Bisisopropyl peroxydicarbonate

Endpoint summary

Description of key information

OECD 422 study

The potential toxic effects of diisopropyl peroxydicarbonate was evaluated following daily oral administration (gavage) to male and female rats from before mating, during mating and, for the females, throughout gestation until Day 13 post partum (p.p.).

This study provides information:

. on the possible health hazards likely to arise from repeated exposure over a relative limited period of time,

. on male and female reproductive performance, such as gonadal function, mating behavior, conception, development of the conceptus and parturition.

Three groups of ten male and ten female Sprague-Dawley rats received the test tem, diisopropyl peroxydicarbonate, daily by the oral route (gavage) at dose levels of 25, 75 or 150 mg/kg/day, under a constant dosage volume of 5 mL/kg/day. Males were treated for 2 weeks before mating, during the mating period and until the day before sacrifice (4 weeks in total). Females were treated 2 weeks before mating, throughout mating and gestation and until Day 13 p.p. inclusive. Another group of ten males and ten females received the vehicle only (corn oil) under the same experimental conditions and acted as a control group. The actual test item concentrations in the dose formulations were determined in Weeks 1 and 6 using a validated HPLC/UV analytical method. Animals were checked daily for clinical signs and mortality. Detailed clinical observations were performed once a week. Body weights and food consumption were recorded weekly until mating (no food consumption during the mating period) and then at designated intervals throughout gestation and lactation. Hematology and blood biochemistry investigations as well as urinalysis were performed for five males and females at sacrifice. Thyroid hormones (TSH and T4) were determined in males at sacrifice. Five males and females were submitted to a functional observation battery (FOB) at the end of the treatment period (Day 13p.p.). Males were sacrificed after 4 weeks of treatment, and dams on Day 14 p.p. A full macroscopic post-mortem examination was performed in adults, with a particular attention to the reproductive organs. Designated organs (adrenals, brain, epididymides, heart, kidneys, liver, pituitary gland, prostate, seminal vesicles, spleen, testes and thymus) were weighed and more tissue specimens were preserved. A microscopic examination was performed on selected tissues from five males and females in the control- and high-dose groups.

The test item concentrations were within an acceptable range of variations (± 10% of the nominal concentrations required). No test item was observed in the control dose formulations. There were no test item-related unscheduled deaths. Piloerection, round back, emaciated appearance and/or mainly loud/abdominal breathing were transiently observed in 3/20 animals at 150 mg/kg/day. Ptyalism was noted at all dose levels with dose-related incidences. These clinical signs were considered to be test item-related and non-adverse. There were no effects on mean body weight, mean body weight change and mean food consumption. There were no test item-related changes at reactivity to manipulation, to different stimuli and at motor activity evaluation (FOB) at any dose level. At laboratory investigations (hematology, blood biochemistry, urines, thyroid hormones), no differences from controls were attributed to the test item treatment. At pathology, there were no organ weights, macroscopic or microscopic changes.

Based on the experimental conditions and results of this study:

. the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 150 mg/kg/day based on the absence of adverse findings at this high-dose level.

 

14 -day range-finding study

The potential toxicity of diisopropyl peroxydicarbonate was evaluated following daily oral administration (gavage) to rats for 2 weeks in order to assist the selection of dose levels for a further 4-week toxicity/OECD 422 study (Alloun, 2017). Three groups of five male and five female Sprague-Dawley rats were treated daily by oral route (gavage) with the test item at dose levels of 250, 500 or 1000/750 (1000 from Day 1 to Day 4, 750 from Day 5 to Day 14) mg/kg/day for 2 weeks. Another group of five males and five females received the vehicle alone (corn oil) under the same experimental conditions and acted as a control group. The test item was administered as a solution in the vehicle, under a constant dosage-volume of 5 mL/kg/day. The animals were observed daily for mortality and clinical signs. Body weight was recorded once on pre-test, on the first day of treatment and then at least once a week until the end of the study. Food consumption was recorded once a week during the treatment period. On completion of the treatment period, the surviving animals were euthanized and a full macroscopic post-mortem examination was performed. The same procedure was performed for all prematurely euthanized animals. The heart, kidneys, liver, ovaries, spleen and testes were weighed and selected tissue specimens were preserved. No microscopic examination was performed.

