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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No study required since no adverse effects on reproductive organs were seen in the available repeated dose toxicity studies with glycine and N-acetylglycine.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

Prenatal developmental toxicity (similar to OECD 414), oral, rat:

NOAEL developmental toxicity = ≥ 855 mg/kg bw/day

NOAEL maternal toxicity = ≥ 855 mg/kg bw/day

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
analytical purity of test substance not specified, limited documentation, only organogenesis covered (days 6-15 of gestation)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
(analytical purity of test substance not specified, limited documentation, only organogenesis covered (days 6-15 of gestation))
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 206-215 g
- Housing: individually in mesh bottom cages
- Diet (ad libitum)
- Water (ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- temperature and humidity-controlled quarters
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 1 to 3 mL/kg bw
Details on mating procedure:
- Impregnation procedure: cohoused
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6-15 of gestation
Frequency of treatment:
daily
Duration of test:
20 days
Dose / conc.:
9 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
185 mg/kg bw/day (actual dose received)
Dose / conc.:
855 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
23 (control group, 185 mg/kg bw/d dose group, 250 mg/kg bw/d Aspirin)
21 (9 mg/kg bw/d)
22 (40, 855 mg/kg bw/day)
Control animals:
yes, sham-exposed
other: positive control: 250 mg/kg bw/d Aspirin
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 6, 11, 15, and 20 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- daily observation, but no recording

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 (caesarean section under surgical anesthesia)
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of implantations: Yes
- Number of resorptions: Yes
- Other: number of live and dead fetuses was recorded and the urigenital tract of each dam was examined in detail for anatomical normality
Fetal examinations:
Number of live and dead fetuses were recorded and body weights of the live pups were recorded.
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [one-third per litter]
- Skeletal examinations: Yes: [two-thirds per litter]
- Head examinations: Yes
Details on maternal toxic effects:
Maternal toxic effects:no effects. Remark: no treatment-related effects
Dose descriptor:
NOAEL
Effect level:
>= 855 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects. Remark: no treatment-related effects

Details on embryotoxic / teratogenic effects:
Besides the effects listed in Table 1-3 (see " Any other information on resutls incl. tables"), the following soft tissue abnormalities were found in the positive control group pups delivered by different dams: acrania, craniocele; spina bifida, subcutaneous edema.
Dose descriptor:
NOAEL
Effect level:
>= 855 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Average maternal body weights (in g)

 Day

 

0

6

11

15

20

Dose group

 

 

 

 

 

Sham

206

236

260

283

352 (23)

Positive Control

214

236

252

270

309 (23)

9 mg/kg bw TS

209

230

246

275

344

(21)

40 mg/kg bw TS

215

240

262

286

351

(22)

185 mg/kg bw TS

207

227

250

273

243

(23)

855 mg/kg bw TS

207

229

246

277

343

(22)

- TS: test substance

- number of surviving dams in parentheses

Table 2: Litter response (caesarean section data)

Dose group

Sham

Positive Control

9 mg/kg bw TS

40 mg/kg bw TS

185 mg/kg bw TS

855 mg/kg bw TS

Pregnancies

 

 

 

 

 

 

Total No.

23

23

21

22

23

22

Died or aborted (before day 20)

0

0

0

0

0

1

To term (on day 20)

23

23

21

22

23

22

Corpora lutea

 

 

 

 

 

 

Total No.

268

270

244

267

265

253

Average/dam mated

11.2

11.3

10.2

11.1

11.0

10.5

Live litters

 

 

 

 

 

 

Total No.

23

15

21

22

23

22

Implant Sites

 

 

 

 

 

 

Total No.

253

256

233

253

251

252

Average/dam

11.0

11.1

11.1

11.5

10.9

11

Resorptions

 

 

 

 

 

 

Total No.

12

106

8

15

6

4

Dams with 1 or more sites resorbed

6

16

6

11

5

3

Dams with all sites resorbed

0

8

0

0

0

0

% partial resorptions

26.1

69.6

28.6

50.0

21.7

13.6

% complete resorptions

--

34.8

--

--

--

--

Live fetuses

 

 

 

 

 

 

Total No.

240

150

225

238

245

248

Average/dam

10.4

6.52

10.7

10.8

10.7

10.8

Sex ratio (M/F)

0.81

0.95

0.67

0.68

0.55

0.76

Dead Fetuses

 

 

 

 

 

 

Total No.

1

0

0

0

0

0

Dams with 1 or more dead

1

--

--

--

--

1

Dams with all dead

0

--

--

--

--

--

% partial dead

4.35

--

--

--

--

--

% all dead

--

--

--

--

--

--

Average fetus weight (g)

3.91

2.63

3.81

3.81

3.92

3.75

Table 3: Summary of skeletal findings

Dose group

Sham

Positive Control

9 mg/kg bw TS

40 mg/kg bw TS

185 mg/kg bw TS

855 mg/kg bw TS

Live Fetuses (at term)

161/23

99/15

148/21

159/22

164/23

167/22

Sternebrae

 

 

 

 

 

 

Incomplete oss.

15/11

94/16

10/9

8/7

11/8

13/9

Scrambled

--

--

--

--

--

--

Bipartite

--

1/1

--

1/1

--

--

Fused

--

--

--

--

--

--

Extra

--

--

--

--

--

--

Missing

2/1

64/14

--

--

--

--

Other

--

--

--

--

--

--

Ribs

Incomplete oss.

1/1

12/6

--

--

--

--

Fused/Split

3/2

4/3

--

--

--

--

Wavy

5/2

27/11

12/8

12/6

4/3

1/1

Less than 12

--

3/3

--

1/1

--

1/1

More than13

--

26/9

--

--

--

--

Other

--

--

--

--

--

--

Vertebrae

Incomplete oss.

3/1

75/14

3/3

--

2/1

4/4

Scrambled

--

--

--

--

--

--

Fused

--

2/2

--

--

--

--

Extra ctrs. oss.

--

--

--

--

--

--

Scoliosis

--

7/4

--

--

--

--

Other

--

--

--

--

--

--

 Skull            
 Incomplete closure  19/11 69/13  16/10  28/10  14/8  20/10 
 Craniostosis  -- 1/1  --  --  --  -- 
 Miscellaneous            
 Hyoid; missing  9/4 73/15  11/6  13/8  9/7  15/9 
 Hyoid; reduced  3/2 1/1  --  --  1/1  -- 
Conclusions:
The test substance had no effect on intrauterine development.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
855 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Comparable to guideline study (Klimisch = 2).
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

Prenatal developmental toxicity of the test substance was investigated in a study equivalently performed as described in OECD 414. Wistar rats received the test substance by oral gavage from gestation day 6 to 15 at doses of 9, 40, 185 and 855 mg/kg bw/day (FDA, 1972).

There were no treatment-related mortalities in any dose group and no effects on body weight development of the dams. For all dose groups, no litter parameters were affected, including the number of corpora lutea, live litters, implant sites, resorptions, live and dead fetuses. At external, visceral and skeletal fetal examination, no treatment-related findings were observed. A positive control group was included into the study design. These animals received Aspirin at a dose of 250 mg/kg bw/day. In this group, clear effects on intrauterine development were observed: decrease in the number of live litters and live fetuses, increase in resorptions as well as skeletal findings when compared to the negative control group.

In conclusion, for maternal and developmental toxicity, the NOAEL was determined to be ≥ 855 mg/kg bw/day.

Justification for classification or non-classification

The available data on reproductive toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008 and Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.