Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Information from public copy of a correspondance letter to US EPA, reliability not known but contributing to a weight of evidence assessment.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Principles of method if other than guideline:
A one-generation reproduction study was conducted in which the test substance was administered in the feed to groups of male and female rats (10/group), at dietary concentrations of 0, 300, 1500, 5000 ppm. Rats were fed for two weeks prior to cohabitation (premating period), during the cohabitation period (up to 2 weeks), and during gestation and lactation.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
not specified
Details on mating procedure:
- Length of cohabitation: up to 2 weeks
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
- Rats were fed for two weeks prior to cohabitation (premating period), during the cohabitation period (up to 2 weeks), and during gestation and lactation.
- The F1 generation rats were not exposed after postnatal day 21.
Remarks:
Doses / Concentrations:
0, 300, 1500, 5000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
10 animals per dose group
Control animals:
yes, plain diet
Parental animals: Observations and examinations:
- Cage site observations for mortality and moribundity were performed daily. Clinical signs were recorded weekly.
- Body weights were recorded weekly during premating and cohabitation and on days 0, 7, 14, 21 of gestation and lactation for P1 generation rats.
- Food consumption was recorded with body weights, except for the P1 cohabitation and lactation periods, when food consumption was not determined.
-A functional observation battery (FOB) and motor activity (MA) were evaluated in P1 male and female rats at the end of the 2-week premating period.
Litter observations:
- Body weights were recorded weekly for F1 generation rats beginning at weaning on postnatal day (PND) 21.
- F1 pups were counted by sex and individually weighed at birth, and on PND 4, 7, 14, and 21.
- F1 pups were culled to 8 per litter on PND 4 and unselelected pups were discarded without further evaluation.
- On PND 21, 1 pup/sex/litter was randomly selected and retained to comprise the F1 generation.
Postmortem examinations (parental animals):
NECROPSY PERFORMED: Yes
- P1 females on lactation day 21
- P1 males after siring litters
- Testes epididymides, prostate, seminal vesicles, uterus, ovaries, thyroid, and liver were weighed and retained for possible histopathological examination.
- The number of uterine implantation sites was recorded in P1 females.
Postmortem examinations (offspring):
- On PND 21, unselected weanling pups (3/sex/litter) underwent a gross pathological examination.
- At postnatal day 60 remaining animals were necropsied
- Testes epididymides, prostate, seminal vesicles, uterus, ovaries, thyroid, and liver were weighed and retained for possible histopathological examination.
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- At the high dose level, three females were found dead on the second day of the study. They were replaced with three extra females; one of these females was found dead the next morning. This animal was replaced with an extra female, which survived the first day of diet administration and thereafter. No clinical signs of toxicity were observed in the P1 generation rats.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- In P1 females fed 5000 ppm, body weight gain and food consumption on days 7-14 of gestation were 79 % and 90 % of control, respectively. Overall gestation body weight gain was 89 % of control in P1 females at 5000 ppm.

FUNCTIONAL OBSERVATION BATTERY AND MOTOR ACTIVITY
- There was no effect on functional observation battery parameters or motor activity in P1 rats.

REPRODUCTION PARAMETERS
- There were no compound-related effects on the following reproduction parameters: mating and fertility indices, gestation length, number of uterine implantation sites, implantation efficiency, number of pups born, born alive, and alive on PND 4, 7, 14, and 21. Litter sex ratio, gestation index, percent pups born alive, lactation index, and litter survival were unaffected at any dose level.

ORGAN WEIGHTS (PARENTAL ANIMALS)
- Liver weight was significantly increased in P1 male and female rats at the mid and high dose level, whereas thyroid weight was increased at the high dose level in P1 male rats only.

HISTOPATHOLOGY (PARENTAL ANIMALS)
- Hepatocellular hypertrophy, characterized by cells with an enlarged and homogeneously eosinophilic cytoplasm, was observed at all dose levels in P1 male and female rats. Hepatocellular hypertrophy was considered and adaptive physiologic response to exposure to a xenobiotic and not biologically adverse.
- Follicular thyroid hypertrophy and/or colloid depletion were observed at the mid and high dose level in P1 male and female rats. Follicular hypertrophy was characterized by follicles lined with columnar, rather than cuboidal epithelium. Colloid depletion was diagnosed when the usually eosinophilic follicular colloid was markedly pale and/or absent.
Dose descriptor:
NOAEL
Remarks:
General toxicity
Effect level:
300 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Only effect observed at this dose level was hepatocellular hypertrophy, but this effect is considered to be an adaptive physiologic response to exposure to a xenobiotic and not biologically adverse.
Dose descriptor:
NOAEL
Remarks:
Fertility
Effect level:
5 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects were observed on fertility ay any dose level.
VIABILITY (OFFSPRING)
- A statistically significant reduction in 0-4 Day viability of F1 pups was observed at the mid and high dose levels (97-98% vs. 100% in control group).