Five animals were prematurely euthanized during this study: one male from the high-dose group (on Day 4), one female from the low-dose group (on Day 13), one female from the intermediate-dose group (on Day 12), and two females from the high-dose group (on Days 5 and 8). Test item-related clinical signs were observed in the treated groups (in both sexes) and at all dose levels as hunched posture, ptyalism, abdominal breathing and piloerection. Body weight, body weight change and food consumption were unaffected by the test item treatment except in the prematurely euthanized females. The mean absolute and relative liver weights were minimally and statistically higher in females at 1000/750 mg/kg/day. This was considered to be most likely treatment-related. Other organ weight changes were not considered to be related to the test item as they were small in amplitude, had no gross correlates, were not dose-related in magnitude, and/or were not consistent in both sexes.

Macroscopic findings observed in the prematurely euthanized animals were similar to other treated animals and are described below.

Treatment-related findings were observed in the digestive tract as follows:

. the forestomach of all treated animals presented either with a thickened wall, a diffuse white discoloration, focal to multifocal red discolorations and/or white masses. These findings were considered to be related to the test item administration,

. the stomach, duodenum, ileum, jejunum, cecum and colon were often distended with gas, thickened and/or with diffuse yellow or white discoloration, with a dose-related increase.

The potential toxicity of Diisopropyl peroxydicarbonate was evaluated after daily administration (gavage) to Sprague-Dawley rats at dose levels of 250, 500 or 1000/750 (1000 from Day 1 to Day 4, 750 from Day 5 to Day 14) mg/kg/day for 2 weeks.

The repeated oral administration of the test item induced signs of toxicity at all dose levels (i.e.hunched posture, hypoactivity, prostration, ptyalism, abdominal and loud breathing, dyspnea, piloerection, thin appearance and an increase of the abdomen size).The premature euthanasia was necessary in five animals (including all dose levels), due to poor health conditions following the test item treatment.

At necropsy, a moderate increase in liver weights was noted in females treated at 1000/750 mg/kg/day. The thickening and discolorations of the gastrointestinal tract were also considered to be related to test item treatment.

Consequently, under the experimental conditions of this study, because of the premature deaths and toxicity recorded at all dose levels, the maximal tolerated dose level was lower than 250 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

29 July 2016

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

In the males:
- 2 weeks before mating,
- during the pairing period,
- until sacrifice (at least 4 weeks in total),

In the females:
- 2 weeks before mating,
- during the mating period,
- during gestation,
- during lactation until Day 13 post-partum inclusive,
- until sacrifice for females with no evidence of mating.

Frequency of treatment:

Daily

Dose / conc.:

25 mg/kg bw/day (actual dose received)

Dose / conc.:

75 mg/kg bw/day (actual dose received)

Dose / conc.:

150 mg/kg bw/day (actual dose received)

Control animals:

yes, concurrent no treatment

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

Executive summary:

The potential toxic effects of diisopropyl peroxydicarbonate was evaluated following daily oral administration (gavage) to male and female rats from before mating, during mating and, for the females, throughout gestation until Day 13 post partum (p.p.).

This study provides information:

.            on the possible health hazards likely to arise from repeated exposure over a relative limited period of time,

.            on male and female reproductive performance, such as gonadal function, mating behavior, conception, development of the conceptus and parturition.

Three groups of ten male and ten female Sprague-Dawley rats received the test item,Diisopropyl peroxydicarbonate, daily by the oral route (gavage) at dose levels of 25, 75 or 150 mg/kg/day, under a constant dosage volume of 5 mL/kg/day. Males were treated for 2 weeks before mating, during the mating period and until the day before sacrifice (4 weeks in total). Females were treated 2 weeks before mating, throughout mating and gestation and until Day 13 p.p.inclusive. Another group of ten males and ten females received the vehicle only (corn oil) under the same experimental conditions and acted as a control group. The actual test item concentrations in the dose formulations were determined in Weeks 1 and 6 using a validated HPLC/UV analytical method. Animals were checked daily for clinical signs and mortality. Detailed clinical observations were performed once a week.Body weights and food consumption were recorded weekly until mating (no food consumption during the mating period) and then at designated intervals throughout gestation and lactation. The animals were paired for mating after 2 weeks of treatment and the dams were allowed to litter and rear their progeny until Day 13 p.p. The total litter sizes and numbers of pups of each sex were recorded after birth. The size of each litter was adjusted on Day 4 p.p.by culling extra pups to obtain as nearly as possible four males and four females per litter. The pups were observed daily for clinical signs or abnormal behaviour and were weighed on Days 1, 4, 8 and 13 p.p.The physical development of pups was assessed by measuring the anogenital distance on Day 1 p.p.and by counting the number of nipples and areolae in male pups on Day 12 p.p. Hematology and blood biochemistry investigations as well as urinalysis were performed for five males and females at sacrifice. Thyroid hormones (TSH and T4) were determinedin males at sacrifice and in pups sacrificed on Day 13 p.p. Five males and females were submitted to a functional observation battery (FOB) at the end of the treatment period (Day 13p.p.). Males were sacrificed after 4 weeks of treatment, and dams on Day 14 p.p. A full macroscopic post-mortem examination was performed in adults, with a particular attention to the reproductive organs. Designated organs (adrenals, brain, epididymides, heart, kidneys, liver, pituitary gland, prostate, seminal vesicles, spleen, testes and thymus) were weighed and more tissue specimens were preserved. A microscopic examination was performed on selected tissues from five males and females in the control- and high-dose groups. Pups not selected on Day 4 p.p.were sacrificed and discarded without further examination.Pups selected were sacrificed on Day 13 p.p.and submitted to a detailed external examination with a particular attention to the external genital organs.

