Pentapotassium bis(peroxymonosulphate) bis(sulphate)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2004-02-03 - 2004-09-15

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in full compliance with OECD 414. This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

January 2001

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Pentapotassium bis(peroxymonosulphate) bis(sulphate)

EC Number:

274-778-7

EC Name:

Pentapotassium bis(peroxymonosulphate) bis(sulphate)

Cas Number:

70693-62-8

Molecular formula:

H3K5O18S4

IUPAC Name:

pentapotassium bis((hydroperoxysulfonyl)oxidanide) hydrogen sulfate sulfate

Test material form:

solid

Test animals

Species:

rat

Strain:

other: Crl:CD(SD)IGS BR

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina, U.S.A
- Age at study initiation: 66-67 days
- Weight at study initiation: 201-225 g

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Deionized water

Details on exposure:

- Concentration in vehicle: 0; 7.5; 25; 75 mg/mL
- volume applied: 10mL/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Data from the analysis of the samples collected near the beginning, middle, and end of the study indicate that the test substance was mixed uniformly in the vehicle and was at the targeted concentrations.

Details on mating procedure:

- Impregnation procedure: purchased timed pregnant; animals were 1, 2, or 3 days of gestation at arrival

Duration of treatment / exposure:

Days 6-20 of gestation.

Frequency of treatment:

daily for a duration of about 14 days

Duration of test:

About 14 days (days 6 through 20 of pregnancy)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

750 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

250 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

75 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

0 mg/kg bw/day (nominal)

No. of animals per sex per dose:

22 animals (females) per group

Control animals:

yes

Details on study design:

not indicated

Examinations

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and clinical signs


BODY WEIGHT: Yes
- Time schedule for examinations: daily


FOOD CONSUMPTION: Yes
- Days 4, 6, 8, 10, 12, 14, 16, 18, 20 and 21 of gestation

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
The intact and the empty uterus of each dam having at least one viable foetus was weighed to permit calculation of maternal body weight adjusted to exclude the products of conception. The corpora lutea count for each ovary of females with viable foetuses was recorded.
For each female with visible implantation sites, the types of implants (live and dead foetuses, and resorptions) and their relative positions were recorded.

Fetal examinations:

- General examinations: Resorptions, interuterine location, sex and body weight of each foetus was recorded
- Soft tissue examinations: Yes: For each litter, the first live foetus and every other liver foetus thereafter (approximately 50 % of the foetuses) were examined for visceral alterations. In addition, all live foetuses with malformations visible at external examination were examined for soft tissue alterations.
- Skeletal examinations: Yes: After fixation in Bouin’s fixative, the heads of decapitated foetuses were examined and alterations were recorded. After alcohol fixation, the alizarin-stained skeletons were examined and skeletal alterations were recorded for all live foetuses, excluding the foetal heads fixed in Bouin’s fixative.

Statistics:

For litter parameters, the proportion of affected foetuses per litter or the litter mean was used as experimental unit for statistical evaluation.
For each parameter analysed with a trend test, the test was applied to the data sequentially. If a significant dose-response was detected, data from the top dose group was excluded and the test repeated until no further trend was detected. The level of significance selected was p ≤ 0.05.

Analysis of dosing solutions:
Three sets of samples were collected near the beginning, middle, and end of he study. Analyses addressed concentration verification and uniformity of mixing. Two independent samples from each test formulation were collected. One sample of the vehicle and two samples from each test formulation were analysed immediately after submission

Indices:

Please refer to Table 1-4

Historical control data:

