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Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Qualifier:
according to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: CD
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
other: diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Continuously for 2 generations
Frequency of treatment:
Continuously in diet
Details on study schedule:
P and F1 generation were exposed to the diet for a 10 week pre-breed period, a 21 day mating period and through gestation, parturition and lactation. F2 generation were exposed through lactation and until one week after weaning.
Remarks:
Doses / Concentrations:
2000ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
6000ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
20000ppm
Basis:
nominal in diet
No. of animals per sex per dose:
28
Control animals:
yes, plain diet
Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily for mortality and moribund status and once daily for any clinical signs of toxicity. Detailed clinical examinations were conducted weekly.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: Weekly

WATER CONSUMPTION: Yes
- Time schedule for examinations: Weekly

Oestrous cyclicity (parental animals):
Not evaluated
Sperm parameters (parental animals):
Not evaluated
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in offspring:
number and sex of pups, weight gain, physical abnormalities
Postmortem examinations (parental animals):
ORGAN WEIGHTS
- not evaluated

HISTOPATHOLOGY
Control and high dose groups:
Vagina, uterus, ovaries, testis, epididymis, seminal vesicle, prostate, Other tissues with gross lesions
For low and intermediate dose groups:
Testes and epididymides from males which did not sire litters and any tissues which exhibited gross lesions.
Postmortem examinations (offspring):
ORGAN WEIGHTS
- not evaluated

HISTOPATHOLOGY
F1, Control and high dose groups:
Vagina, uterus, ovaries, testis, epididymis, seminal vesicle, prostate, Other tissues with gross lesions
For low and intermediate dose groups:
Testes and epididymides from males which did not sire litters and any tissues which exhibited gross lesions.

F1 not selected for mating, F2
Vagina, uterus, ovaries, testis, epididymis, seminal vesicle, prostate, Other tissues with gross lesions
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Parent males: In the 20000 ppm treatment group consistently increased food consumption values and increases in body weight were noted throughout the treatment period.
Parent females: Maternal food consumption was consistently increased in the 20000 ppm treatment group during gestation.




Dose descriptor:
LOAEL
Effect level:
> 20 000 ppm
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOAEL
Effect level:
20 000 ppm
Based on:
test mat.
Sex:
male/female
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
F1 males: Reduced body weights in the 20000ppm treatment group in the last two weeks of lactation and one week after weaning (postnatal day 28). Weight gains substantially reduced from postnatal days 7 to 14 and slightly reduced from postnatal days 14 to 28.

F1 females: Reduced body weights in the 20000ppm treatment group in the last two weeks of lactation and one week after weaning (postnatal day 28) Weight gains substantially reduced from postnatal days 7 to 14 and slightly reduced from postnatal days 14 to 28

F2 males: Reduced body weights in the 20000ppm treatment group for days 14-28 but not sufficient to reach statistical significance.

F2 females: Reduced body weights in the 20000ppm treatment group for lactation days 14, 21 and one week after weaning.
Dose descriptor:
LOAEL
Generation:
F1
Effect level:
20 000 ppm
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
6 000 ppm
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LOAEL
Generation:
F2
Effect level:
20 000 ppm
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
6 000 ppm
Based on:
test mat.
Sex:
male/female
Reproductive effects observed:
not specified
Conclusions:
The NO(A)ELs are as follows:
Parent males = 20000 ppm (~1395 mg/kg bw/d)
Parent females = 20000 ppm (~1774 mg/kg bw/d)
F1 males = 6000 ppm (~379 mg/kg bw/d)
F1 females = 6000 ppm (~475 mg/kg bw/d)
F2 males = 6000ppm
F2 females = 6000ppm
Executive summary:

DMH is not a reproductive toxin in this study but there may be an effect on lactation.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 395 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Sufficient to meet data requirements. The study is Klimisch 1.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Quality of whole database:
An inhalation toxicity study is scientifically unjustified and is not in the interests of animal welfare.
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Quality of whole database:
A dermal toxicity study is scientifically unjustified and is not in the interests of animal welfare.
Additional information

DMDMH readily undergoes hydrolysis to DMH and therefore chronic effects are most appropriately assessed by testing DMH rather than DMDMH. DMH was tested in a two generation reproductive toxicity study and did not demonstrate parental toxicity or adverse effects on reproductive performance or reproductive tissues at dietary concentrations as high as 20000ppm (equivalent to 1395 mg/kg in males and 1774 mg/kg in females).


