Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

No data is available for the target substance Calcium (S)-lactate itself. The target substance completely dissociates into Ca2+ ions and lactate under aqueous and/or physiological conditions. Therefore, the requirement for reproduction toxicity shall/can be addressed based on information for lactic acid and calcium ions. For more details on the read-across justification, please refer to IUCLID section 13.

Based on the physiological role of both calcium and lactate, Calcium (S)-lactate is considered not to exert any negative effects on fertility.

Nevertheless, in repeated dose toxicity and reproductive/developmental toxicity studies conducted with suitable source substances, no adverse effects on reproductive tissues or organs were observed. Thus, in accordance with REACH Annex IX, section 8.7.3, column 1, it is not necessary to conduct an extended one-generation reproductive toxicity study with the target substance Calcium (S)-lactate.

Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
Reproductive effects observed:
not specified
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

No data is available for the target substance Calcium (S)-lactate itself. To assess the developmental toxicity of Calcium (S)-lactate, data from the suitable read-across partners calcium chloride and ethylhexyl lactate were used.

In a developmental toxicity study, female CD-1 mice were orally exposed to calcium chloride at doses up to 189 mg/kg bw/day (corresponding to 372 mg/kg bw/day Calcium (S)-lactate) and female Wistar rats were orally exposed to doses up to 176 mg/kg bw/day (corresponding to 346 mg/kg bw/day Calcium (S)-lactate) between gestation day 6 and 15. In a third study, female rabbits were orally exposed to calcium chloride at doses up to 169 mg/kg bw/day (corresponding to 327 mg/kg bw/day Calcium (S)-lactate) In all three studies, no adverse effects were observed.

In another developmental toxicity study conducted according to OECD 414, no treatment-related effects on developmental or maternal parameters were detected in rats after inhalation of ethylhexyl lactate. Therefore, it can be stated that no teratogenic effects were observed in this study and the maternal and developmental NOAEC is considered to be 600 mg/m³. 

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
For justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
See Table 1 in box " Any other information on results incl. tables".
Body weight and weight changes:
no effects observed
Description (incidence and severity):
See Table 5 in box " Any other information on results incl. tables".
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No adverse effects were observed/described.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Early or late resorptions:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Dead fetuses:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Other effects:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Key result
Dose descriptor:
NOAEL
Effect level:
> 189 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed at the highest dose tested
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in sex ratio:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
not examined
Skeletal malformations:
no effects observed
Description (incidence and severity):
See Table 3 in box " Any other information on results incl. tables".
Visceral malformations:
no effects observed
Description (incidence and severity):
See Table 4 in box " Any other information on results incl. tables".
Other effects:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
> 189 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed at highest dose tested
Abnormalities:
no effects observed
Developmental effects observed:
no
Table 1: Fate Summary
Group Material Dose Total Surviving at Term
mg/kg bw Mated Pregnant Total Pregnant*
341 Vehicle control 0 25 22 25 22
342 Aspirin** 150 25 19 25 19
347 CaCl2 1.89 25 22 25 22
348 CaCl2 8.78 25 21 24 20
349 CaCl2 40.8 25 21 25 21
350 CaCl2 189.0 25 23 25 23

*includes all dams examined at term

**positive control

Table 2: Reproduction data
Group 341 342 347 348 349 350
Dose (mg/kg bw) Neg Con Aspirin* 1.89 8.78 40.8 189.0
Pregnancies
Total No. 22 19 22 21 21 23
Died/aborted before Day 17 0 0 0 1 0 0
To term (Day 17) 22 19 22 20 21 23
Live Litters
Total No. 21 29 21 20 21 21
Implant Sites
Total No. 251 240 244 248 235 272
Average per dam 11.4 12.6 11.6 12.4 11.2 11.8
Resorptions
Total No. 19 8 12 7 5 35
Dams with 1 or more sites resorbed 6 5 8 6 4 13
Dams with all sites resorbed 1 0 1 0 0 2
% partial resorptions 27.3 26.3 36.4 30.0 19.1 56.5
% complete resorptions 4.55 0 4.55 0 0 8.70
Live Fetuses
Total No. 229 224 229 238 227 234
Average per dam** 10.4 11.8 10.4 11.9 10.8 10.2
Sex ratio (m/f) 1.16 1.07 0.80 0.84 0.89 0.93
Dead Fetuses
Total* 3 8 3 3 3 3
Dams with 1 or more dead 2 6 3 3 3 3
Dams with all dead 0 0 0 0 0 0
Per cent partial dead 9.09 31.6 13.6 15.0 14.3 13.0
Per cent all dead 0 0 0 0 0 0
Average Fetus weight (g) 0.89 0.87 0.90 0.93 0.91 0.90