not data provided with the study report

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
(Note: Tables mentioned below are presented under “Remarks on results including tables and figures”)
One animal in the 750 mg/kg bw/day group was found dead on day 13 of gestation. No abnormal clinical signs of toxicity were noted prior to death. However, on days 8-10 of gestation, the rat lost 10 g of weight, and food consumption during this period was substantially below the control mean and the 750 mg/kg bw/day group mean. Over days 10-12 of gestation, the animal appeared to temporarily recover, gained 16.1 g of weight, and food consumption was similar to both the control and 750 mg/kg group mean values. No postmortem gross abnormalities were detected.
On day 21 of gestation, gross postmortem abnormalities in the stomach were observed in 4 dams administered 750 mg/kg bw/day.
Two animals in the 750 mg/kg bw/day dose group exhibited salvation and stained fur, and one animal was gasping. The incidences of these observations were not significantly increased.
Test substance-related, statistically significant decrease in body weight gain occurred in dams administered 750 mg/kg bw/day (please refer to table 2). Mean body weight gain values in 750 mg/kg bw/day females were slightly lower than the control values during days 14-18 of gestation, and were significantly reduced on days 18-21 of gestation. Mean maternal weight gain for the 750 mg/kg bw/day group, both absolute and net (corrected to exclude the product of conception) were significantly reduced (13 % and 29% lower than the respective control values) on days 6-21 of gestation. In addition, absolute and net final body weights on day 21 of gestation were 5 % lower than the control values.
There were no test substance related effects on the body weight gain in rats administered 250 mg/kg bw/day.
Test substance related decreases in food consumption occurred in dams administered 750 mg/kg bw/day of the test substance. Over the entire dosing period (days 6-21 of gestation) food consumption for 750 mg/kg bw/day dams was 7.5 % lower than the control value. The reduction in food consumption in 750 mg/kg bw/day dams was consistent with the decreased body weight and weight gain. There were no test substance related effects on food consumption in the 250 mg/kg bw/day group.
All substance related gross postmortem changes were only observed in the 750 mg/kg bw/day group. Increased thickness of the nonglandular stomach was observed in 4 of 22 dams, and red discoloration of the glandular stomach was observed in one dam. In addition, the small and large intestines of one rat were distended with fluid.

Effect levels (maternal animals)

1

Dose descriptor:

LOAEL

Effect level:

750 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
(Note: Tables mentioned below are presented under “Remarks on results including tables and figures”)
The mean number of corpora lutea, implantation sites, resorptions, live foetuses, and sex ratio were comparable across all groups (please refer to tables 1-3 and 4). One dam in the 750 mg/kg bw/day group had one early resorption and 10 late resorptions (no live foetuses were born). The resorptions were considered secondary to poor maternal health (weight loss, reduced food consumption, intestines distended with fluid) since the incidence of both early and late foetal resorptions for the remaining dams in the 750 mg/kg bw/day group were similar to control.
Mean foetal weight in the 750 mg/kg bw/day group was 4 %lower than the control value. Although not statistically significant, this change was considered to be substance related and adverse by the study author since it occurred at a dosage where maternal toxicity was observed. The notifier however, does not consider the effect to be adverse due to the low magnitude of body weight reductions in foetuses of the high dose group and since the slightly lower weight correlates with the lower body weight of the dams. In addition lower fetal body weights were observed in a small number of foetuses in 9/20 litters of the high dose group only which lead to the overall and not significant reduction of fetal body weight. Mean foetal weights for the 75 and 250 mg/kg bw/day groups were similar to the control value.
There were no test substance related foetal malformations (please refer to table 5) or variations (see table 6) at any dosage. One foetus in the control group had branched and fused ribs, one foetus in the 75 mg/kg bw/day group had cleft palate and anophthalmia, and one had a filamentous tail. No foetal malformations were detected in the 750 mg/kg bw/day group.
The number and type of variations was similar for all groups, and was common to this strain and developmental age. The incidence of size 3 renal papilla was slightly higher in the treated groups compared to the control group. This was due to an unusually low incidence in the control group whereas the incidence in the treated groups was either below or within the historical control range.

