Diallyl isophthalate

Endpoint summary

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

Study period:

23 March to 26 June 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

Source: Hino Breeding Centre, Charles River Laboratories Japan, Inc
Animals were quarantined for a minimum of 5 days with acclimatisation (from receipt to the day before dosing) 5, 7 and 12 days respectively for groups 1, 2 and 3. Group 4 animals were not used.
Age at study initiation: All group animals 9 weeks at dose administration
Weight at study initiation: Group 1 (194.2-204.6g), Group 2 (205.8-213.1g), Group 3 (193.9-209.5g)
Fasting: Animals were fasted ca. 19 hours (pre-dose) and 3 hours (post-dose)
Housing: One animal housed per cage (W226 x D346 x H198). Stainless steel cage and feeders changed at dose administration, cage racks at animal grouping and cage trays weekly.
Feed: Autoclave-sterilised pellet diet (CRF-1 Oriental Yeast Co., Ltd) ad libitum. Lot analysis performed, contaminants were within acceptable limits.
Water: Well water mixed with NaCLO (free residual chlorine concentration at 2ppm) ad libitum. Analysis performed twice yearly and confirmed within acceptable limits.
Environmental enrichment: Autoclaved alumina balls exchanged on the day of administration.
Temperature: 22.5-23.3°C
Humidity: 49.5-61%
Air changes: 10-20 p/h
Lighting: 12 hour light/dark 07:00 to 19:00
In life phase: 1st April (dosing expt 1) – 17 April (necropsy expt 2)

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Dosing solutions: 30 mg/mL (groups 1 & 2) 200 mg/mL (group 3). Starting dose set at 300 mg/kg due to no toxicological data or information on a similar test substance known

Doses:

Group: 1 (300 mg/kg) 2: (300 mg/Kg) 3: (2000 mg/kg)

No. of animals per sex per dose:

Three females

Control animals:

no

Details on study design:

Based on the step wise procedure in accordance with OECD 423 Guideline requirements
Duration of observation period: 14 days
Frequency of observations: 0.5, 1, 3 and 5 hours post dose on administration day. Thereafter once daily for 14 days unless clinical observations necessitated increased frequency based on clinical observations
Frequency of bodyweight: On day 1 before dosing and days 2, 4, 8 and 15
Necropsy of survivors performed: Yes
Other examinations performed: clinical observations, bodyweight and gross pathology (macroscopic examination)

Sex:

female

Dose descriptor:

LD50

Effect level:

500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Estimated

Mortality:

No mortality was observed in either group 1 or 2 animals dosed at 300 mg/kg. In group 3 animals dosed at 2000 mg/kg, two rats died, one on day 2 and one on day 3, the remainder was moribund on Day 3.

Clinical signs:

In group 1 (300 mg/kg) no clinical signs were observed in group animals.
In group 2 (300 mg/kg) a mucous stool was observed in a single animal 3-hours post dose on Day 1.
In group 3 (2000 mg/kg), one animal showed slight salivation 0.5 hours post-dose with slight decrease in locomotor activity observed at 0.5 and 3.0 hours. No clinical signs were present 5 hours. The following morning (Day 2), slight decreased locomotor activity was again present. In the afternoon moderate decreased locomotor activity, bradypnea, hypothermia, pale skin and slight lacrimation were observed which also persisted throughout day 3 where the animals was judged moribund.

One animal showed slight lacrimation 0.5 and 1.0 hour post-dose with slight decrease in locomotor activity observed at 0.5 and 3 hours. No clinical signs were present 5 hours post-dose, however they had returned on of the morning Day 2. In the afternoon moderate decrease locomotor activity (moderate), bradypnea, hypothermia, pale skin and slight lacrimation were observed. The animal died the following morning (Day 3).

One animal showed slight decrease in locomotor activity 3 hours post-dose. No clinical signs were present at 5 hours, however the animal died the following morning (Day 2).

