Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

MPA is considered to not lead to reproductive toxicity, with NOAEL set at 1000 mg/kg bw/day.

Link to relevant study records
Reference
Endpoint:
reproductive toxicity, other
Remarks:
other: 90d gavage test in rats including fertility parameters
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018-12-03 until 2019-03-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
other: OECD 408
Version / remarks:
25 June 2018
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
No. of animals per sex per dose:
10
Clinical signs:
effects observed, non-treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related effects were found for all haematological and coagulation parameters of all male and female dose groups at the end of the treatment period.
A statistical significant decrease of 71.4 % below control was found for the mean value of eosinophils in the male MD dose group and for an increase of monocytes in the female MD dose group (51.1 % above control). The statistical significant changes from control group were found without dose dependency and therefore the single findings are not considered to be of toxicological relevance.
No statistical significances were noted for coagulation parameters in any male and female dose group when compared to control group.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Treatment with the test item had no toxicologically relevant effects on parameters of clinical biochemistry or hormone analysis of males and females in any of the test item-treated groups.
Statistical significance was found in the female HD group for a decrease of 64.87 % below control for total bile acid. Differences between test item-treated males or females and their respective controls showed no dose-dependency or consistency. Additionally, no test item- related effects were noted at histopathological assessment. Therefore, the statistical significance is considered to be of no biological or toxicological relevance.
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes were observed during the histopathological evaluation. All findings recorded in decedent and surviving animals were deemed to be incidental or were within the range of background alterations that may be recorded in animals of this strain and age and in this study type.
Considering histopathological assessment, there were no organ weight changes, gross lesions or histological alterations that could be attributed to the treatment with the test item. Thus, the histopathological NOEL (no observed effect level) could be established at 1000 mg/kg bw.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no adverse effect on fertility parameters in this 90-day oral toxicity study
Critical effects observed:
no
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related effects were found for all haematological and coagulation parameters of all male and female dose groups at the end of the treatment period.
A statistical significant decrease of 71.4 % below control was found for the mean value of eosinophils in the male MD dose group and for an increase of monocytes in the female MD dose group (51.1 % above control). The statistical significant changes from control group were found without dose dependency and therefore the single findings are not considered to be of toxicological relevance.
No statistical significances were noted for coagulation parameters in any male and female dose group when compared to control group.
Remarks on result:
not measured/tested
Critical effects observed:
not specified
Reproductive effects observed:
no
Conclusions:
The no observed adverse effect level (NOAEL) of the test item MPAAU in this sub-chronic study is considered to be 1000 mg/kg body weight/day.
Executive summary:

In this sub-chronic study, the safety of MPAAU was examined in Wistar rats (four groups of 10 males and 10 females each). The test substance was administered as a solution in tap water by daily oral gavage during 90 consecutive days, at levels of 0 (tap water only), 100, 300 or 1000 mg MPAAU/kg body weight/day.

No test-item related mortality was observed and no adverse effects of the test item were found for male and female clinical observations, functional observations, body weight development, food consumption, haematology and coagulation, clinical biochemistry and hormone analysis, urinalysis, gross macroscopic findings at necropsy, organ weights and histopathology in all treated dose groups.

Especially, there were no effects of the test substance on organ weight, macroscopic examination or histopathology of organs and tissues of the reproductive system (ovaries, oviducts, testes, prostate and seminal vesicles with coagulating glands as a whole, uterus with cervix and vagina). Further, no test item-related adverse effect on thyroid hormone levels (T3, T4, TSH) has been observed.

The no observed adverse effect level (NOAEL) of the test item MPAAU in this sub-chronic study is considered to be 1000 mg/kg body weight/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
High quality GLP study
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Currently no reproductive toxicity for MPA or the source substance, MPAAU, is available. However, MPAAU was assessed for effects on reproductive parameters in the 90 day as well as 28 oral gavage repeated dose toxicity studies.