Effect levels (fetuses)

1

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

2

Dose descriptor:

NOEL

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: absence of effects

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

Table 2: Mean maternal body weight changes (g)

Group: Dose (mg/kg bw/day)	I 0	II 75	III 250	IV 750
Gestation Days	-
0-4	12.5	14.6	13.7	13.2
16-18	25.0	25.8	24.0	23.8
18-21	51.5	52.9	52.4	41.5*
6-21	135.0	147.3	133.3	117.1*

·    *    Parametric comparison to control (Dunnett/Tamhane-Dunnett) significant

 

Table 3: Reproductive outcome

Dose Group (mg/kg bw/day)	I 0	II 75	III 250	IV 750
No. Pregnant	22	22	22	22
No. Aborted	0	0	0	0
No. Early Deliveries	0	0	0	0
No. Deaths	0	0	0	1
No. Females with total Resorptions	0	0	0	1a
No. Litters	22	22	22	20
No. Live Foetuses	270	272	265	250
No. Dead Foetuses	0	0	0	0
No. Foetal Resorptions	6	5	13	3

a Data from the female with total resorptions were excluded from statistical analyses.

 

 

Table 4: Reproductive outcome (means per litter)

Dose Group (mg/kg bw/day)	I 0	II 75	III 250	IV 750
Live Foetusesa:	-	-	-	-
Total	12.3 (2.1)b	12.4 (1.8)	12.0 (2.3)	12.5 (1.9)
Males	6.0	5.4	5.4	7.0
Females	6.2	7.0	6.7	5.5
Dead Foetuses	0	0	0	0
Resorptions:	-	-	-	-
Total	0.3 (0.6)	0.2 (0.4)	0.6 (0.7)	0.2 (0.4)
Early	0.3 (0.6)	0.2 (0.4)	0.6 (0.7)	0.2 (0.4)
Late	0	0	0	0
Implantations/ Nidations	12.5 (1.8)	12.6 (1.8)	12.6 (2.0)	12.7 (1.8)
Mean Corpora Luteac	13.8 (2.2)	14.0 (1.8)	14.3 (2.0)	14.2 (2.0)
Mean Foetal Weighta	-	-	-	-
Total	5.25 (0.06)	5.44 (0.07)	5.28 (0.08)	5.04 (0.04)
Males	5.38	5.57	5.43	5.14
Females	5.12	5.32	5.16	4.93
Sex Ratiod	0.49 (0.12)	0.43 (0.18)	0.45 (0.17)	0.57 (0.15)

a Statistical analyses were only conducted on the mean total number of live foetuses per litter and total mean foetal weight.

b Standard deviation is reported in parentheses.

c Statistical analyses are not conducted on mean corpora lutea data; these data are presented for information only.

d Number male foetuses/total number foetuses per litter

 

Table 5: Incidence of foetal malformations

Dose Group (mg/kg bw/day)	I 0	II 75	III 250	IV 750
External: No. examined      Tail filamentous No. affected	270 [22] - 0 [0]	272 [22] - 0 [0]	265 [22] 1 [1] 1 [1]	250 [20] - 0 [0]
Visceral: No. examined No. affected	139 [22] 0 [0]	142 [22] 0 [0]	140 [22] 0 [0]	129 [20] 0 [0]
Head: No. examined   Eye - Absent   Palate - Cleft No. affected	139 [22] - - 0 [0]	142 [22] 1 [1] 1 [1] 1 [1]	140 [22] - - 0 [0]	129 [20] - - 0 [0]
Skeletal: No. examined   Rib        - Branched        - Fused No. affected	270 [22] 1 [1] 1 [1] 1 [1]	272 [22] - - 0 [0]	265 [22] - - 0 [0]	250 [20] - - 0 [0]
Total No. affected	1 [1]	1 [1]	1 [1]	0 [0]

Number examined and affected, including the number affected with the listed malformations are expressed as foetuses [litters].

 

 

