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Key value for chemical safety assessment

Effects on fertility

Description of key information

In an one-generation study according to OECD guideline 415, Mesamoll was administered to groups of 25 male and 25 female rats each at concentrations of 0 (control), 600, 3000, and 15000 ppm in their diet (male rats: 46.86; 234.3; 1171.5 mg/kg bw/d; female rats: 67.86; 339.3; 1696,5 mg/kg bw/d) (Eiben R. / Rinke M., Bayer AG, 2002).

The dietary concentration of 600 ppm (= male rats: 46.86 mg/kg bw/d; female rats: 67.86 mg/kg bw/d) is estabished as NOAEL for the parent animals and reproduction parameters).

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on test guideline (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study.
Qualifier:
according to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
other: administered in diet
Details on mating procedure:
Premating period of F0 rats= 10 weeks
mating period F0 rats = up to 21 days
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Exposure period: 10 weeks pretreatment
up to 3 weeks mating
3 weeks gestation
4 nursing
Premating exposure period (males): 10 weeks
Premating exposure period (females): 10 weeks
Duration of test: 17 - 20 weeks
Frequency of treatment:
permanent
Remarks:
Doses / Concentrations:
0, 600, 3000 and 15000 ppm in diet
Basis:

No. of animals per sex per dose:
25/sex/dose
Control animals:
yes, concurrent no treatment
Key result
Dose descriptor:
NOAEL
Effect level:
600 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Increase in altered follicular colloid in the thyroids
Remarks on result:
other: see 'Remark'
Remarks:
One-generation study in Wistar rats (Administration in the diet)
Remarks on result:
other: see 'Remarks'
Remarks:
One-generation study in Wistar rats (Administration in the diet)
Reproductive effects observed:
not specified

Result: above 600 ppm in the diet: reductions of food consumption and body weight  gain in females during gestation and lactation (high dose), retardation  of fetal weight and development (mid and high dose)
No other effects

Executive summary:

In an one-generation study Mesamoll was administered to groups of 25 male and 25 female rats each at concentrations of 0 (control), 600, 3000, and 15000 ppm in their diet.

Parenteral F0 animals were pretreated over a period of about 10 weeks and allowed to mate over a period of up to three weeks. F1 offspring were nursed up to an age of four weeks. Some of them were selected for further treatment up to necropsy when developmental milestones has occured.

Clinical signs, body weight, food intake, mating performance, fertiliy, duration of pregnancy, estrus cycling and sperm parameters were examined in F0 rats. Litter size, percentage of male born and pup weight at birth as well as viability, rearing, lactation and body weight gain were studied in F1 offspring. developmental milestones were examined in F1 weanlings. necropsies were done in all rats. Implantation sites were recorded in F0 females. Selected organs were weighed (F0 and F1) and histopatological evaluations were performed on some organs of F0 rats.

Mortality and clinical appearance in F0 and post weaned F1 animals were unchanged at levels of up to 15000 ppm.

There was no adverse effect on body weight development in F0 males up to 15000 ppm. 15000 ppm F0 females exhibited retarded body weights mainly during gestation and lactation. Significant body weight reduction was also noted at necropsy of 15000 ppm post weaned F1 males.

The increase in food intake of 3000 and 15000 ppm F0 females is not considered as adverse.

The reproduction parameters insemination index, mating performance, fertility index, gestation index, duration of pregnancy, life birth index, birth weights, percentages of males born, total number of pups born, prenatal loss, mean litter size at birth as well as viability and lactation index were not affected at levels of up to 15000 ppm.

The body weight development of F1 pups was retarded at 3000 and 15000 ppm resulting in pup organ weight changes at 15000 ppm.

No test substance-related clinical or gross pathological findings were observed in F1 offspring up to 15000 ppm. The skeletal development of the offspring was unaffected.

No adverse effect was seen in sperm parameters at 15000 ppm.

The occurring of developmental milestones was unaffected in 600 ppm F1 rats. From 3000 ppm onwards delayed balano-preputial separation and at 15000 ppm delayed vaginal opening were noted as a consequence of retarded body weight development during lactation and/or post weaning period.

F0 females exhibited no treatment effects on estrus cycling up to 15000 ppm.

The increase in altered follicular colloid in the thyroids from 3000 ppm onwards in F0 animals (males 15/25, 16/25, 22/25 and 23/25 at 0, 300, 600 and 3000 ppm respectively; females 1/25, 4/25, 4/25 and 5/25, respectively) and the slightly higher frequency of males exhibited follicular cell hypertrophy at 15000 ppm (1/25, 1/25, 1/25, 7/25, respectively) are not interpreted as a specific effect on the hormone system because these findings are noted frequently especially in male rats and are considered as unspecific expression of adaptive physiological changes and the observations in females are not dose dependent. In addition, no effects on thyroid histopathology was reported in the sub-chronic toxicity study .

Elevated kidney weights in F0 rats partly from 3000 ppm onwards indicate unspecific changes in kidney function, because morphological correlates are missing. Since indications of liver damage are lacking the increase of liver weights found in females at 3000 ppm and above are interpreted to be a result of changed liver function.