In the 90 day sub-chronic study, the safety of MPAAU was examined in Wistar rats (four groups of 10 males and 10 females each). The test substance was administered as a solution in tap water by daily oral gavage during 90 consecutive days, at levels of 0 (tap water only), 100, 300 or 1000 mg MPAAU/kg body weight/day. No test-item related mortality was observed and no adverse effects of the test item were found for male and female clinical observations, functional observations, body weight development, food consumption, haematology and coagulation, clinical biochemistry and hormone analysis, urinalysis, gross macroscopic findings at necropsy, organ weights and histopathology in all treated dose groups.

Especially, there were no effects of the test substance on organ weight, macroscopic examination or histopathology of organs and tissues of the reproductive system (ovaries, oviducts, testes, prostate and seminal vesicles with coagulating glands as a whole, uterus with cervix and vagina). Further, no test item-related adverse effect on thyroid hormone levels (T3, T4, TSH) has been observed. Hence, the no observed adverse effect level (NOAEL) of the test item MPAAU in this sub-chronic study is considered to be 1000 mg/kg body weight/day.

The 28-day study in rats covers the critical observations which would be needed to assess the effects of a substance on fertility. There were no effects of the test substance on fertility parameters (oestrus cyclicity, epididymal sperm motility, sperm count and sperm morphology, and testicular sperm count and daily sperm production). Because the administration of the test substance did not induce any changes that were considered to be of toxicological significance, the no-observed-adverse-effect level (NOAEL) was placed at the highest dose level, 1000 mg MPAAU/kg body weight/day.

Effects on developmental toxicity

Description of key information
MPAAU is considered to not have developmental toxicity, with NOAEL being set at 1000 mg/kg bw/day.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-11-23 till 2011-12-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Ninety time-mated female New Zealand White rabbits of 4-5 months were obtained from a colony maintained under SPF conditions at Centre Lago, Vonnas, France. The time-mated females arrived at the testing facilities on GD 1 (23-25 November 2011 for Lot 1, 2 and 3, respectively). The rabbits were checked for overt signs of ill health and abnormalities upon arrival.
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The content, homogeneity and stability of the test substance in the carrier (tap water) were confirmed by HPLC-UV analysis.
Dilutions of the test substance in the vehicle were prepared weekly (namely on 25 November, 2 December, 5 December (only the adapted high-dose level), 9 December and 16 December 2011), and used within 9 days after preparation. The dilutions were stored in a refrigerator (2-10°C) in portions sufficient for one day. The vehicle for dosing the controls was similarly stored.
Details on mating procedure:
Ninety time-mated female New Zealand White rabbits of 4-5 months were obtained from a colony maintained under SPF conditions at Centre Lago, Vonnas, France. The time-mated females arrived at the testing facilities on GD 1 (23-25 November 2011 for Lot 1, 2 and 3, respectively).
Duration of treatment / exposure:
22 consecutive days
The test substance was administered once daily by oral gavage, as a dilution in tap water from GD 6 up to and including GD 28. Controls were treated with vehicle (tap water) only. The animals were dosed for the last time on the day prior to necropsy.
Frequency of treatment:
once daily
Duration of test:
Arrival of time-mated animals : 23-25 November 20111 (on GD 1)2
Start of the treatment : 28-30 November 20111 (from GD 6)
Date of scheduled necropsy : 21-23 December 20111 (GD 29)
Remarks:
Doses / Concentrations:
0, 50, 300, 500/400 mg MPAAU/kg bw/day
Basis:
analytical conc.
No. of animals per sex per dose:
22 pregnant females/group
Details on study design:
On account of adverse effects observed, the high-dose level was reduced to 400 mg MPAAU/kg body weight/day from GD 14.
Maternal examinations:
Clinical observations: Each animal was observed daily in the morning hours by cage-side observations and, if necessary, handled to detect signs of toxicity. On working days, all cages were checked again in the afternoon for dead or moribund animals. On Saturdays, Sundays and public holidays only one check per day was carried out. All abnormalities, signs of ill health or reactions to treatment were recorded.
Animals showing signs of severe intoxication, particularly if death appeared imminent, were humanely killed to prevent loss of tissues by autolytic degeneration.

Body weight: The body weight of each animal was recorded on GD 1, 6, 9, 12, 15, 18, 21, 24 and 29.

Feed consumption: The feed consumed by each mated female was measured over the periods: GD 1-6, 6-9, 9-12, 12-15, 15-18, 18-21, 21-24, 24-29 by weighing the feeders.

