed Neurotoxicity: does not produce delayed neurotoxicity in hens.
Key value for chemical safety assessment
Effect on neurotoxicity: via oral route
Link to relevant study records
- Endpoint:
- neurotoxicity: acute oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1990-01-23 to 1990-03-01
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 418 (Delayed Neurotoxicity of Organophosphorus Substances Following Acute Exposure)
- Deviations:
- not specified
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- hen
- Strain:
- other: gallus gallus domesticus
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- 41 healthy young adult white leghorn hens (Gallus gallus domesticus), 17 months old, and weighting a mean of 1.53 kg (range 1.40 – 1.70 kg, Feather Down Farm, Raleigh, NC) were used.
Hens were vaccinated against Marek’s disease at hatching, and for Newcastle-Bronchitis at 10 days of age, along with a booster at 8 weeks of age, and were vaccinated at 18 weeks of age against Laryngotracheitis.
The hens were uniquely numbered (685-690 and 701-716) with metal leg tags. the hens were pre-designated to treatment groups by using randomisation tables.
Groups of 4 hens were placed in 3×3×3 ft stainless-steel cages in a humidity and temperature controlled room with a 12 hour artificial light, 12 hour dark cycle before and during the study.
Birds were provided with a fee supply of feed (Layena Poultry Feedm Ralston Purina Co., St. Louis, MO) and water - Route of administration:
- oral: unspecified
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- A group of 6 hens was given a single oral dose of 5000 mg/Kg/bw of XP-2563 without a vehicle.
A group of 5 hens was similarly treated with a single oral dose of 750 mg/Kg/bw of TOCP and served as a positive control for delayed neurotoxicity.
A third group of 5 hens was not treated and used as a control. - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 24 hours
- Frequency of treatment:
- Single oral dose
- Dose / conc.:
- 5 000 mg/kg bw/day
- No. of animals per sex per dose:
- A group of 6 hens was given a single oral dose of 5000 mg/Kg bw of XP-2563 without a vehicle.
A group of 5 hens was similarly treated with a single oral dose of 750 mg/Kg bw of TOCP and served as a positive control for delayed neurotoxicity.
A third group of 5 hens was not treated and used as a control. - Control animals:
- yes, concurrent no treatment
- Details on study design:
- XP-2563 was orally administrated at a dose level of 5000 mg/kg/bw to 5 unprotected hens without atropine sulphate or pyridine-2-aldoxime dimethyl-chloride (2-PAM) against anticholinesterase effects. Treated hens were kept for observation for 14 days prior to termination.
Dose level of 5000 mg/kg/bw was used to study the effect of XP-2563 on hen brain NTE and AChE and plasma BuChE.
24 hours after treatments, treated and control hens was anesthetised with carbon dioxide and killed by heart exsanguination followed by decapitation and dissection of the brain. - Specific biochemical examinations:
- NEUROPATHY TARGET ESTERASE (NTE) ACTIVITY: Yes
Brain NTE was determined by the differential assay of phenyl valerate hydrolyzing activity using paraoxon and mipafox as selective inhibitors. In two tubes a 50 µL aliquot of the 10% brain homogenate was incubated with a 40 µM paraoxon and 50 mM Tris-HCl buffer containing 0.1 mM disodium EDTA, pH 8.0, in a total volume of 2 mL at 37C for 20 min. Two similar tubes that contained an additional 50 µM Mipafox were incubated for 20 mins at 37C.
Following the initial incubation period, a 2 mL substrate solution consisting of 1.4 mM phenyl valerate in 0.03% Triton X-100 an 3.3% of dimethyl formamide was added and incubated for another 15 min at 37C. The enzymatic reaction was stopped with 2 mL of stopping solution containing 1% sodium dodecyl sulfate and 0,025% 4-aminoantipyrine. Finally, a 0.5 mL of 0.8% potassium ferricyanide solution was added, followed by a 2 min wait, and then the coloured solution was read at 510 nm. NTE activity was expressed as nanomoles of phenyl valerate hydrolyzed per minute per mg of brain protein.
CHOLINESTERASE ACTIVITY: Yes
The brain AChE activity was determined by measuring the initial rate of acetylthiocholine (ATCH) hydrolysis at 37°C. A 0.02 mL sample of the 10% brain homogenate in the sodium phosphate buffer was added to a reaction mixture containing 1.0 mM ATCH, 100 mM NaCl, 20 mM MgCl2, 20 mM sodium phosphate buffer (pH adjusted to 8.2) and 1.0 mM 5,5-dithiobis-2-nitrobenzoic acid (DTNB) in a final volume of 4 mL. Parallel blank incubations were carried out in the same buffer without acetylthiocholine. The initial hydrolysis rate of ATCH was measured at an absorbance of 412 nm. Brain AChE activity was expressed as micromoles ATCH hydrolyzed per minute per milligram of brain protein.