Gross pathology and histopathology in remaining organs revealed no treatment-related lesions.

Thus, the dietary concentration of 600 ppm is established as NOAEL for the parent animals and reproduction parameters.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
46.86 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP guideline 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

In an one-generation study according to OECD guideline 415, Mesamoll was administered to groups of 25 male and 25 female rats each at concentrations of 0 (control), 600, 3000, and 15000 ppm in their diet (male rats: 46.86; 234.3; 1171.5 mg/kg bw/d; female rats: 67.86; 339.3; 1696,5 mg/kg bw/d).

Parenteral F0 animals were pretreated over a period of about 10 weeks and allowed to mate over a period of up to three weeks. F1 offspring were nursed up to an age of four weeks. Some of them were selected for further treatment up to necropsy when developmental milestones has occurred. Clinical signs, body weight, food intake, mating performance, fertility, duration of pregnancy, estrus cycling and sperm parameters were examined in F0 rats. Litter size, percentage of male born and pup weight at birth as well as viability, rearing, lactation and body weight gain were studied in F1 offspring. Developmental milestones were examined in F1 weanlings. Necropsies were done in all rats. Implantation sites were recorded in F0 females. Selected organs were weighed (F0 and F1) and histopatological evaluations were performed on F0 rats.

Mortality and clinical appearance in F0 and post weaned F1 animals were unchanged at levels of up to 15000 ppm. There was no adverse effect on body weight development in F0 males up to 15000 ppm. 15000 ppm F0 females exhibited retarded body weights mainly during gestation and lactation. Significant body weight reduction was also noted at necropsy of 15000 ppm post weaned F1 males. The increase in food intake of 3000 and 15000 ppm F0 females is not considered as adverse.

The reproduction parameters insemination index, mating performance, fertility index, gestation index, duration of pregnancy, life birth index, birth weights, percentages of males born, total number of pups born, prenatal loss, mean litter size at birth as well as viability and lactation index were not affected at levels of up to 15000 ppm.

The body weight development of F1 pups was retarded at 3000 and 15000 ppm resulting in pup organ weight changes at 15000 ppm. No test substance-related clinical or gross pathological findings were observed in F1 offspring up to 15000 ppm. The skeletal development of the offspring was unaffected.

No adverse effect was seen in sperm parameters at 15000 ppm. The occurring of developmental milestones was unaffected in 600 ppm F1 rats. From 3000 ppm onwards delayed balano-preputial separation and at 15000 ppm delayed vaginal opening were noted as a consequence of retarded body weight development during lactation and/or post weaning period.

F0 females exhibited no treatment effects on estrus cycling up to 15000 ppm.

The increase in altered follicular colloid in the thyroids from 3000 ppm onwards in F0 animals (males 15/25, 16/25, 22/25 and 23/25 at 0, 300, 600 and 3000 ppm respectively; females 1/25, 4/25, 4/25 and 5/25, respectively) and the slightly higher frequency of males exhibited follicular cell hypertrophy at 15000 ppm (1/25, 1/25, 1/25, 7/25, respectively) are not interpreted as a specific effect on the hormone system because these findings are noted frequently especially in male rats and are considered as unspecific expression of adaptive physiological changes and the observations in females are not dose dependent. In addition, no effects on thyroid histopathology was reported in the sub-chronic toxicity study. Elevated kidney weights in F0 rats partly from 3000 ppm onwards indicate unspecific changes in kidney function, because morphological correlates are missing. Since indications of liver damage are lacking the increase of liver weights found in females at 3000 ppm and above is interpreted to be a result of changed liver function. Gross pathology and histopathology in remaining organs revealed no treatment-related lesions. Thus, the dietary concentration of 600 ppm (46.86 mg/kg in male rats and 67.86 mg /kg in female rats) is established as NOAEL for the parent animals and reproduction parameters based on reduced body weight in parent and offspring animals at 3000 ppm (Eiben R. / Rinke M., Bayer AG, 2002).

Classification is not required.


Short description of key information:
In an one-generation study according to OECD guideline 415, Mesamoll was administered to groups of 25 male and 25 female rats each at concentrations of 0 (control), 600, 3000, and 15000 ppm in their diet (male rats: 46.86; 234.3; 1171.5 mg/kg bw/d; female rats: 67.86; 339.3; 1696,5 mg/kg bw/d) (Eiben R. / Rinke M., Bayer AG, 2002).

Effects on developmental toxicity

Description of key information

n a developmental toxicity guideline study according to OECD guideline 414, female Wistar rats were treated daily orally by gavage with Mesamoll solved in polyethylene glycol 400/etahnol (9:1) from day 6 to day 19 p.o. in doses of 0; 100; 300 and 1000 mg/kg bw/d, respectively.

No developmental toxicity was seen at a dose level up to and including 1000 mg/kg bw/d.