The test item concentrations were within an acceptable range of variations (± 10% of the nominal concentrations required). No test item was observed in the control dose formulations.

F0 animals

There were no test item-related unscheduled deaths. Piloerection, round back, emaciated appearance and/or mainly loud/abdominal breathing were transiently observed in 3/20 animals at 150 mg/kg/day. Ptyalism was noted at all dose levels with dose-related incidences. These clinical signs were considered to be test item-related and non-adverse. There were no effects on mean body weight, mean body weight change and mean food consumption. There were no test item-related changes at reactivity to manipulation, to different stimuli and at motor activity evaluation (FOB) at any dose level. At laboratory investigations (hematology, blood biochemistry, urines, thyroid hormones), no differences from controls were attributed to the test item treatment.

At pathology, there were no organ weights, macroscopic or microscopic changes. There were no test item-related effects on estrous cycles during the first 2 weeks of treatment and at termination, and on mean fertility, mating and delivery data.

Pups

There were notest item-related effects in terms ofpup mortality/viability, clinical signs, terminal external examination, development of nipples and areolae in male pups on Day 13 p.p.,percentage of male pups at birthormean T4 and TSH levels on Day 13 p.p.There were no toxicologically significant effects on mean pup body weight.An effect of the test item treatmenton the lower mean anogenital distance at 25 and 150 mg/kg/day compared with controls was considered to be doubtful and non-adverse.

Based on the experimental conditions and results of this study:

.            the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 150 mg/kg/day based on the absence of adverse findings at this high-dose level,

.            the No Observed Effect Level (NOEL) for reproductive performance (mating and fertility) was considered to be 150 mg/kg/day based on the absence of test item-related effects on mating and fertility at this dose level,

.            the NOAEL for toxic effects on progeny was considered to be 150 mg/kg/day based on the absence of adverse findings on pups at this high-dose level.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

11 Septembre 2017 - 09 October 2017

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:

no guideline followed

Principles of method if other than guideline:

Range-finding study

GLP compliance:

no

Remarks:

not required for a range-finding study

Limit test:

no

Specific details on test material used for the study:

Test item:
Name: Diisopropyl peroxydicarbonate
Synonyms:
- Di-isopropyl peroxydicarbonate
- Bisisopropyl peroxydicarbonate
CAS No.: 105-64-6

Test item received:
Name: LUPEROX IPP50EA Experimental
Batch No.: LUG1381
Description: Colorless liquid
Storage conditions: In the freezer set at -20°C
Composition: 51.5% of peroxide in ethyl acetate
Correction factor: 1.94 (taking into account the peroxide content)
Expiry (or re-test) date: 29 December 2017.

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: breeder: Charles River Laboratories Italia, Calco, Italy
- Age on the first day of treatment: the animals were approximately 5 weeks old
- Mean body weight: on the first day of treatment, the males had a mean body weight of 170 g (range: 158 g to 186 g) and the females had a mean body weight of 133 g (range: 120 g to 143 g)
- Fasting period before study: no
- Housing: the animals were housed by five from the same sex and group in polycarbonate cages with stainless steel lids (Tecniplast 2000P, 2065 cm2) containing autoclaved sawdust
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: for a period of 6 days before the beginning of the treatment period.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 8 to 15 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: 25 September 2017 to 09 October 2017.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING FORMULATIONS: Solution in the vehicle
- Concentration in vehicle: 50, 100, 200 until Day 7 and 150 from Day 8.
A constant dosage-volume of 5 mL/kg/day was used in groups 1, 2 and 3. In group 4, a constant dosage volume of 5 mL/kg/day was used from Days 1 to 4 and from Days 8 to 14. A constant dosage volume of 3.75 mL/kg/day was used from Days 5 to 7.
- Amount of vehicle: 5 mL/kg/day.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