Water consumption: Water consumption was not measured.

Necropsy: The study was terminated with the necropsy of the rabbits on GD 29 (on 21, 22 and 23 December 2011 for the rabbits of lot 1, 2 and 3, respectively). Two high-dose rabbits, who had an early delivery were necropsied during partus on GD 28¹.
The rabbits were killed by an intravenous injection in the ear of sodium pentobarbital and examined for gross abnormalities. Fetuses were killed by hypothermia. Any dam found dead or killed in extremis during the study was also examined macroscopically, and the number of corpora lutea and implantations were recorded. Maternal tissues showing severe macroscopic abnormalities and the kidneys were sampled and fixed in a neutral, aqueous phosphate buffered 4% solution of formaldehyde for possible future microscopic examination.

¹ Rabbit no 149 (lot 2) had an early delivery and was necropsied (during partus) on 21 December 2011.
Rabbit no 167 (lot 3) had and early delivery and was necropsied (during partus) on 22 December 2011.
Ovaries and uterine content:
The uteri (including the fetuses), ovaries and placentas of all females killed at the end of the study were examined for the following parameters:
- number of corpora lutea
- number of implantation sites
- number of early and late resorptions
- number of live and dead fetuses
- number of grossly visible malformed fetuses and fetuses with external
abnormalities
- weight of ovaries
- weight of uterus, containing placentas and fetuses
- weight of uterus, empty
- weight of fetuses
- weight of the placentas
- gross evaluation of the placentas.


Fetal examinations:
Fetopathological examination:
All fetuses of all litters were examined by careful dissection for visceral abnormalities, but visceral examination of the head was conducted in only half of the fetuses in each litter (the head of the other fetuses was subjected to skeletal evaluation, see below). During the visceral examination, the sex of the fetuses was determined.
To examine the head for visceral abnormalities, half of the number of foetuses in each litter was decapitated and their heads fixed in Bouin’s fixative and subsequently free-hand sectioned according to Van Julsinga and Bennett (1977). The sections obtained were examined for visceral abnormalities.
After the visceral examinations, the intact and decapitated bodies were eviscerated, fixed in 70% alcohol, cleared in potassium hydroxide and stained with Alizarin Red S. All skeletons of each group were examined for skeletal abnormalities and then retained. The skull was examined in only half of the fetuses of each litter (the head of the other fetuses was subjected to visceral evaluation, see above). During the fetopathological examinations the observer was unaware of the group of the fetuses.
Statistics:
Statistical analysis of the results:

The data were analysed using the methods mentioned below.
Clinical findings, mortality data, number of pregnant females, females with live fetuses, parental necropsy observations and the fetopathological screening: Fisher's exact probability test.
Body weight, body weight gain, organ weights and feed consumption data: one way analysis of variance (ANOVA) followed by Dunnett's multiple comparison tests.
Number of corpora lutea, implantations, live and dead embryos or fetuses and early and late resorptions: Kruskal-Wallis nonparametric analysis of variance followed by the Mann-Whitney U-test.
Statistical evaluations on variables associated with the fetuses were considered on a litter basis in accordance to standard procedures. The statistics applied are indicated in the tables.
Results were taken as statistically significant where the probability of the results was <0.05 or <0.01. The final interpretation of results was based not only on statistical analysis but also on other considerations such as nature of the finding, dose-response relationships and whether the results were significant in the light of other biological and pathological findings.
Indices:
Reproductive performance:

For each group the following data were presented:
- number of females mated
- number of females pregnant
- number of females with no viable fetuses
- number of females with live fetuses
- number of corpora lutea
- number of implantation sites
- number of live fetuses
- number of dead fetuses
- number of live male fetuses
- number of live female fetuses
- number of early/late/total number of resorptions.