Body weight:

In group 1 a decrease in bodyweight or suppression of bodyweight gain was observed in a single animal between days 1 and 2. This effect was observed in all group 2 animals. In both groups no effects were observed on Day 3.

In group 3, suppressed bodyweight gain was observed in a single animal with no abnormalities observed in the remainder between days 1 and 2.

Gross pathology:

In all animals from groups 1 and 2 no abnormalities were observed. In group 3 animals, no abnormalities were present in the two animals found dead on days 2 and 3. In the moribund animal a dark reddish change to the duodenum and edema of the lungs (and bronchus) was observed. Hyposthenia following haemorrhage of the duodenum and pulmonary edema was judged to be the cause of the moribundity.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

No clinical observations of concern were observed in groups 1 and 2 dosed at 300 mg/kg. In group 3, two animals died and one was judged moribund. Based on the step wise procedure in accordance with OECD 423, DAIM was GHS/CLP categorised as category 4, with its approximate LD50 estimated to be 500 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

500 mg/kg bw

Quality of whole database:

Klimisch 1

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1982

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Reference to the study indicates it is performed under GLP, according to FIFRA Guidelines 43 FR 37336. A copy of the original study report could not be obtained.

Justification for type of information:

ANALOGUE APPROACH JUSTIFICATION
Please refer to attached document.

Qualifier:

according to guideline

Guideline:

other: FIFRA Guidelines 43 FR 37336

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: FMC Corp./ Lot no. E104-19
- Expiration date of the lot/batch:
- Purity test date:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:
- Stability under test conditions:
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
- Preliminary purification step (if any):
- Final dilution of a dissolved solid, stock liquid or gel:
- Final preparation of a solid:

FORM AS APPLIED IN THE TEST (if different from that of starting material)

TYPE OF BIOCIDE/PESTICIDE FORMULATION (if applicable)

OTHER SPECIFICS:

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breending Laboratories, Portage, MI
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: no data
- Weight at study initiation: Males 200 - 265g, females 216 - 284g
- Fasting period before study: no data
- Housing: one rat per cage
- Diet (ad libitum): Purina Certified Rodent Chow 5002
- Water(ad libitum): filtered tap water libitum except during 1 hour exposure.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 13° to 24°C
- Humidity (%): 27 to 62%
- Air changes (per hr): yes
- Photoperiod: 12 hours light / 12 hours dark.

IN-LIFE DATES: From: To:

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

not specified

Mass median aerodynamic diameter (MMAD):

>= 1.89 - <= 2.1 µm

Duration of exposure:

1 h

Concentrations:

0.94, 3.09, 5.93, 6.66, 8.03, 9.17 and 9.71 mg/L

No. of animals per sex per dose:

20

Control animals:

yes

Details on study design:

- Duration of observation period following administration: Every day form day 1 to day 14
- Frequency of observations and weighing: Before exposure, on Days 7 and 14, or at death
- Necropsy of survivors performed: External surface, body orifices, cervical organs, Thoracic organs, abdominal and pelvic organs, and the brain. Specific Condition of the nasal passages, trachea, bronchi, and lungs
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Key result

Sex:

female

Dose descriptor:

LC01

Remarks:

1 hour exposure

Effect level:

0.58 mg/L air

Based on:

test mat.

95% CL:

>= 0.12 - <= 2.89

Exp. duration:

1 h

Sex:

female

Dose descriptor:

LC50

Remarks:

1 hour exposure

Effect level:

5.2 mg/L air

Based on:

test mat.

95% CL:

>= 3.23 - <= 8.36

Exp. duration:

1 h

Sex:

male

Dose descriptor:

other: LC99

Remarks:

1 hour exposure

Effect level:

30.49 mg/L air

Based on:

test mat.