2 weeks

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

until Day 4 then 750 mg/kg bw/d from Day 5

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

yes, concurrent vehicle

Details on study design:

Rationale for dose selection:
The dose levels were selected following the results of an acute oral toxicity study in rats where no mortality or clinical sign was observed at the dose level of 1000 mg/kg body weight.

Observations and examinations performed and frequency:

MORTALITY/MORBIDITY:
- Time schedule: each animal was checked for mortality and morbidity once a day during the acclimation period and at least twice a day during the treatment period, including weekends.

CLINICAL SIGNS:
- Time schedule: each animal was observed once a day, at approximately the same time on the days of treatment, for the recording of clinical signs.

BODY WEIGHT:
- Time schedule: the body weight of each animal was recorded once before the beginning of the treatment period, on the first day of treatment and at least once a week until the end of the study.

FOOD CONSUMPTION:
- Time schedule: the quantity of food consumed by the animals in each cage was measured once a week during the treatment period.
Food consumption was calculated per animal and per day.

Sacrifice and pathology:

ORGAN WEIGHTS:
The body weight of each animal was recorded before euthanasia at the end of the treatment period. The organs specified in the Tissue Procedure Table were weighed wet as soon as possible after dissection.
The ratio of organ weight to body weight (recorded immediately before euthanasia) was calculated.

GROSS PATHOLOGY:
A complete macroscopic post-mortem examination was performed on all study animals. This included examination of the external surfaces, all orifices, the cranial cavity, the external surfaces of the brain, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the neck with its associated organs and tissues.

PRESERVATION OF TISSUES:
For all animals, the tissues specified in the Tissue Procedure Table, were preserved in 10% buffered formalin (except for the testes, which were fixed in Modified Davidson’s Fixative).

HISTOPATHOLOGY:
No microscopic examination was performed in the first instance.

Statistics:

Citox software was used to perform the statistical analysis of body weight data.
PathData software was used to perform the statistical analysis of organ weight data.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

See table 1.
Hunched posture and piloerection were observed in two females treated with 250 mg/kg/day (from Day 12), in one female treated with 500 mg/kg/day (from Day 8) and in all males and females from the 1000/750 mg/kg/day dose group (from Day 4 for both sexes).
Abdominal breathing was noticed in one male and three females from the high-dose group (on Day 4 and from Day 5, respectively), in two females from the low-dose group (from Day 12) and in one female from the intermediate-dose group (from Day 8).
Hypoactivity was observed in all females treated with 1000/750 mg/kg/day (on Day 4).
Those clinical signs reflected the poor general health of the animals and therefore, they were considered to be adverse effects.
Other clinical signs were recorded, with a lower incidence, in test item-treated animals (i.e. reflux at dosing, loud breathing and dyspnea) which confirmed a toxicological importance. However, females seemed to be more clinically impacted than males by the test item.
Ptyalism was noted in males from all treated groups (from Day 3), in two females treated with 250 mg/kg/day (from Day 5), in all females treated with 500 mg/kg/day (from Day 5) and in all females treated with 1000/750 mg/kg/day (from Day 3).
This clinical sign was considered to be related to test item treatment but non-adverse.

Mortality:

mortality observed, treatment-related

Description (incidence):

Five animals were prematurely euthanized, for humane reasons, during this study:
- one male from the high-dose group (on Day 4): presented on Day 4, hunched posture, piloerection, coldness to the touch, abdominal breathing and loud breathing,
- one female from the low-dose group (on Day 13): presented ptyalism (from Days 5 to 12), dyspnea (from Days 9 to 13), piloerection and prostration (from Day 12). On the day of euthanasia, thin appearance, hunched posture, pallor on the ears, reflux at dosing, abdominal breathing and loud breathing were observed,
- one female from the intermediate dose group (on Day 12): presented ptyalism (from Day 5), hunched posture, piloerection, abdominal breathing and an increase of the abdomen size (from Day 8). On the day of euthanasia, prostration and dyspnea were noted,
- two females from the high-dose group (on Days 5 and 8):
* the first animal presented, from Day 4, hunched posture, piloerection and hypoactivity. The day of euthanasia (on Day 5), thin appearance, ptyalism, abdominal breathing and loud breathing were observed,
* the second animal presented hypoactivity on Day 4. This animal showed hunched posture and piloerection from Day 4. From Day 5, ptyalism was recorded. The day of euthanasia (on Day 8), thin appearance, slight soft feces, abdominal breathing and an increase of the abdomen size were observed.