For each group the following indices were calculated:
- female fecundity index = (number of pregnant females/number of females mated) x 100
- pre-implantation loss = [(number of corpora lutea - number of implantation sites)
/ number of corpora lutea] x 100
- post-implantation loss = [(number of implantation sites- number of live fetuses)
/ number of implantation sites] x 100
- gestation index = (number of females with live fetuses/number of females pregnant) x 100
- sex ratio = (number of live male fetuses/number of live fetuses) x 100.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Summary of parental data
Maternal toxicity were noted in the high-dose group and included:
- Mortality; one rabbit of the high-dose group was found dead on GD 9. Two other rabbits of this group were killed in extremis on GD 13 and GD 21.
- Conditional decline; 10 rabbits in the high-dose group showed blood around the perineum and/or in the cage.
- Weight loss or growth retardation, and reduced feed intake were noted in the high-dose group.
These changes were most evident in the initial phase of the study, but remained after reduction of the high-dose level to 400 mg/kg bw/day.
No treatment-related macroscopic findings of the dams were observed at Caesarean section. The carcass weight was reduced in the high-dose group. Two high-dose rabbits had an early delivery and were necropsied (during partus) on GD 28.
- Feed intake also tended to be reduced in the mid-dose group, but the differences with the controls were not statistically significant.
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Reproduction data
A number of 22 mated females per group resulted in 21, 20, 18 and 17 litters for the control, low-dose, mid-dose and high-dose group, respectively. Two high-dose rabbits (no’s 149 and 167) had an early delivery and were necropsied (during partus) on GD 28. Results obtained in these two rabbits are not included in the mean data (tables), but all data are shown in the individual data (appendices).
The percentage of live fetuses per animal was statistically significantly decreased in the high-dose group. Postimplantation loss and the number of resorptions per animal were increased in this group. The latter finding was statistically significant and mainly due to an increase in late resorptions.

Fetal placental findings
Fetal placental findings were not affected by the treatment.

Fetal and placental weights
Fetal weights were decreased in the mid- and high-dose group. The differences with the controls were statistically significant for all fetuses and for male fetuses. Fetal weights were also relatively low in the low-dose group. The latter finding was not statistically significant, and, moreover, due to the higher number of fetuses per animal in this group. Therefore the changes in fetal weights in the low-dose group are not considered to be treatment-related.
Placental weights were not affected by the treatment.

Fetal external observations
There was one fetus in the mid-dose group (from dam no.105) showing a malformed head (namely agenesis of all soft tissues and all skull bones, except tongue and lower jaw). One fetus, from a high-dose dam (no. 149) with an early delivery, showed absence of the cranial vault. Umbilical hernia was observed in one fetus of the low-dose and the mid-dose group, and a small fetus was noted in the low-dose and the high-dose group.
Because there was no dose-response relationship, the latter findings were not ascribed to treatment.

Visceral examination

Visceral malformations
One fetus in the mid-dose group (from dam no.105) showed agenesis of all soft tissues and all skull bones, except tongue and lower jaw . The umbilical hernia, observed in one fetus of the low-dose and the mid-dose group was associated with lobular torsion of the liver. Retrocaval uterus was an incidental finding noted in two control fetuses and one low-dose fetus. No other visceral malformations were observed.

Visceral anomalies
No statistically significant or treatment-related differences in the incidences of visceral anomalies were observed among the groups.

Visceral variations
The incidences of fetuses and litters showing a lobular appendix of the gallbladder were statistically significantly increased in the high-dose group.
Four fetuses of the high-dose group showed cysts in the ovaries. This finding was statistically significant, but because it involved only one litter it is probably incidental. Other incidental findings were statistically significant decreased incidences of haemorrhagic areas in the uterus (low- and mid-dose group), and haemorrhagic fluid in the pericard and abdomen (high-dose group). No other statistically significant visceral variations were observed.

Skeletal examination

Skeletal malformations
One fetus in the mid-dose group (from dam no.105) showed agenesis of all skull bones and all soft tissues, except lower jaw and tongue. One fetus, from a high-dose dam with an early delivery (no. 149), showed agenesis of frontal, parietal and supra occipital skull bones. Acephaly has been observed, though at a low incidence, in previous studies conducted in our laboratory with this strain of rabbits without a correlation with treatment. Because of the absence of similar or correlated findings in any other animal in this study, the present findings are not ascribed to treatment.
Other skeletal malformations included the ribs, sternebrae, vertibral column, thoracal bodies and arches. They were equally divided among the various groups and/or present in one or a few fetuses. Because no remarkable or statistically significant differences between the treatment groups and the controls were observed in the incidences of these findings, they were not ascribed to treatment.