The conduction of a developmental study according OECD guideline 414 on a second species is proposed (see 7.8.2 Test proposal - 2nd species).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
other: UA-EPA Health Effects Test Guidelines OPPTS 870.2700, 1998
Qualifier:
according to
Guideline:
other: EEC Commission Directive 88/302/EEC, 1988
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
days 6 to 19 of gestation
Frequency of treatment:
once daily
Duration of test:
14 days
No. of animals per sex per dose:
26 to 27 inseminated female Wistar rats per group.
Control animals:
yes, concurrent vehicle
Details on study design:
Sex: female
Duration of test: 14 days
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Result: No teratogenic  effects
RS-Freetext:
Mortality: none
clin. signs(without toxicol. relevance: no dose/ effect-relation):  Salivation, soft or light feces 
Food consumtion: marginal reduction (high dose)
Body weight gain: decrease (high dose)
Necropsy (dams): no adverse findings

Development of fetuses: No adverse findings

Executive summary:

In this guideline study groups of 26 to 27 inseminated female Wistar rats each were treated daily orally by gavage with Mesamoll solved in polyethylene glycol 400/etahnol (9:1) from day 6 to day 19 p.c. in doses of 0; 100; 300 and 1000 mg/kg bw/d, respectively. The fetusses were delivered by cesarean section on day 20 of gestation. Investigations were performed on general tolerance of the test compound by the females including liver weights as well as its effect on intrauterine development.

No mortality occured during the study. Toxicological relevance was nor assumed for increased incidence of salivation after administration, increased incidence of soft feces and light colored feces seen at all dose levels tested without dose relationship. These findings were possibly related to a gustatory component of the test substance and/or to the vehicle used. A marginal reduction of feed intake could not be completely excluded at the 1000 mg/kg dose level and was related to impaired body weight development characterized by decreased body weight gain during the treatment and overall gestation period and decreased corrected body weight gain. Necropsy revealed no treatment related alterations at a dose level up to and including 1000 mg/kg bw/day. Liver weight and liver-to-carcass weight ratio were neither affected by treatment to a toxicologically meaningful degree at a dose level up to and including 1000 mg/kg bw/day.

Intrauterine development, i.e. gestation rate, postimplantation loss and accordingly the number of fetuses, fetal sex distribution, fetal weight and placental weight and appearance were not affected to a toxicologically relevant degree by treatment with Mesamoll at a dose level up to and including 1000 mg/kg bw/day.

Evaluation of fetal external, visceral and skeletal including cartilaginous findings resulted in the conclusion that meaningful effects of the test substance were not assumed at a dose level up to and including 1000 mg/kg bw/day.

A teratogenic potential was not assumed at a dose level up to and including 1000 mg/kg bw/day.

Summarizing and evaluating all data investigated, the following no-observed-and adverse-effect levels (NOAEL) were determined:

Maternal toxicity: 300 mg/kg bw/day.

Developmental toxicity: 1000 mg/kg bw/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP guideline study
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

In a developmental toxicity guideline study according to OECD guideline 414, groups of 26 to 27 inseminated female Wistar rats each were treated daily orally by gavage with Mesamoll solved in polyethylene glycol 400/etahnol (9:1) from day 6 to day 19 p.o. in doses of 0; 100; 300 and 1000 mg/kg bw/d, respectively. The fetuses were delivered by cesarean section on day 20 of gestation. Investigations were performed on general tolerance of the test compound by the females including liver weights as well as its effect on intrauterine development. No mortality occurred during the study. Toxicological relevance was nor assumed for increased incidence of salivation after administration, increased incidence of soft feces and light colored feces seen at all dose levels tested without dose relationship. These findings were possibly related to a gustatory component of the test substance and/or to the vehicle used. A marginal reduction of feed intake could not be completely excluded at the 1000 mg/kg dose level and was related to impaired body weight development characterized by decreased body weight gain during the treatment and overall gestation period and decreased corrected body weight gain. Necropsy revealed no treatment related alterations at a dose level up to and including 1000 mg/kg bw/day. Liver weight and liver-to-carcass weight ratio were neither affected by treatment to a toxicologically meaningful degree at a dose level up to and including 1000 mg/kg bw/day. Intrauterine development, i.e. gestation rate, post implantation loss and accordingly the number of fetuses, fetal sex distribution, fetal weight and placental weight and appearance were not affected to a toxicologically relevant degree by treatment with Mesamoll at a dose level up to and including 1000 mg/kg bw/day. Evaluation of fetal external, visceral and skeletal including cartilaginous findings resulted in the conclusion that meaningful effects of the test substance were not assumed at a dose level up to and including 1000 mg/kg bw/day. No teratogenic potential was seen at a dose level up to and including 1000 mg/kg bw/day. Summarizing and evaluating all data investigated, the following no-observed-and adverse-effect levels (NOAEL) were determined: Maternal toxicity: 300 mg/kg bw/d based on body weight retardation at 1000 mg/kg bw/d. Developmental toxicity: 1000 mg/kg bw/d (Klaus A.M., Bayer AG, 2002).

Toxicity to reproduction: other studies

Description of key information

No data

Additional information

No data

Justification for classification or non-classification

Classification is not required.