*positive control

**includes only those dams examined at term

Table 3: Summary of Skeletal findings**
Group No. 341 342 347 348 349 350
Dose (mg/kg bw) Neg. Con. Aspirin* 1.89 8.78 40.8 189.0
Live fetuses examined (at term) 158/21 160/19 160/21 162/20 159/21 161/21
Sternebrae
Incomplete oss. 25/10 28/10 21/11 15/6 24/10 12/5
Scrambled  
Bipartie 11/9 9/7 3/3 12/8 13/10 7/6
Fused  
Extra  
Missing 9/7 11/5 16/10 12/5 10/6 12/5
Other            
Rids
Incomplete oss.            
Fused/split  
Wavy 1/1  
Less than 12  
More than 13 41/14 30/12 28/12 42/14 35/14 20/12
Other            
Vertebrae
Incomplete oss. 3/3 1/1 2/2     2/2
Scrambled  
Fused  
Extra crts. Oss.  
Scoliosis  
Tail defects  
Other            
Skull
Incomplete closure            
Missing  
Craniostosis  
Other: facial bones, inc 1/1            
Extremities
Incomplete oss. 1/1 1/1 1/1     2/2
Missing    
Extra            
Miscellaneous
Hyoid, missing 23/14 23/11 33/14 26/11 20/10 30/13
Hyoid, reduced 23/13 4/4 22/14 12/9 23/12 12/9

*positive control

**numerator= number of fetuses affected, denominator= number of litters affected

Table 4: Summary of Soft Tissue Abnormalities
Group Material Dose (mg/kg bw) Dam No. Of Pups Description
342 Aspirin* 150.0 A6102 1 Gastroschisis
349 CaCl2 40.8 N5070 1 Umbilical hernia
350 Cacl2 189.0 N5112 1 Cleft palate

*positive control

Table 5: Average body weights (g)
Group Material Dose (mg/kg bw) Day 0 Day 6 Day 11 Day 15 Day 17
341 Neg. Con. 0.0 27.7 30.6 34.5 41.1 46.8
342 Aspirin* 150.0 28.7 31.9 35.0 43.4 50.2
347 CaCl2 1.89 29.3 31.3 35.4 43.6 49.2
348 CaCl2 8.78 28.7 30.7 35.2 45.2 51.5
349 CaCl2 40.8 29.0 30.9 35.8 44.1 50.2
350 CaCl2 189.0 30.9 33.6 37.4 45.4 50.4

*positive control

Conclusions:
In this study conducted similar to OECD TG 414, oral administration of calcium chloride given once a day to CD1 mouse dams from Day 6 to 15 of gestation was well tolerated of up to the highest dose applied of 189 mg/kg bw/day. As no adverse results were observed in any examined parameter, the NOAEL for reproductive/developmental and maternal toxicity is considered to be greater than 189 mg/kg bw/day.
Executive summary:

In a developmental toxicity study conducted similar to OECD TG 414, calcium chloride was administered to groups of 25 pregnant adult female CD1 mice/dose by gavage at dose levels of 0, 1.89, 8.78, 40.8 and 189.0 mg/kg bw/day from day 6 through day 15 of gestation. The animals were sacrificed on gestation day 17.

No treatment-related effects were seen in maternal or offspring survival and no maternal/foetal toxicity was observed. In addition, no differences were seen in either soft or skeletal examinations of the fetuses. As no adverse results were observed in any examined parameter, the NOAEL for reproductive/developmental and maternal toxicity is considered to be greater than 189 mg/kg bw/day.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
For justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Specific details on test material used for the study:
- Name of the test material used in the report: calcium chloride
- Batch No.: FDA 71-87
- Appearance: fine white granular material
Species:
rabbit
Strain:
Dutch
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: adult females
Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
On Day 0, each virgin, adult, female rabbits was given an injection of 0.4 mL of human chorionic gonadotropin (400 IU) via the marginal ear vein. Three hours later, each doe was inseminated artificially with 0.3 mL of diluted
semen from a proven donor buck using approximately 20 x 10^6 motile sperm according to the procedure described by Vogin et al. (Pharmacologist 11, 282 (1969)).
Duration of treatment / exposure:
gestation day 6 to 15
Frequency of treatment:
daily
Duration of test:
until gestation day 29
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control
Dose / conc.:
1.69 mg/kg bw/day (nominal)
Dose / conc.:
7.85 mg/kg bw/day (nominal)
Dose / conc.:
35.6 mg/kg bw/day (nominal)
Dose / conc.:
169 mg/kg bw/day (nominal)
Dose / conc.:
2.5 mg/kg bw/day (nominal)
Remarks:
Positive control ( 6-aminonicotinamide)
No. of animals per sex per dose:
16 - 22 females
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: all animals were observed daily for appearance and behaviour with particular attention to food consumption and weight.