OTHER:
PLASMA BUTYRYLCHOLINESTERASE
Plasma BuChe activity was assayed by adding 0.02 mL of plasma to a reaction mixture consisting of 0.2 mM butyrylthiocholine (BuTCh), 40 mM MgCl2, 4 mM Tris buffer (pH adjusted to 7.4), and 0.1 mM DTNB in a final volume of 4.0 mL. Initial rate of hydrolysis of BuTCh was measured spectrophotometrically at 412 nm. Plasma BuChE activity was expressed as micromoles of BuTCh hydrolyzed per minute per milligram of plasma protein.
PROTEIN DETERMINATION
Brain and plasma protein levels were determined by the Lowry protein assay, using bovine serum albumin (BSA) as the standard. All spectrophotometric measurements were carried out in a Shimadzo Model 3000 UV-Vis spectrophotometer. - Sacrifice and (histo)pathology:
- 24 hours after treatments, treated and control hens was anesthetised with carbon dioxide and killed by heart exsanguination followed by decapitation and dissection of the brain.
- Positive control:
- A group of 5 hens was similarly treated with a single oral dose of 750 mg/kg/bw of TOCP and served as a positive control for delayed neurotoxicity.
- Statistics:
- The differences between enzyme activity of control and treated hens were assessed by the Student's t-test. A p value of 0.05 or less was considered significant.
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- not examined
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Neuropathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Neither brain NTE nor AChE was significantly inhibited by XP-2563. Only plasma BuChE was significantly inhibited and had activity of 53.77% (46.23% inhibition; P <0.001, P value of 0.05 or less was considered significant) of the controls.
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Details on results:
- The acute effects of a single oral dose of 5000 mg/kg/bw of XP-2563 or a single dose of 750 mg/kg/bw of TOCP on brain NTE and AChE and plasma BuChE were determined 24 hours after administration.
Neither brain NTE nor AChE was significantly inhibited by XP-2563. Only plasma BuChE was significantly inhibited and had activity of 53.77% (P <0.001, P value of 0.05 or less was considered significant) of the controls. In contrast, the OPIDN-producing TOCP inhibited hen brain NTE with activity of 10.12% of control (P<0.001) and brain AChE which had activity of 90.83% (P<0.05) of control. TOCP also inhibited plasma BuChE with activity of 11.22% (P<0.001) of the control
The result that the 5000 mg/kg/bw of XP-2563 was not fatal to the treated hens in consistent with the finding that this dose did not significantly inhibit brain AChE, the target for cholinergic effect of organophosphorus esters, nor did this dose inhibit hen brain NTE. These results suggest that XP-2563 does not have the potential to produce delayed neurotoxity (OPIDN) in hens. An inhibition by approx. 75% or greater of hen brain NTE one day after dosing is used as an indicator for the ability of an organophosphorus compound to produce OPIDN
The dose of 750 mg/kg/bw, of TOCP, the positive control for delayed neurotoxicity, resulted in 89.88% inhibition of hen brain NTE. NTE, an enzyme that has been proposed as the putative target for OPIDN, is inhibited by delayed neurotoxic agents but not by nondelayed neurotoxic organophosphorus compounds. Both XP-2563 and TOCP resulted in severe inhibition of plasma BuChE, an enzyme with unknown biochemical or physiologic functions. Neither brain AChE, nor plasma BuChE seem to play a direct role in the development of OPIDN. - Key result
- Dose descriptor:
- dose level: 5000 mg/Kg bw
- Effect level:
- 5 000 mg/kg bw (total dose)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- neuropathology
- Key result
- Critical effects observed:
- not specified
- Lowest effective dose / conc.:
- 5 000 mg/kg bw (total dose)
- System:
- central nervous system
- Organ:
- brain
- Conclusions:
- This study demonstrates that a single oral dose of 5000 mg/kg/bw of XP-5263 did not significantly inhibit hen brain neurotoxic esterase 24 hours after administration. the results suggest that XP-2563 does not produce delayed neurotoxicity in hens.
