dimethyl 1,2-benzenedicarboxylate;reaction mass of: 1,2-dimethylpropylidene dihydroperoxide

Endpoint summary

Description of key information

The oral LD50 value of MIPKP in Wistar rats was established to be within the range of 200-2000 mg/kg body weight.

The dermal LD50 value in Wistar rats was established to exceed 2000 mg/kg body weight. There is no data on acute inhalation.

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:

07 August 2001 - 30 August 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 7-8 weeks
- Weight at study initiation: mean 192g
- Fasting: Food was withheld overnight (for a maximum of 20 hours) prior to dosing until approximately 3-4 hours after administration of the testsubstance
- Housing: Group housing of 3 animals per sex per cage in labelled Macrolon cages (type IV; height 15 cm.) containing purified sawdust as bedding material (SAWI, Jelu Werk, Rosenberg, Germany). Certificates of analysis were examined and then retained in the NOTOX archives.
- Diet (e.g. ad libitum): Free access to standard pelleted laboratory animal diet (from Altromin (code VRF 1), Lage, Germany). Certificates of analysis were examined and then retained in the NOTOX archives.
- Water (e.g. ad libitum):Free access to tap-water. Certificates of quarterly analysis were examined and then retained in the NOTOX archives.
- Acclimation period: Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 07 August 2001 - 30 August 2001

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED:
2000 mg/kg (1.74 ml/kg) body weight.
200 mg/kg (0.174 ml/kg) body weight.
Dose volume calculated as dose level: density.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: none

Doses:

2000 and 200 mg/kg

No. of animals per sex per dose:

3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality: Twice daily. The time of death was recorded as precisely as possible. Body weight: Days 1 (pre-administration), 8 and 15 and at death (if found dead after day 1).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs:
At periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The symptoms were graded according to
fixed scales and the time of onset, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
For females and males given 200 mg/kg no clinical observations were performed on day 13 and 11, respectively. Since sufficient data on clinical observations were available, this protocol deviation was considered not to have affected the study integrity.

Statistics:

No statistical analysis was performed.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 200 - <= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

All females given 2000 mg/kg were found dead. The decedents were found on day 1 or 2 posttreatment. No further mortality occurred.

Clinical signs:

other: Lethargy, uncoordinated movements, alopecia, hunched posture and/or piloerection were noted on day 1 among the females given 2000 mg/kg. Piloerection or hunched posture was noted on day 1 among the females given 200 mg/kg and males given 200 mg/kg showed

Gross pathology:

At post mortem examination, dark red discolouration of the medulla of the kidneys was found in one female given 2000 mg/kg. Macroscopic post mortem examination of the other animals that died during the study and of the surviving animals at termination did not reveal any abnormalities.

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information

Conclusions:

The oral LD50 value of MIPKP in Wistar rats was established to be within the range of 200-2000 mg/kg body weight.

Executive summary:

Assessment of acute oral toxicity in the rat (Acute Toxic Class Method). The study was carried out based on the guidelines described in: EC Commission Directive 96/54/EC, Part B.1 tris "Acute Toxicity-Oral, Acute Toxic Class Method" and OECD No.423, "Acute Oral Toxicity - Acute Toxic Class Method".

Initially, the test substance was administered by oral gavage to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure additional groups of animals were dosed at 200 (females) and 200 (males) mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (day 15).

All females given 2000 mg/kg were found dead, on day 1 or 2 post-treatment. No further mortality occurred. Lethargy, uncoordinated movements, alopecia, hunched posture and/or piloerection were noted on day 1 among the females given 2000 mg/kg. Piloerection or hunched posture was noted on day 1 among the females given 200 mg/kg and males given 200 mg/kg showed lethargy on day 1.

The mean body weight gain shown by the surviving animals over the study period was considered to be normal. At post mortem examination, dark red discolouration of the medulla of the kidneys was found in one female given 2000 mg/kg. Macroscopic post mortem examination of the other animals that died during the study and of the surviving animals at termination did not reveal any abnormalities.

The oral LD50 value MIKP in Wistar rats was established to be within the range of 200-2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Quality of whole database:

K1 study, OECD guideline and GLP

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Endpoint conclusion

Endpoint conclusion:

no study available

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:

22 November 2001 - 06 December 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

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

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Germany.
- Age at study initiation: ± 11 weeks old
- Weight at study initiation: males mean: 415g, females mean: 272g
- Fasting period before study: none
- Housing: Individually housed in labelled polycarbonate cages (type III, height 15 em.) containing purified sawdust as bedding material (SAWI, Jelu Werk, Rosenberg, Germany). Certificates of analysis were examined and then retained in the NOTOX archives.
- Diet (e.g. ad libitum): Free access to standard pelleted laboratory animal diet (from Altromin (code VRF 1), Lage, Germany). Certificates of analysis were examined and then retained in the NOTOX archives.
- Water (e.g. ad libitum): Free access to tap-water. Certificates of quarterly analysis were examined and then retained in the NOTOX archives.
- Acclimation period: Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 22 November 2001 - 06 December 2001

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: back
- % coverage: The test substance was applied in an area of approx. 10% of the total body surface, i.e. approx. 25 cm2 for males and 18 cm2 for females.
- Type of wrap if used: The test substance was held in contact with the skin with a dressing, consisting of a surgical gauze (Surgy 1D), successively covered with aluminium foil and Coban flexible bandage·. A piece of Micropore tape was additionally used for fixation of the bandages in females only.

REMOVAL OF TEST SUBSTANCE
24 hours, after which dressings were removed and residual test substance removed using a tissue moistened with water.

TEST MATERIAL
2000 mg/kg (1.72 ml/kg) body weight. Dose volume calculated as follows: dose level: density.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality: twice daily. Body weight: Days 1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs:
At periodic intervals on the day of dosing (day 1) and once daily
thereafter, until day 15. The time of onset, degree and duration
were recorded and the symptoms graded according to fixed scales:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).

Statistics:

No statistical analysis was performed.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No mortality occurred.

Clinical signs:

other: Chromodacryorrhoea was noted among the animals between days 2 and 6. One male and one female showed hunched posture on day 2. Maculate or general erythema, scales, fissures, scabs, necrosis and/or wounds were seen in the treated skin-area of the animals d

Gross pathology:

Most males showed isolated scab formation on the treated skin. No further abnomalities were found at macroscopic post mortem examination of the animals.

Other findings:

None

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information

Conclusions:

The dermal LD50 value in Wistar rats was established to exceed 2000 mg/kg body weight.

Executive summary:

Assessment of acute dermal toxicity in the rat.

The study was carried out based on the guidelines described in: EC Commission Directive 92/69/EEC, Part B.3, "Acute Toxicity-Dermal" and OECD No.402, "Acute Dermal Toxicity". The test substance was administered to five rats of each sex by dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15).

No mortality occurred. Chromodacryorrhoea was noted among the animals between days 2 and 6. One male and one female showed hunched posture on day 2. Maculate or general erythema, scales, fissures, scabs, necrosis and/or wounds were seen in the treated skin-area of the animals during the observation period. One male showed brown staining of the head on day 1. The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity. Most males showed isolated scab formation on the treated skin. No further abnomalities were found at macroscopic post mortem examination of the animals.

The dermal LD50 value of MIKP in Wistar rats was established to exceed 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

K1 study, OECD guideline and GLP

Justification for classification or non-classification

The oral LD50 is 200 -2000 mg/kg body weight. Therefore MIPKP is classified Acute Toxicity Oral cat. 4.

The dermal LD50 value in Wistar rats was established to exceed 2000 mg/kg body weight. This LD50 value does not warrant classification.

There is no data on acute inhalation available.