Skeletal anomalies
No statistically significant differences between the treatment groups and the controls were observed in the incidences of skeletal anomalies.

Skeletal variations
The incidence of fetuses showing an irregular shape of one strenebra was slightly, though statistically significantly increased in the high-dose group. This finding is probably a chance finding because the incidence of irregular shape of ‘two or more’ strenebrae was not affected.
No other statistically significant differences between the treatment groups and the controls were observed, except for an incidental decrease in fetuses showing accessory lumbar rib(s) in the mid-dose group.

Skeletal retardations
Various statistically significant differences were observed in incidences of retardations in ossification, namely:
- Sternebrae: The incidence of fetuses showing one unossified sternebra was increased in the high-dose group.
- Coracoids: The incidence of fetuses showing unossified coracoid was increased in the mid- and high-dose group. An incidental decrease was noted in incidence of incompletely ossified coracoid in the low-dose group.
- Metacarpals: The incidence of fetuses showing 1-2 unossified metacarpals was increased in the mid-dose group, but this finding was not confirmed in the high-dose group.
- Phalanges: The incidence of fetuses showing 1-4 incompletely ossified medial digits of the frontal phalanges was increased in the high-dose group.
In the low-dose group, the incidence of fetuses with 1-4 unossified medial digits of the frontal phalanges was increased. This finding was, however, not confirmed by dose-related or statistically significant changes in the higher-dose groups and is therefore considered a chance finding.
- Epiphyses of the femur: The incidence of fetuses of which the distal epiphysis of the femur was unossified was increased in the mid- and high-dose group.
- Epiphysis of the tibia: The incidence of fetuses of which the proximal epiphysis of the tibia was unossified was increased in the mid- and high-dose group.
An incidental decrease in incompletely ossified proximal epiphysis of the tibia was observed in the fetuses of the low-dose group.
- Epiphysis of the humerus: The incidence of fetuses of which the proximal epiphysis of the humerus was unossified was increased in the mid- and high-dose group. The incidence of fetuses with the distal epiphysis of the humerus unossified, was increased in the low- and mid-dose group. This finding was, however, not confirmed by dose-related or statistically significant changes in the high-dose group and is therefore considered a chance finding.
As a result of the above retardations in ossification, the total incidence of fetuses showing skeletal retardations was increased in the mid- and high-dose group.

Summary of reproduction data
- No differences were noted in the female fecundity and gestation indices. No effects on the number of corpora lutea, implantation sites, live and dead fetuses, sex ratio, placenta or placental weights were observed.
- The gravid uterus weight tended to be lower in the high-dose group.
- The percentage of live fetuses per animal was decreased and postimplantation loss and the number of (late) resorptions per animal were increased in the high-dose group.
- Fetal weights were decreased in the mid- and high-dose group.

Summary of fetal examination
One fetus of a high-dose dam that had an early delivery showed absence of the cranial vault (agenesis of frontal, parietal and supra occipital skull bones). A fetus of a mid-dose dam showed a malformed head (agenesis of all soft tissues and all skull bones, except tongue and lower jaw). These findings were considered incidental and not ascribed to treatment. There were no other remarkable visceral and skeletal malformations or anomalies. However, a visceral variation (increased incidence of a lobular appendix of the gall bladder) was noted in the high-dose group, while several skeletal retardations in ossification were observed in the mid- and the high-dose group.
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: embryotoxicity
Abnormalities:
not specified
Developmental effects observed:
no
Conclusions:
MPAAU was not teratogentic in the NZW rabbit. The developmental no-observed-adverse-effect level (NOAEL) was 500 mg MPAAU/kg body weight/day.
Executive summary:

The objective of this study was to provide data on the effects of MPAAU on pregnant New Zealand White rabbits and the development of the embryo and fetus following daily oral administration by gavage during gestation days (GD) 6-28. The dose levels were 0 (tap water only), 50, 300 or 500 mg MPAAU/kg body weight/day. On account of adverse effects observed, the high-dose level was reduced to 400 mg MPAAU/kg body weight/day from GD 14. The dams were sacrificed on GD 29 and macroscopically examined. Fetuses, placentas and reproductive organs were weighed. The fetuses were macroscopically examined and processed for visceral and skeletal examinations.