- Executive summary:
The effect of a single oral dose of XP-2563 on white leghorn hen brain neurotoxic esterase (NTE) and acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) and plasma butylcholinesterase (BuChE) was determined 24 hours after dosing. A 5000 mg/kg bw dose was used since it exceeded the LD50dose in unprotected hens, against the acute cholinergic effects of XP-2563. The dose caused statistically significantly inhibition of plasma BuChE activity (46.23% inhibition), yet neither brain NTE nor AChE was significantly inhibited by this treatment. The inhibition of 3.27% of brain NTE in the present study suggests that XP-2563 does not produce delayed neurotoxicity in hens since an inhibition of approx. 75% of brain NTE 24 hours after dosing is required to have the potential to produce delayed neurotoxicity. This conclusion is supported by the findings that a delayed neurotoxic dose of tri-o-cresyl phosphate (TOCP) significantly inhibited brain NTE (89.88% inhibition), plasma BuChE (88.78% inhibition) and brain AChE (9.17% inhibition), neither of which is directly involved in the development of delated neurotoxicity.
This study demonstrates that a single oral dose of 5000 mg/kg/bw of XP-5263 did not significantly inhibit hen brain neurotoxic esterase 24 hours after administration. the results suggest that XP-2563 does not produce delayed neurotoxicity in hens.
Reference
Effect of a single oral dose of 5000 mg/kg XP-2563 (alkyl diphenyl phosphate ester/dialkyl phenyl phosphate ester mixture) or 750 mg/kg TOCPaon the activity of hen brain neurotoxic esterase (NTE) and acetylcholinesterase (AChE) and plasma butyryl cholinesterase (BuChE)b
Enzymeb |
Control |
XP-2563 |
TOCP |
|||
Enzymatic activity |
% |
Enzymatic activity |
% |
Enzymatic activity |
% |
|
Brain NTE |
22.33 ± 0.98 |
100.00 ± 4.3 |
21.60 ± 0.50 |
96.73 ± 2.23 |
2.26 ± 0.36c |
10.12 ± 1.71c |
Brain AChE |
24.0 ± 1.2 |
100.00 ± 5.0 |
23.8 ± 0.5 |
99.17 ± 2.08 |
21.8 ± 0.7 |
90.83 ± 2.92d |
Plasma BuChE |
0.6928 ± 0.1263 |
100.00 ± 18.23 |
0.3725 ± 0.0792c |
53.77 ± 11.43c |
0.0777 ± 0.0243c |
11.22 ± 3.51c |
a A group of 6 hens was given a single oral dose of 5000 mg/kg bw of XP-2563 and a group of 5 hens was given 750 mg/kg bw of TOCP. Treated and untreated control hens were killed 24 hours after dosing
b Enzymatic activity is expressed as: brain NTE, nmoles phenyl valerate hydrolysed/mg brain protein/min; brain AChE, nmoles ATCH hydrolysed/mg brain protein/min; plasma BuChE, nmoles BuTCh hydrolysed/mg plasma protein/min
c P<0.001
d P<0.05
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- 5 000 mg/kg bw/day
- Species:
- hen
Effect on neurotoxicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Effect on neurotoxicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The effect of a single oral dose of XP-2563 on white leghorn hen brain neurotoxic esterase (NTE) and acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) and plasma butylcholinesterase (BuChE) was determined 24 hours after dosing (Monsanto Company, 1990d). A 5000 mg/kg bw dose was used since it exceeded the LD50 dose in unprotected hens, against the acute cholinergic effects of XP-2563. The dose caused statistically significantly inhibition of plasma BuChE activity (46.23% inhibition), yet neither brain NTE nor AChE was significantly inhibited by this treatment. The inhibition of 3.27% of brain NTE in the present study suggests that XP-2563 does not produce delayed neurotoxicity in hens since an inhibition of approx. 75% of brain NTE 24 hours after dosing is required to have the potential to produce delayed neurotoxicity. This conclusion is supported by the findings that a delayed neurotoxic dose of tri-o-cresyl phosphate (TOCP) significantly inhibited brain NTE (89.88% inhibition), plasma BuChE (88.78% inhibition) and brain AChE (9.17% inhibition), neither of which is directly involved in the development of delated neurotoxicity.
This study demonstrates that a single oral dose of 5000 mg/kg/bw of XP-5263 did not significantly inhibit hen brain neurotoxic esterase 24 hours after administration. The results suggest that XP-2563 does not produce delayed neurotoxicity in hens.
Justification for classification or non-classification
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.