95% CL:

>= 11.72 - <= 79.28

Exp. duration:

1 h

Mortality:

Dose Observed
(mg/l) deaths
---------------------------------
Male Female
--------------------------------------------
0.94 0/5 0/5
3.09* 0/5 2/5
5.93* 1/5 2/5
6.66* 0/5 3/5
8.03 3/5 4/5
9.17* 0/5 4/5
9.71* 3/5 3/5

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LC1 of 580 mg/m3 was calculated by the authors and this is the basis for deriving the DNEL since it is the most sensitive starting point. The lowest 1h-LC50 value was 5200 mg/m3 for female rats, corresponding with 1300 mg/m3 extrapolated to 4 h exposure, assuming a simple linear relationship.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

580 mg/m³

Quality of whole database:

In an acute inhalation study in the rat a LC50 of 8.3 mg/L = 8300 mg/m3 for a 1 hour exposure was identified (SIDS 1982). The LC1 of 580 mg/m3 was calculated by the authors and this is the basis for deriving the DNEL since it is the most sensitive starting point. Another acute inhalation study identified a LC100 of 4470 mg/m3 for a 4 hour exposure (FMC, 1980).
It is proposed to use the LC1 of 580 mg/m3 to derive the DNEL since the appropriate LC50 has been estimated.

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

Study period:

Date of Study Report: August 25, 1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given: comparable to guidelines/standards

Justification for type of information:

ANALOGUE APPROACH JUSTIFICATION
Please refer to attached document.

Qualifier:

according to guideline

Guideline:

other: 16CFR 1500.40

Deviations:

not specified

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

other: albino

Sex:

not specified

Details on test animals or test system and environmental conditions:

The acute dermal toxicity study (single exposure) was conducted on adult albino rabbits selected from healthy, acclimated animals.

Type of coverage:

not specified

Vehicle:

not specified

Details on dermal exposure:

No details provided in report

Duration of exposure:

No details provided in report

Doses:

200, 2000 and 5000 mg/kg

No. of animals per sex per dose:

30 rabbits used in total (no details provided whether they were male or female)

Control animals:

not specified

Details on study design:

No details provided in report

Statistics:

No details provided in report

Preliminary study:

N/A

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 300 mg/kg bw

Based on:

test mat.

Mortality:

No details provided in report

Clinical signs:

No details provided in report

Body weight:

No details provided in report

Gross pathology:

No details provided in report

Other findings:

No details provided in report

Results:

 

Dosage Level (mg/kg)	No.*Rabbits Dosed	Deaths
		Day
		1	2	3	4	5	6	7	8	9	10	11	12	13	14	Mortality after 14 Days
200	10	3	0	0	0	0	0	0	0	0	0	0	0	0	0	3/10
2000	10	1	0	0	1	0	0	0	1	0	0	0	1	0	0	4/10
5000	10	1	2	3	0	0	0	0	0	0	0	0	0	0	0	6/10

* Administered as received.

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The approximate acute Dermal LD50 obtained for the test material identified above is 3300 mg/kg of body weight estimated by interpolation from the probit response curve.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 300 mg/kg bw

Additional information

The oral study was conducted using DAIP, the acute dermal and inhalation studies are read-across using DAP.

Justification for classification or non-classification

Acute oral toxicity: Classification as Category 4, LC50 is between 300 and 2000 mg/kg b.w.

Acute dermal toxicity: No classification as the LD50 > 2000 mg/kg bw, the upper limit for classification.

Acute toxicity for inhalation: Classification as Category 4; motivation is firstly based on 4470mg/m³inducing 100 % mortality in a 4 -h exposure study, which confirms that the LC50 of DAP for inhalation is below 5 mg/l. Secondly, based on the secondary source data from ToxiGenics' study 420-0402 with an overall LC50 for rats which was 8300mg/m³after 1 hour of exposure, the LC50 value for the 4h-exposure would correspond with 2075mg/m³(assuming a simple linear relationship between time and LC50). The lowest 1h-LC50 value was 5200mg/m³for female rats, corresponding with 1300mg/m³extrapolated to 4 h exposure (again, assuming a simple linear relationship). These values indicate that the LC50 of DAP for inhalation is between 1000 and 5000mg/m³, the limits for classification as Category 4.