BODY WEIGHT: Yes
- Time schedule for examinations: body weights were recorded on gestation day 0, 6, 12, 18 and 29

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes, after caesarean section under surgical anesthesia and the numbers of the numbers of corpora lutea, implantation sites, resorption sites, live and dead fetuses were recorded.
Blood sampling:
n.a.
Fetal examinations:
Body weights of the live pups were recorded. In addition, all fetuses underwent a detailed gross examination for the presence of external congenital abnormalities. The live fetuses of each litter were then placed in an incubator for 24 hours for the evaluation of neonatal survival. All surviving pups were sacrificed, and all pups examined for visceral abnormalities (by dissection). All fetuses were then cleared in potassium hydroxide (KOH), stained with alizarin red S dye and examined for skeletal
defects.
Statistics:
n.a.
Indices:
Numbers of implantation sites, resorption sites, live and dead fetuses, sex ratio
Historical control data:
n.a.
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
See Table 1 in box " Any other information on results incl. tables".
Body weight and weight changes:
no effects observed
Description (incidence and severity):
See Table 5 in box " Any other information on results incl. tables".
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No adverse effects were observed/described.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Early or late resorptions:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Dead fetuses:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Other effects:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Key result
Dose descriptor:
NOAEL
Effect level:
> 169 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed at the highest dose tested
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in sex ratio:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
not examined
Skeletal malformations:
no effects observed
Description (incidence and severity):
See Table 3 in box " Any other information on results incl. tables".
Visceral malformations:
no effects observed
Description (incidence and severity):
See Table 4 in box " Any other information on results incl. tables".
Other effects:
not examined
Dose descriptor:
NOAEL
Effect level:
> 169 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed at the highest dose tested
Abnormalities:
no effects observed
Developmental effects observed:
no
Table 1: Fate Summary
Group Material Dose Total Surviving at Term
mg/kg bw Mated Pregnant Total Pregnant*
341 Vehicle control 0 18 13 18 13
342 6 -AN** 2.5 20 10 19 10
347 CaCl2 1.69 22 13 18 12
348 CaCl2 7.85 22 14 16 11
349 CaCl2 35.6 17 14 14 12
350 CaCl2 169.0 16 16 14 14

*includes all dams examined at term

**positive control, dosed on day 9

Table 2: Reproduction data
Group 341 342 347 348 349 350
Dose (mg/kg bw) Neg Con 6 -AN* 1.69 7.85 35.6 169.0
Pregnancies
Total No. 13 10 13 14 14 16
Died/aborted before Day 29 0 1 1 3 2 2
To term (Day 29) 13 10 12 11 12 14
Live Litters
Total No. 12 10 12 9 11 12
Implant Sites
Total No. 69 56 86 63 69 72
Average per dam 5.31 5.60 7.17 5.73 5.75 5.14
Resorptions
Total No. 4 2 12 8 8 4
Dams with 1 or more sites resorbed 3 1 4 4 6 3
Dams with all sites resorbed 1 0 0 2 1 0
% partial resorptions 23.1 10.0 33.3 36.4 50.0 21.4
% complete resorptions 7.69 0 0 18.2 8.33 0
Live Fetuses
Total No. 65 54 74 55 61 58
Average per dam** 5.00 5.40 6.17 5.00 5.55 4.83
Sex ratio (m/f) 0.86 0.74 1.47 1.04 1.16 1.24
Dead Fetuses
Total* 0 0 0 0 0 10
Dams with 1 or more dead 0 0 0 0 0 2
Dams with all dead 0 0 0 0 0 1
Per cent partial dead 0 0 0 0 0 14.3
Per cent all dead 0 0 0 0 0 7.14
Average Fetus weight (g) 38.2 33.8 37.3 38.0 36.8 39.2

