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Toxicological information

Neurotoxicity

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Description of key information

After two doses of 5000 mg/kg bw of Triisobutyl phosphate in hens by gavage, no effects were observed.
Furthermore, a single oral 5000 mg/kg bw dose Triisobutyl phosphate did not significantly inhibit hen brain neurotoxic esterase 24 hours after administration. The results suggest that Triisobutyl phosphate does not produce delayed neurotoxicity in hens.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: acute oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06.02.1986 - 20.03.1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 418 (Delayed Neurotoxicity of Organophosphorus Substances Following Acute Exposure)
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material: Etingal
- Physical state: liquid
- Analytical purity: 99.7%
- Purity test date: 1984-05-28
- Lot/batch No.: 84/175
- Stability under test conditions: unlimited
- Storage condition of test material: Room temperatur
Species:
hen
Strain:
other: Hybridstamm
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Frima Leib. landwirtschaftlicher Betrieb, Hassloch/Pfalz, BRD
- Age at study initiation: 12-14 Months
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: as a group in an aviary
- Diet: from 28.10.85; Legehennen-Alleinfutter 9B Pres (Frima Raiffeisen). From 21.12.85; Hübler Ln/G-Futter (Firma Ssniff Spezialdiäten GmbH). From 13.02.86; LA-Eierblitz, Alleinfutter für Legehennen (Firma Ssniff Spezialdiäten GmbH).
- Water (ad libitum): Tapwater
- Acclimation period: 3 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 20
- Humidity (%): 50-60
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

IN-LIFE DATES: no data
Route of administration:
oral: gavage
Vehicle:
olive oil
Remarks:
DAB8
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- preperation on the day of exposure
- concentrations: 0, 5, 10, 20, 50%

VEHICLE
- Justification for use and choice of vehicle: not specified
- Amount: 10 mL/kg bw
- Purity: not specified
Analytical verification of doses or concentrations:
not specified
Frequency of treatment:
500 and 1000 mg/kg bw: 1 treatment
2000 and 5000 mg/kg bw: 2 treatments (2nd after 21 days)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Remarks:
one treatment
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
one treatment
Dose / conc.:
2 000 mg/kg bw/day (actual dose received)
Remarks:
two treatments
Dose / conc.:
5 000 mg/kg bw/day (actual dose received)
Remarks:
two treatments
No. of animals per sex per dose:
Contol group 1 and 2: 5 females per group
Test group 3: 4 females
Test group 4, 5 and 6: 5 females per group
Positive contol group 7, 8 and 9: 5 females per group
Control animals:
yes, concurrent vehicle
other: Tri-ortho-cresylphosphat solved in olive oil
Details on study design:
- Dose selection rationale: according to OECD guideline maximal 5000 mg/kg bw is required
- Rationale for animal assignment: random
- Rationale for selecting satellite groups: not specified
- Post-exposure recovery period in satellite groups: no data
Observations and clinical examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- mortality and symptomatology: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: on day 42

BODY WEIGHT: Yes
- Time schedule for examinations: day 1 and day 42. On day 21 for the test groups with doses 2000 and 5000 mg/kg bw.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, the first 6 days
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not applicable.

WATER CONSUMPTION AND COMPOUND INTAKE: No

OPHTHALMOSCOPIC EXAMINATION: No data

OTHER: NEUROTOXIC SURVEY FINDINGS
- Time schedule for examinations: on day 1, 5, 20 and 42
Specific biochemical examinations:
NEUROPATHY TARGET ESTERASE (NTE) ACTIVITY: No data

CHOLINESTERASE ACTIVITY: No data
Neurobehavioural examinations performed and frequency:
The animals were individually placed on a 40 cm high box and forced to jump, on day 1, 5, 20 and 42.
Sacrifice and (histo)pathology:
- Time point of sacrifice: day 42
- Number of animals sacrificed: all
- Parameters measured: not specified
- Brain weight: no data
- Length and width of brain: no data
- Procedures for perfusion: not specified
- Number of animals perfused: no data
- Tissues evaluated: Parameters checked in table were examined: no
- Type of staining: no data
- Methodology of preparation of sections: no data
- Thickness: no data
- Embedding media: no data
- Number of sections: no data
- Number of animals evaulated from each sex and treatment group: all animals
Positive control:
CAGE SIDE OBSERVATIONS: Yes
- mortality and symptomatology: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: on day 42

BODY WEIGHT: Yes
- Time schedule for examinations: day 1 and day 42.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, the first 6 days
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: not applicable

WATER CONSUMPTION AND COMPOUND INTAKE: No

OPHTHALMOSCOPIC EXAMINATION: No data

OTHER: NEUROTOXIC SURVEY FINDINGS
- Time schedule for examinations: on day 1, 5, 20 and 42
Statistics:
No data
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Clinical biochemistry findings:
not specified
Behaviour (functional findings):
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Details on results:
In the positive control animals, treatment-related deaths (5 of 15), serious of severe neurotoxic symptoms (7 of 15) and weight loss occurred, while in the triisobutyl phosphate-treated hens there were no effects that could be attributed to treatment, even after the administration of two doses of 5000 mg/kg bw.
Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
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

A study of the possible neurotoxic effect of Triisobutyl phosphate (99,7% pure) was carried out based on OECD 418 in groups of 5 adult domestic hens (aged ca. 12 to 14 months) (BASF, 1987). Two groups were given single doses of 500 and 1000 mg/kg bw, respectively, (dissolved in olive oil) by gavage and were then observed for 42 days. Further groups were given single doses of 2000 and 5000 mg/kg bw, respectively, and were then given the same dose again 21 days later with a total observation period of 42 days. As a positive control 3 groups of 5 hens were given a single dose of 500 mg tri-o cresyl phosphate/kg bw by gavage (also in olive oil) and were also observed for 42 days. In the positive control animals, treatment-related deaths (5 of 15), serious of severe neurotoxic symptoms (7 of 15) and weight loss occurred, while in thetriisobutyl phosphate-treated hens there were no effects that could be attributed to treatment, even after the administration of two doses of 5000 mg/kg bw.

 

The effect of a single oral dose of Triisobutyl phosphate(TiBP) on white hen brain neurotoxic esterase (NTE) and acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) was determined 24 hours after receiving a single oral dose (Monsanto, 1990). A 5000 mg/kg bw dose was used since it exceeded the oral LD50 dose in unprotected hens again the acute cholinergic effects of TiBP. This dose caused statistically significant inhibition of plasma BuChE activity (98.1% inhibition), yet neither brain NTE nor AChE was significantly inhibited by this treatment. The inhibition of 9.45 of brain NTE suggests that TiBP does not produce delayed neurotoxicity in hens since an inhibition of approximately 75% of brain NTE 24 hours after dosing is required for an organophosphorus compound 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 (86.2% inhibition). This TOCP dose also significantly inhibited plasma BuChE (89.2% inhibition) and brain AChE (20.7% inhibition), neither of which is directly involved in the development of delayed neurotoxicity.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. Based on the results of the oral delayed neurotoxicity study, the substance does not need to be classified for neurotoxicity under Regulation (EC) No. 1272/2008, as amended for the tenth time in Regulation (EC) No. 2017/776.