Macroscopic findings were similar to other treated animals.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Apart from the animals which were prematurely sacrificed, there were no significant differences between the control group and the test item-treated groups on mean body weight and body weight change in both sexes.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Mean food consumption was unaffected by the test item treatment in both sexes, whatever the dose level.

Food efficiency:

not examined

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:

effects observed, treatment-related

Description (incidence and severity):

See table 2.
The mean absolute and relative liver weights were minimally and statistically higher in females at 1000/750 mg/kg/day. This was considered to be most likely treatment-related.

Other organ weight changes were not considered to be related to the test item as they were small in amplitude, had no gross correlates, were not dose-related in magnitude, and/or were not consistent for the sexes.

Unscheduled deaths
There were five unexpected deaths. One male and one female treated at 1000 mg/kg/day, another female treated at 1000/750 mg/kg/day, one female treated at 500 mg/kg/day and another female treated at 250 mg/kg/day. Macroscopic findings were similar to other treated animals and are described below.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Treatment-related findings were observed in the digestive tract as follows:
- the forestomach of all treated animals presented either with a thickened wall, a diffuse white discoloration, focal to multifocal red discolorations and/or white masses. These findings were considered to be related to the test item administration,
- the stomach, duodenum, ileum, jejunum, cecum and colon were often distended with gas, thickened and/or with diffuse yellow or white discoloration, with a dose-related increase.
On the liver, a red mass and a white discoloration were noted in two males treated at 250 mg/kg/day. In the absence of a clear dose-related trend and since there were no increase in liver weights in males, this finding was considered to be most probably incidental and unrelated to the test item administration.
In the uterus, dilatation of the horns with translucent content was noted in one female treated at 250 mg/kg/day and one female treated at 500 mg/kg/day but was not seen in any controls. Since this finding is commonly observed in control rats as a consequence to estrous cycle variations, a relationship to treatment was excluded.
The few other gross findings observed (renal cysts, spleen reduced in size, red and black discoloration of the thymus), were considered to be incidental or part of the normal background in all groups.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Dose descriptor:

other: Maximum Tolerated Dose Level

Effect level:

< 250 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

gross pathology

mortality

organ weights and organ / body weight ratios

Critical effects observed:

not specified

Table 1: Clinical signs

Group	1	2	3	4
Dose level (mg/kg/day)	0 (control)	250	500	1000/750
Hunched posture
. Male	0/5	0/5	0/5	4/4
. Female	0/5	1/4	0/4	3/3
Piloerection
. Male	0/5	0/5	0/5	4/4
. Female	0/5	1/4	0/4	3/3
Ptyalism
. Male	0/5	5/5	5/5	4/4
. Female	0/5	2/4	4/4	3/3
Abdominal breathing
. Male	0/5	0/5	0/5	0/4
. Female	0/5	1/4	0/4	2/4
Hypoactivity
. Male	0/5	0/5	0/5	0/4
. Female	0/5	0/4	0/4	4/4

 

Table 2: Organ weights

 

Sex	Male			Female
Group	2	3	4	2	3	4
Dose level (mg/kg/day)	250	500	1000/750	250	500	1000/750
Nb of animals	5/5	5/5	4/5	4/5	4/5	3/5
- Final body weight	-4	-13	-11	-2	-1	+7
- Liver . absolute weight
	-2	-14	-7	+4	+4	+28*
. range   . relative weight	[7.7130- 10.4510]	[6.1440- 10.3900]	[7.7900- 9.1000]	[5.2380- 6.8670]	[5.595- 6.4120]	[7.1880- 7.8090]
	+3	-1	+5	+6	+6	+20*
. range	[3.106- 3.805]	[2.972- 3.615]	[3.305- 3.711]	[3.257- 3.856]	[3.422- 3.640]	[3.748- 4.378]

Statistically significant from controls: *: p<0.05.

Statistical significance determined for organ weights values and not percent changes.