*positive control

**includes only those dams examined at term

Table 3: Summary of Skeletal findings**
Group No. 341 342 347 348 349 350
Dose (mg/kg bw) Neg. Con. 6 -AN* 1.69 7.85 35.6 169.0
Live fetuses examined (at term) 65/12 53/10*** 74/12 54/9*** 61/11 58/12
Sternebrae
Incomplete oss. 2/1 1/1
Scrambled  
Bipartie 1/1
Fused 1/1  
Extra  
Missing
Other            
Rids
Incomplete oss.            
Fused/split 2/1  
Wavy  
Less than 12  
More than 13
Other            
Vertebrae
Incomplete oss.    
Scrambled 5/1  
Fused  
Extra crts. Oss.  
Scoliosis 1/1  
Tail defects 10/3  
Other            
Skull
Incomplete closure  1/1          
Missing  
Craniostosis 2/1  
Other: facial bones, inc 1/1            
Extremities
Incomplete oss.    
Missing    
Extra            
Miscellaneous

*positive control

**numerator= number of fetuses affected, denominator= number of litters affected

***one pup lost in processing

Table 4: Summary of Soft Tissue Abnormalities
Group Material Dose (mg/kg bw) Dam No. Of Pups Description
342 6 -AN* 2.5 Z7640 2 Medial rotation of hind limbs

*positive control

Table 5: Average body weights (kg)

Group

Material

Dose (mg/kg bw)

Day 0

Day 6

Day 12

Day 18

Day 29

341

Neg. Con.

0.0

2.23

2.32

2.40

2.48

2.59

342

6 -AN*

2.50

1.86

1.94

2.03

2.08

2.18

347

CaCl2

1.69

2.20

2.31

2.43

2.51

2.64

348

CaCl2

7.85

2.12

2.16

2.16

2.25

2.33

349

CaCl2

36.6

2.22

2.31

2.34

2.40

2.50

350

CaCl2

169.0

2.27

2.39

2.41

2.46

2.50

*positive control

Conclusions:
In this study conducted similar to OECD TG 414, oral administration of calcium chloride given once a day to Dutch rabbits from Day 6 to 18 of gestation was well tolerated of up to the highest dose applied of 169 mg/kg bw/day. As no adverse results were observed in any examined parameter, the NOAEL for reproductive/developmental and maternal toxicity is considered to be greater than 169 mg/kg bw/day.
Executive summary:

In a developmental toxicity study conducted similar to OECD TG 414, calcium chloride was administered to groups of pregnant adult female Dutch rabbits by gavage at dose levels of 0, 1.69, 7.85, 35.6 and 169.0 mg/kg bw/day from day 6 through day 18 of gestation. The animals were sacrificed on gestation day 29.

No treatment-related effects were seen in maternal or offspring survival and no maternal/foetal toxicity was observed. In addition, no differences were seen in either soft or skeletal examinations of the fetuses. As no adverse results were observed in any examined parameter, the NOAEL for reproductive/developmental and maternal toxicity is considered to be greater than 169 mg/kg bw/day.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
See Table 5 in box " Any other information on results incl. tables".
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No adverse effects were observed/described.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Early or late resorptions:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Dead fetuses:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Other effects:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Key result
Dose descriptor:
NOAEL
Effect level:
> 176 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects oberved at the highest dose tested
Abnormalities:
no effects observed
Fetal body weight changes:
not examined
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in sex ratio:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
not examined
Skeletal malformations:
no effects observed
Description (incidence and severity):
See Table 3 in box " Any other information on results incl. tables".
Visceral malformations:
no effects observed
Description (incidence and severity):
See Table 4 in box " Any other information on results incl. tables".
Key result
Dose descriptor:
NOAEL
Effect level:
> 176 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed at highest dose applied
Abnormalities:
no effects observed
Developmental effects observed:
no
Table 1: Fate Summary
-------------------------------------------------------
Group Material   Dose***  Total   Surviving at           
                                       Term
                         ---------------------------
                 mg/kg   Mated  Pregnant Total Pregnant*
--------------------------------------------------------
 341  Sham       0.0     25       25      25        25
 342  Aspirin**  250.0   25       23      25        23
 347  CaCl2      1.76    25       22      25        22
 348  CaCl2      8.18    25       24      25        24
 349  CaCl2      38.0    25       22      25        22
 350  CaCl2      176.0   25       24      24        23
--------------------------------------------------------
*Includes all dams examined at term
**Positive Control: 250.0 mg/kg
***Administered as a water solution     
Table 2: Reproduction Data
--------------------------------------------------------
Group              341    342     347   348    349    350
Dose (mg/kg)      sham Aspirin*  1.76  8.18   38.0  176.0
--------------------------------------------------------
-----Pregnancies----- 
Total No.           25    23      22    24      22    24
Died or Aborted 
(before Day 20)     0      0       0     0       0     1
To term (on Day 20) 25    23       22    24     22    23
-----Live Litters-----
 Total No.**        25    18       22    24     22    23
-----Implant Sites-----
 Total No.          279   231     234   261     254   246
 Average/dam**     11.2  10.0    10.6  10.9    11.6  10.7
-----Resorptions-----
Total No.**          4    62       3     1       1     2
Dams with 1 or more 
sites resorbed       3     1       2     1       1     2
Dams with all 
sites resorbed       -    4        -     -       -     -
% partial resorptions
                    12.0   47.8   9.09  4.17   4.55  8.70
% complete resorptions 
                    -     17.4     -      -      -     -
-----Live Fetuses-----
Total No.           275    168     231    260    253   244
Average/dam**      11.0    7.30   10.5   10.8   11.5  10.6
Sex ratio (M/F)    1.07    1.06   1.10   0.95   0.90  0.89
-----Dead Fetuses-----
Total**             -       1       -      -      -     -
Dams with 1 or 
more dead           -       1       -      -      -     -
Dams with all dead  -       1       -      -      -     -
% partial dead      -     4.35      -      -      -     -
% all dead          -     4.35      -      -      -     -
-----Average Fetus Weight (g)-----
                  3.68   2.39    4.13    3.80   3.84  3.72
----------------------------------------------------------
* Positive Control: Aspirin 250.0 mg/kg
** Includes only those dams examined at term.

