Registration Dossier

Administrative data

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)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The test material is the hydrolysis degradation product of DMDMH which was considered relevant for long term testing

Test animals

Species:
rat
Strain:
other: CD
Sex:
male/female

Administration / exposure

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.
Doses / concentrationsopen allclose all
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

Examinations

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

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

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 / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined

Details on results (P0)

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.




Effect levels (P0)

open allclose all
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

Results: F1 generation

General toxicity (F1)

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

Details on results (F1)

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.

Effect levels (F1)

open allclose all
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

Results: F2 generation

Effect levels (F2)

open allclose all
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

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

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.