Marked maternal toxicity were observed in the high-dose group, and the maternal no-observed-adverse-effect level (NOAEL) was 300 mg MPAAU/kg body weight/day.

No visceral or skeletal malformations or anomalies were observed at any dose level that are treatment related. Effects on reproductive parameters were noted in the high-dose group, consisting of  increased postimplantation loss and decreased percentage of live fetuses per animal. A visceral variation was noted in the high dose group. In the mid- and high-dose group, fetal weights were decreased and skeletal retardations in ossification were observed.

No frank malformation were observed. The visceral variation in the high dose group, and the skeletal retardations in ossification in high and mid dose groups are considered transient in nature and deemed to be secondary to reduced maternal feed intake and the overall growth retardation in these groups. Therefore, the results indicate that MPAAU was not teratogentic in the NZW rabbit. The developmental no-observed-adverse-effect level (NOAEL) was 500 mg MPAAU/kg body weight/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The test substance on its on has not been tested so results and endpoint selection should take this into account. A developmental screening study was conducted in New Zealand White rabbits and high doses were used in order to set appropriate dose groups for the main study. The results are consistent and can be used set a NOAEL for this endpoint.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Currently, no developmental toxicity study with MPA is available, however the source substance, MPAAU, was assessed in an OECD 414 study (Stricker, 2020). In this prenatal developmental toxicity study, pregnant female Wistar rats were administered with MPAAU at dose levels of 100, 300 and 1000 mg/kg body weight/day administered by oral gavage on GD 5 to 19.No mortality was observed during the treatment period of this study. All clinical signs observed in terminally sacrificed females were incidental or non-adverse in nature. No treatment-related effect considered of toxicological relevance were observed on body weight development, food consumption, prenatal data parameters, litter data parameters and pathology of terminally sacrificed females up to highest tested dose of 1000 mg/kg bw/day. No treatment-related and toxicologically relevant external, visceral, craniofacial or skeletal findings were observed in any of the test item-treated groups. Few skeletal findings including incomplete ossification of bones and other skeletal findings showed no dose-dependency or relevant statistical significance and thus were not considered to be adverse effects caused by treatment with the test item. No adverse systemic effects of the test item were found up to 1000 mg/kg bw/day. Thus, the NOAEL for both maternal toxicity and fetal toxicity in this study is considered to be 1000 mg/kg bw/day.

 

In another OECD 414 guideline study conducted with MPAAU (Bar, 2012), the pregnant NewZealand White rabbits were dosed at 0, 50, 300, 500/400 mg MPAAU/kg bw/day for 22 days i.e. GD 6-28. No differences were noted in the female fecundity and gestation indices. No effects on the number of corpora lutea, implantation sites, live and dead fetuses, sex ratio, placenta or placental weights were observed. The gravid uterus weight tended to be lower in the high-dose group. The percentage of live fetuses per animal was decreased and post-implantation loss and the number of (late) resorptions per animal were increased in the high-dose group. Fetal weights were decreased in the mid- and high-dose group. retardations in ossification, the total incidence of fetuses showing skeletal retardations was increased in the mid- and high-dose group Four fetuses of the high-dose group showed cysts in the ovaries. This finding was statistically significant, but because it involved only one litter it is probably incidental. Other incidental findings were statistically significant decreased incidences of haemorrhagic areas in the uterus (low- and mid-dose group), and haemorrhagic fluid in the pericardium and abdomen (high-dose group). No other statistically significant visceral variations were observed.

 

Based on the above data on developmental toxicity, it can be concluded that MPAAU is not reproductive toxicant and should not be classified.

NOAEL maternal toxicity for MPAAU is set at 300 mg/kg bw/day

NOAEL teratogenicity for MPAAU is set at 400 mg/kg bw/day

NOAEL embryotoxicity for MPAAU is set 300 mg/kg bw/day

Justification for classification or non-classification

No classification applicable for toxicity for reproduction.