Short description of key information:
DMDMH readily undergoes hydrolysis to DMH and therefore long-term data is provided for DMH. In a two generation study, DMH is not a reproductive toxin.

Justification for selection of Effect on fertility via oral route:
Only one study available

Effects on developmental toxicity

Description of key information
DMDMH readily undergoes hydrolysis to DMH and therefore long-term data is provided for DMH. DMH is not a developmental toxin.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: CD
Route of administration:
oral: gavage
Vehicle:
water
Duration of treatment / exposure:
Day 6-15 post mating
Frequency of treatment:
Once daily
Duration of test:
To gestation day 21
Remarks:
Doses / Concentrations:
100 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
25 females/group
Control animals:
yes, concurrent vehicle
Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily (twice daily during dosing)

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0, 6, 9, 12, 15, 18 and 21

FOOD CONSUMPTION: Yes
- Time schedule for examinations: measured at 3 day intervals throughout the study (gd 0-21)
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
Fetal examinations:
- General examinations: Yes, litter Size, no. of dead foetuses, foetal weight, sex ratio, early and late resorptions
- Soft tissue examinations: Yes, approximately one-half of the live foetuses
- Skeletal examinations: Yes, pproximately one-half of the live foetuses
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
LOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified

Maternal Examinations: No females died, aborted, delivered early or were removed from the study prior t sacrifice. All females that bore litters had one or more viable fetuses. No treatment-related clinical signs were observed during or subsequent to treatment at any dose level. There were no dose related changes in maternal body weights or body weight changes throughout gestation. Statistically significant reductions in average weight gain for days 9-12 at 1000mg/kg/day were not considered to be related to treatment but rather were considered to reflect stabilization of body weight in the 1000mg/kg/day group which exhibited a slightly higher weight gain for days 6-9. There were no differences in body weight gain at 1000mg/kg/day fro the entire treatment period. There were no treatment-related effects on food consumption during or subsequent to dosing. There were no treatment related findings observed at necropsy. There were no effects on terminal body weight, gravid uterine weight, corrected body weight, corrected weight change, or relative and absolute liver weights.

Fetal Examinations: No treatment-related effects on fetal body weights for male and female were observed in any group. There were no differences in individual external, visceral or skeletal malformations by category, or in total malformations among groups. There were no treatment-related increases in the incidences of individual fetal external, visceral or skeletal variations by category, or of total variations among groups. Statistically significant decreases in 1 external variation, excessive bleeding at the umbilicus, and 1 skeletal variation, majority of proximal phalanges unossified at 1000mg/kg/day were not considered to be treatment related or biologically significant due to the lack of a dose-related trend.

Conclusions:
NO(A)EL maternal toxic effects >=1000 mg/kg/day
NO(A)EL embryotoxic / teratogenic effects >=1000mg/kg/day
Executive summary:

DMH is not a developmental toxin.

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:
Sufficient to meet data requirements. The study is Klimisch 1.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Quality of whole database:
An inhalation toxicity study is scientifically unjustified and is not in the interests of animal welfare.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Quality of whole database:
A dermal toxicity study is scientifically unjustified and is not in the interests of animal welfare.
Additional information

DMDMH readily undergoes hydrolysis to DMH and therefore chronic effects are most appropriately assessed by testing DMH rather than DMDMH. DMH was tested in three developmental toxicity studies and did not demonstrate developmental toxicity. The structurally related substance EMH was also tested in three developmental toxicity studies and also did not demonstrate developmental toxicity.


Justification for selection of Effect on developmental toxicity: via oral route:
Six studies are available, three on the hydrolysis product DMH and three on the structurally related substance EMH. All are good quality, reliable, GLP, guideline studies which gave the same negative result. This study is the most recent study on the hydrolysis product DMH.

Justification for classification or non-classification

DMDMH readily undergoes hydrolysis to DMH which did not demonstrate adverse effects on reproductive performance, reproductive tissues or developmental toxicity. The structurally related substance EMH also did not demonstrate developmental toxicity. Therefore there is no justification for classification of DMDMH.