CLINICAL SIGNS (OFFSPRING)
- No clinical signs of toxicity were observed in F1 generation rats, or in the F1 litters during lactation

BODY WEIGHT (OFFSPRING)
- F1 pup weights were significantly reduced on PND 0-4 and 0-7 at the mid and high dose, respectively (91-94 % of control). In the F1 generation, body weight gain was significantly reduced at the high dose level on PND 21-28 in males (88 % of control) and PND 28-42 in females (82-84 % of control.)

FOOD CONSUMPTION (OFFSPRING)
- Food consumption was significantly reduced in F1 males at the mid and high dose level (86-90 % of control) on PND 21 -35.

SEXUAL MATURATION (OFFSPRING)
- The mean age at preputial separation and vaginal opening in F1 generation rats were unaffected at any dose level.

ORGAN WEIGHTS (OFFSPRING)
- Thyroid weight was decreased in F1 females, but not in F1 males, at the mid and high dose level. Other organ weights were unaffected in P1 and F1 generation rats.

HISTOPATHOLOGY (OFFSPRING)
- Follicular thyroid hypertrophy was observed in 1 and 2 F1 males at the mid and high dose level, respectively.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
300 ppm
Based on:
test mat.
Sex:
male/female
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

An one-generation reproduction study was conducted in which the test substance was administered in the feed to groups of male and female rats (10/group), at dietary concentrations of 0, 300, 1500, 5000 ppm. Rats were fed for two weeks prior to cohabitation (premating period), during the cohabitation period (up to 2 weeks), and during gestation and lactation. Effects observed in P1 animals included decrease in bodyweight and food consumption in the high dose group and an increase in liver weight in the mid and high dose groups and an increase in thyroid weight in males of the high dose group. Functional observation battery and motor activity parameters were unaffected and no changes in reproduction parameters was observed (including mating and fertiliy indices, gestation length, number of uterine implantation sites, implantation efficiency, number of pups born alive and alive on PND 4, 7, 14, 21). Histopathology revealed hepatocellular hypertrophy at all dose levels (not biologically adverse) and follicular thyroid hypertrophy and/or colloid depletion in the mid and high dose level. In the F1 pups a statistically significant reduction in 0-4 Day viability was observed at the mid and high dose level. No clinical signs of toxicity were observed in F1 generation rats, or in the F1 litters during lactation. Other effects on F1 rats included decrease in bodyweight and food consumption and a decrease in thyroid weight (females) in the mid and high dose group. The mean age at preputial separation and vaginal opening in F1 generation rats were unaffected. Histopathology revealed follicular hypertrophy in 1 and 2 F1 males at the mid and high dose level, respectively.


Short description of key information:
No adverse effects on fertility were observed in rats exposed to the test substance.

Effects on developmental toxicity

Description of key information
Maternal toxicity and developmental toxicity were observed at the mid-dose and high dose level (1500 and 3000 ppm in food, respectively).
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Information from public copy of a correspondance letter to US EPA, reliability not known but contributing to a weight of evidence assessment.
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 415 (One-Generation Reproduction Toxicity Study)
Principles of method if other than guideline:
A one-generation reproduction study was conducted in which the test substance was administered in the feed to groups of male and female rats (10/group), at dietary concentrations of 0, 300, 1500, 5000 ppm. Rats were fed for two weeks prior to cohabitation (premating period), during the cohabitation period (up to 2 weeks), and during gestation and lactation.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
not specified
Route of administration:
oral: feed
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Length of cohabitation: up to 2 weeks
Duration of treatment / exposure:
- Rats were fed for two weeks prior to cohabitation (premating period), during the cohabitation period (up to 2 weeks), and during gestation and lactation.
- The F1 generation rats were not exposed after postnatal day 21.
Remarks:
Doses / Concentrations:
0, 300, 1500, 5000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
10 animals per dose group
Control animals:
yes, plain diet
Maternal examinations:
- Cage site observations for mortality and moribundity were performed daily. Clinical signs were recorded weekly.
- Body weights were recorded weekly during premating and cohabitation and on days 0, 7, 14, 21 of gestation and lactation for P1 generation rats.
- Food consumption was recorded with body weights, except for the P1 cohabitation and lactation periods, when food consumption was not determined.
-A functional observation battery (FOB) and motor activity (MA) were evaluated in P1 male and female rats at the end of the 2-week premating period.
- Necropsy: P1 females on lactation day 21. Uterus, ovaries, thyroid, and liver were weighed and retained for possible histopathological examination. The number of uterine implantation sites was recorded in P1 females.
Fetal examinations:
- Body weights were recorded weekly for F1 generation rats beginning at weaning on postnatal day (PND) 21.
- F1 pups were counted by sex and individually weighed at birth, and on PND 4, 7, 14, and 21.
- F1 pups were culled to 8 per litter on PND 4 and unselelected pups were discarded without further evaluation.
- On PND 21, 1 pup/sex/litter was randomly selected and retained to comprise the F1 generation.
- On PND 21, unselected weanling pups (3/sex/litter) underwent a gross pathological examination.
- At postnatal day 60 remaining animals were necropsied
- Testes epididymides, prostate, seminal vesicles, uterus, ovaries, thyroid, and liver were weighed and retained for possible histopathological examination.
Details on maternal toxic effects:
Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- At the high dose level, three females were found dead on the second day of the study. They were replaced with three extra females; one of these females was found dead the next morning. This animal was replaced with an extra female, which survived the first day of diet administration and thereafter. No clinical signs of toxicity were observed in the P1 generation rats.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- In P1 females fed 5000 ppm, body weight gain and food consumption on days 7-14 of gestation were 79 % and 90 % of control, respectively. Overall gestation body weight gain was 89 % of control in P1 females at 5000 ppm.

