Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
p-phenylene diisocyanate
EC Number:
203-207-6
EC Name:
p-phenylene diisocyanate
Cas Number:
104-49-4
Molecular formula:
C8H4N2O2
IUPAC Name:
1,4-diisocyanatobenzene
Test material form:
solid: crystalline

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Source: In-Vivo Biosciences
Kodigehalli Village
Magadi Road, Bangalore, Code-29
Karnataka State

Age. 9 to 11 weeks

After physical examination for good health and suitability for experiment, the animals were acclimatized six days for G1-FTS and eight days for G1-STS before treatment. Animals were observed once daily during acclimatization period. Females were nulliparous and non-pregnant.

Rats were housed under standard laboratory conditions, air conditioned with adequate fresh air supply (13.7 air changes/hour). Environment: with temperature 20 to 23°C, relative humidity 64 to 66%, with 12 hours light and 12 hours dark cycle. The maximum and minimum temperature and relative humidity in the experimental room were recorded once daily. The relative humidity in the experimental room was calculated from dry and wet bulb temperature recordings.

Rat & Mice pellet feed, manufactured by Krishna Valley Agro Tech LLP, MIDC Kupwad block, Sangli, Maharashtra, was provided to animals.

Deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-line water filter-cum-purifier manufactured by Eureka Forbes Ltd, Mumbai 400 001, India, was provided to animals in polycarbonate bottles with stainless steel sipper tubes.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% w/v NaCMC with 0.1% v/v Tween 80 in MIlli-Q water
Details on oral exposure:
The prepared test item dose formulation was administered at the dose volume of 10 mL/kg bodyweight to attain the dose of 2000 mg/kg body weight (G1 – First and second treatment steps) as a single oral gavage to overnight fasted rats (16 to 18 hours). Each animal was administered orally by gavage using disposable plastic syringe attached with metal feeding cannula. Food was offered about 3 to 4 hours after dosing. Water was not withheld.
Doses:
As per the public available data (MSDS) provided by the sponsor, the acute oral toxicity LD50 of PPDI for rats is 2160 mg/kg. Hence, the study was initiated with the starting dose of 2000 mg/kg body weight (G1-FTS). The test was started as per Annex 2d of the OECD 423 test guideline.
No. of animals per sex per dose:
First treatment group: three
Second treatment group: three
Control animals:
no
Details on study design:
At each step, the animals were observed five times on test day 1 (day of administration) i.e. at 30 minutes and four times at hourly intervals and once daily during days 2 to 15 post administration.
Observations included changes in skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern. Attention was directed to the observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma and all observed clinical signs were recorded.
The body weights were recorded on test day 1 (pre-administration), day 8 (7 days post administration) and day 15 (14 days post administration).The rats surviving to the end of the observation period were euthanised by
using isoflurane anaesthesia and subjected to detailed necropsy. Gross pathological findings were recorded and reported. Microscopic examination was not carried out as no gross pathological changes were observed.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
5 000 mg/kg bw
Based on:
test mat.
Mortality:
No pre-terminal deaths.
Clinical signs:
other: No clinical signs.
Gross pathology:
No abnormalities detected.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of the present study, the test item, P-phenylene diisocyanate, The LD50 is 5000 mg/kg body weight or Unclassified as per LD50 cut-off value.
Executive summary:

The acute oral toxicity study with P-phenylene diisocyanate in Wistar rats was conducted to assess the toxicological profile of the test item. The dose formulation was prepared by using 0.5% w/v Sodium carboxy methyl cellulose (medium viscosity) with 0.1% v/v Tween in Milli-Q water and administered as a single oral gavage to overnight fasted (16 to 18 hours) three female rats (G1-FTS) at the dose of 2000 mg/kg body weight. There were no clinical signs of toxicity and pre-terminal deaths. Based on the scheme - Annex

2d of the guideline OECD 423, three additional female rats were tested at the same dose of 2000 mg/kg body weight (G1-STS). There were no clinical signs of toxicity and pre-terminal deaths. Based on the scheme - Annex 2d of the guideline OECD 423, the dose was stopped The rats were observed for mortality and clinical signs for 14 days post

treatment. Body weights were recorded prior to dosing on day 1 and again on days 8 and 15. Necropsy was performed for all the rats at termination. All survived rats gained weight during experimental period. There were no gross pathological changes at necropsy. Based on the results of the present study, the test item, P-phenylene diisocyanate, The LD50 is 5000 mg/kg body weight or Unclassified as per LD50 cut-off value.

The test item, P-phenylene diisocyanate is classified as follows:

  • The test item is classified “Category 5” or Unclassified as per Globally Harmonized Classification system of Annex 2d of the Guideline, OECD 423.
  • The test item does not meet the criteria for classification as “Category 4” (300 mg/kg < Acute Toxicity Estimates ≤ 2000 mg/kg) as per Regulation (EC) No 1272/2008 of the European Parliament and of the council of 16 December 2008 on classification, labeling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006, as there was no mortality observed at 2000 mg/kg body weight.
  • The test item is classified as “Category 5” (the oral LD50 range of 2000 to 5000 mg/kg) as per OECD: Harmonised Integrated Classification system (OECD, 2001), as there was no mortality observed at 2000 mg/kg body weight.
  • The test item is classified as “Category 5 or unclassified” (oral LD50 in the range of 2000 to 5000 mg/kg) as per Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Seventh Revised Edition, United Nations (2017). ST/SG/AC.10/30/Rev.7, as there was no mortality observed at 2000 mg/kg body weight.