Table 6: Incidence of foetal variations

Dose Group (mg/kg bw/day)	I 0	II 75	III 250	IV 750
Developmental Variations	-	-	-	-
External	-	-	-	-
No. examined	270 [22]	272 [22]	265 [22]	250 [20]
No. affected	0 [0]	0 [0]	0 [0]	0 [0]
Visceral	-	-	-	-
No. examined	139 [22]	142 [22]	140 [22]	129 [20]
No. affected	0 [0]	0 [0]	0 [0]	0 [0]
Head	-	-	-	-
No. examined	139 [22]	142 [22]	140 [22]	129 [20]
No. affected	0 [0]	0 [0]	0 [0]	0 [0]
Skeletal	-	-	-	-
No. examined        Rib - Extra Ossification Site	270 [22] 19 [8]	272 [22] 25 [11]	265 [22] 14 [9]	250 [20] 22 [7]
No. affected	19 [8]	25 [11]	14 [9]	22[7]
Total with developmental Variations	19 [8]	25 [11]	14 [9]	22 [7]
Variations due to retarded development	-	-	-	-
External	-	-	-	-
No. examined	270 [22]	272 [22]	265 [22]	250 [20]
No. affected	0 [0]	0 [0]	0 [0]	0 [0]
Visceral	-	-	-	-
No. examined        Kidney-Papilla-Size 3	139 [22] 1 [1]	142 [22] 4 [3]	140 [22] 2 [2]	129 [20] 5 [4]
No. affected	1 [1]	4 [3]	2 [2]	5 [4]
Head	-	-	-	-
No. examined	139 [22]	142 [22]	140 [22]	129 [20]
No. affected	0 [0]	0 [0]	0 [0]	0 [0]
Skeletal	-	-	-	-
No. examined        Vertebra-Retarded        Ossification	270 [22] -	272 [22] -	265 [22] -	250 [20] 1 [1]
No. affected	0 [0]	0 [0]	0 [0]	1 [1]
Total variations due to retarded development	1 [1]	4 [3]	2 [2]	6 [5]
Total number foetuses with variations	20 [8]	29 [13]	15 [9]	28 [10]

Numbers examined and affected, including the number affected with the listed malformations are expressed as foetuses [litters].

Applicant's summary and conclusion

Conclusions:

The study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability). Under the conditions of the study, the maternal and foetal NO(A)EL was 250 mg/kg bw/day, based on decreased maternal body weight gain, food consumption, and mortality at 750 mg/kg bw/day, and based on the slightly lower foetal weight at 750 mg/kg bw/day. Therefore, the test substance is not uniquely toxic to the conceptus.
No teratogenic effects were observed at any dose level.

Executive summary:

Materials and methods

KMPS triple salt was applied by gavage from day 6 to 20 of gestation to Crl:CD(SD)IGS BR rats at dose levels of 0, 75, 250, and 750 mg/kg bw/day (selection of dose levels was due to the results of a pilot developmental study (please refer to Overall remarks).

During the in-life portion of the study, maternal clinical signs, body weights, and food consumption data were collected. On day 21 of gestation, dams were euthanised and subjected to a gross external and internal examination. Uterine contents were described; all foetuses were removed and individually weighed, sexed, and examined for external alterations. Approximately one-half of the foetuses were subjected to visceral and head evaluations; all foetuses were examined for skeletal alterations.

 

Results and discussion

Adverse test substance related maternal toxicity occurred at 750 mg/kg bw/day. One dam in the 750 mg/kg bw/day group was found dead on day 13 of gestation, however, no clinical signs of toxicity or gross abnormalities were detected in this animal. Dams sacrificed on day 21 of gestation had increased thickness of the non-glandular stomach, red discoloration of the glandular stomach, which is considered to be the consequence of a direct irritating effect of the test material, and distention of the intestines with fluid. Body weight gain and food consumption were also decreased in 750 mg/kg bw/day dams (please refer to table 2). No test substance related clinical signs of toxicity were observed at any dosage.

The mean number of corpora lutea, implantation sites, resorptions, live foetuses, and sex ration were comparable across all groups (please refer to table 4).

Mean foetal weight in the 750 mg/kg bw/day group was slightly lower (4 %, not statistically significant) compared to the control value. Although not statistically significant, this change was considered to be substance related and adverse by the study authors. The notifier however, does not consider the effect to be adverse due to the low magnitude of body weight reductions in foetuses of the high dose group and since the slightly lower weight correlates with the lower body weight of the dams. In addition lower fetal body weights were observed in a small number of foetuses in 9/20 litters of the high dose group only which lead to the overall and not significant reduction of fetal body weight. Mean foetal body weights for the 75 and 250 mg/kg bw/day groups were similar to the control value.

There were no test substance and/or dose related foetal malformations or variations observed at any dosage level (please refer to tables 5 and 6).