FUNCTIONAL OBSERVATION BATTERY AND MOTOR ACTIVITY
- There was no effect on functional observation battery parameters or motor activity in P1 rats.

REPRODUCTION PARAMETERS
- There were no compound-related effects on the following reproduction parameters: mating and fertility indices, gestation length, number of uterine implantation sites, implantation efficiency, number of pups born, born alive, and alive on PND 4, 7, 14, and 21. Litter sex ratio, gestation index, percent pups born alive, lactation index, and litter survival were unaffected at any dose level.

ORGAN WEIGHTS (PARENTAL ANIMALS)
- Liver weight was significantly increased in P1 female rats at the mid and high dose level.

HISTOPATHOLOGY (PARENTAL ANIMALS)
- Hepatocellular hypertrophy, characterized by cells with an enlarged and homogeneously eosinophilic cytoplasm, was observed at all dose levels in female rats. Hepatocellular hypertrophy was considered and adaptive physiologic response to exposure to a xenobiotic and not biologically adverse.
- Follicular thyroid hypertrophy and/or colloid depletion were observed at the mid and high dose level in P1 female rats. Follicular hypertrophy was characterized by follicles lined with columnar, rather than cuboidal epithelium. Colloid depletion was diagnosed when the usually eosinophilic follicular colloid was markedly pale and/or absent.
Dose descriptor:
NOAEL
Effect level:
300 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
300 ppm
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
VIABILITY (OFFSPRING)
- A statistically significant reduction in 0-4 Day viability of F1 pups was observed at the mid and high dose levels (97-98% vs. 100% in control group).

CLINICAL SIGNS (OFFSPRING)
- No clinical signs of toxicity were observed in F1 generation rats, or in the F1 litters during lactation

BODY WEIGHT (OFFSPRING)
- F1 pup weights were significantly reduced on PND 0-4 and 0-7 at the mid and high dose, respectively (91-94 % of control). In the F1 generation, body weight gain was significantly reduced at the high dose level on PND 21-28 in males (88 % of control) and PND 28-42 in females (82-84 % of control.)

FOOD CONSUMPTION (OFFSPRING)
- Food consumption was significantly reduced in F1 males at the mid and high dose level (86-90 % of control) on PND 21 -35.

SEXUAL MATURATION (OFFSPRING)
- The mean age at preputial separation and vaginal opening in F1 generation rats were unaffected at any dose level.

ORGAN WEIGHTS (OFFSPRING)
- Thyroid weight was decreased in F1 females, but not in F1 males, at the mid and high dose level. Other organ weights were unaffected in F1 generation rats.

HISTOPATHOLOGY (OFFSPRING)
- Follicular thyroid hypertrophy was observed in 1 and 2 F1 males at the mid and high dose level, respectively.
Abnormalities:
not specified
Developmental effects observed:
not specified
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Study duration:
subacute
Species:
rat
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

An one-generation reproduction study was conducted in which the test substance was administered in the feed to groups of male and female rats (10/group), at dietary concentrations of 0, 300, 1500, 5000 ppm. Rats were fed for two weeks prior to cohabitation (premating period), during the cohabitation period (up to 2 weeks), and during gestation and lactation. Effects observed in P1 animals included decrease in bodyweight and food consumption in the high dose group and an increase in liver weight in the mid and high dose groups. Functional observation battery and motor activity parameters were unaffected and no changes in reproduction parameters were observed. Histopathology revealed hepatocellular hypertrophy at all dose levels (not biologically adverse) and follicular thyroid hypertrophy and/or colloid depletion in the mid and high dose level groups. In the F1 pups a statistically significant reduction in 0-4 Day viability was observed at the mid and high dose level. No clinical signs of toxicity were observed in F1 generation rats, or in the F1 litters during lactation. Other effects on F1 rats included decrease in bodyweight and food consumption and a decrease in thyroid weight (females) in the mid and high dose group. The mean age at preputial separation and vaginal opening in F1 generation rats were unaffected. Histopathology revealed follicular hypertrophy in 1 and 2 F1 males at the mid and high dose level, respectively.

Justification for classification or non-classification

In the absence of effects on fertility, the substance does not need to be classified according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Based on the available information acquired from the described one generation study, it is not possible to assess whether the observed effects are the result of reproduction toxicity or a secondary non-specific consequence of the other toxic effects. Therefore, classification for developmental toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 is not possible.