Conclusions:

The potential toxicity of diisopropyl peroxydicarbonate was evaluated after daily administration (gavage) to Sprague-Dawley rats at dose levels of 250, 500 or 1000/750 (1000 from Day 1 to Day 4, 750 from Day 5 to Day 14) mg/kg/day for 2 weeks.
The repeated oral administration of the test item induced signs of toxicity at all dose levels (i.e. hunched posture, hypoactivity, prostration, ptyalism, abdominal and loud breathing, dyspnea, piloerection, thin appearance and an increase of the abdomen size). The premature euthanasia was necessary in five animals (including all dose levels), due to poor health conditions following the test item treatment.
At necropsy, a moderate increase in liver weights was noted in females treated at 1000/750 mg/kg/day. The thickening and discolorations of the gastrointestinal tract were also considered to be related to test item treatment.
Consequently, under the experimental conditions of this study, because of the premature deaths and toxicity recorded at all dose levels, the maximal tolerated dose level was lower than 250 mg/kg/day. Lower dose levels should be chosen for a further OECD 422 study in this species.

Executive summary:

The potential toxicity of diisopropyl peroxydicarbonate was evaluated following daily oral administration (gavage) to rats for 2 weeks in order to assist the selection of dose levels for a further 4-week toxicity/OECD 422 study. Three groups of five male and five female Sprague-Dawley rats were treated daily by oral route (gavage) with the test item at dose levels of 250, 500 or 1000/750 (1000 from Day 1 to Day 4, 750 from Day 5 to Day 14) mg/kg/day for 2 weeks. Another group of five males and five females received the vehicle alone (corn oil) under the same experimental conditions and acted as a control group. The test item was administered as a solution in the vehicle, under a constant dosage-volume of 5 mL/kg/day. The animals were observed daily for mortality and clinical signs. Body weight was recorded once on pre-test, on the first day of treatment and then at least once a week until the end of the study. Food consumption was recorded once a week during the treatment period. On completion of the treatment period, the surviving animals were euthanized and a full macroscopic post-mortem examination was performed. The same procedure was performed for all prematurely euthanized animals. The heart, kidneys, liver, ovaries, spleen and testes were weighed and selected tissue specimens were preserved. No microscopic examination was performed.

Five animals were prematurely euthanized during this study: one male from the high-dose group (on Day 4), one female from the low-dose group (on Day 13), one female from the intermediate-dose group (on Day 12), and two females from the high-dose group (on Days 5 and 8). Test item-related clinical signs were observed in the treated groups (in both sexes) and at all dose levels as hunched posture, ptyalism, abdominal breathing and piloerection. Body weight, body weight change and food consumption were unaffected by the test item treatment except in the prematurely euthanized females. The mean absolute and relative liver weights were minimally and statistically higher in females at 1000/750 mg/kg/day. This was considered to be most likely treatment-related. Other organ weight changes were not considered to be related to the test item as they were small in amplitude, had no gross correlates, were not dose-related in magnitude, and/or were not consistent in both sexes.

Macroscopic findings observed in the prematurely euthanized animals were similar to other treated animals and are described below.

Treatment-related findings were observed in the digestive tract as follows:

. the forestomach of all treated animals presented either with a thickened wall, a diffuse white discoloration, focal to multifocal red discolorations and/or white masses. These findings were considered to be related to the test item administration,

. the stomach, duodenum, ileum, jejunum, cecum and colon were often distended with gas, thickened and/or with diffuse yellow or white discoloration, with a dose-related increase.

The potential toxicity of Diisopropyl peroxydicarbonatet was evaluated after daily administration (gavage) to Sprague-Dawley rats at dose levels of 250, 500 or 1000/750 (1000 from Day 1 to Day 4, 750 from Day 5 to Day 14) mg/kg/day for 2 weeks.

The repeated oral administration of the test item induced signs of toxicity at all dose levels (i.e. hunched posture, hypoactivity, prostration, ptyalism, abdominal and loud breathing, dyspnea, piloerection, thin appearance and an increase of the abdomen size).The premature euthanasia was necessary in five animals (including all dose levels), due to poor health conditions following the test item treatment.

At necropsy, a moderate increase in liver weights was noted in females treated at 1000/750 mg/kg/day. The thickening and discolorations of the gastrointestinal tract were also considered to be related to test item treatment.

Consequently, under the experimental conditions of this study, because of the premature deaths and toxicity recorded at all dose levels, the maximal tolerated dose level was lower than 250 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

key study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

No classification is warranted according to CLP/GHS criteria.