Table 3: Summary of Skeletal Findings**
---------------------------------------------------------
Group  No.      341     342     347     348    349   350
Dose (mg/kg)    Sham  Aspirin*  1.76   8.18    38.0 176.0
---------------------------------------------------------
Live Fetuses Examined
     (at term)  
               191/25 120/18  161/22  180/2  176/22 173/23
-----Sternebrae-----
Incomplete oss.
               86/22   44/15   34/13  53/14  51/16  47/17
Scrambled
Bipartite      1/1     2/2      -     1/1       -    1/1
Fused
Extra
Missing       34/17   103/18   15/9  19/10    18/9   12/7
Other
-----Rids-----
Incomplete oss.
                -      15/9     1/1    3/2      -    1/1
Fused/split
Wavy          22/10    41/16   13/9    11/6   34/17  19/10
Less than 12    -       1/1      -      3/1     -       -
More than 13    -      95/17     -      4/3    1/1    2/2
Other
-----Vertebrae-----
Incomplete oss.
              24/14    76/18   23/10   12/7   34/13   20/9
Scrambled
Fused
Extra ctrs. oss.
Scoliosis        -      1/1      -      -       -      -
Tail defects
Other; spina bifida  
                 -      1/1      -      -       -      -
-----Skull-----
Incomplete closure
              36/13    54/17   25/11  54/19   40/17  31/13
 
Missing         -       2/2      -      -       -      -
Craniostosis
Other
-----Extremities-----
Incomplete oss. -       3/3      -      -       -      -
Missing
Extra
-----Miscellaneous-----
Hyoid; 
missing        26/14   57/17   14/9    9/7    25/9    15/9
Hyoid; 
reduced        17/12    8/4    18/7   33/17   23/12  16/10
----------------------------------------------------------
*Positive Control: 250.0 mg/kg
**Numerator = Number of fetuses affected;
  Denominator = Numbre of litters affected.     
Table 4: Summary of Soft Tissue Abnormalities
---------------------------------------------------------
Group   Material  Dose Level Dam   Number    Description
                    (mg/kg)         of Pups
---------------------------------------------------------
342   Aspirin*     250.0   A7088    1 Meningoencephalocele
                           A7093    3 Encephalomyelocele;
                                      umbilical hernia
                                    1 Hydrocephalus;
                                      exophthalmos;
                                      gastroschisis
                           A7107    1 Meningoencephalocele;
                                      umbilical hernia
347    CaCl2       1.76    N6016    1 Gastroschisis
---------------------------------------------------------
*Positive Control: 250.0 mg/kg

Table 5: Average Body Weights*** (g)
---------------------------------------------------------
Group   Material   Dose   Day0  Day6  Day11  Day15  Day20**
                   Level
                  (mg/kg)
---------------------------------------------------------
341       Sham       0.0   232   252   268    295    353
(25)
342      Aspirin*  250.0   226   247   253    268    311
(23)
347        CaCl2    1.76   229   248   265    286    353
(22)
348        CaCl2    8.18   226   246   261    279    345
(24)
349        CaCl2    38.0   226   247   264    285    357
(22)
350        CaCl2   176.0   231   251   262    280    346
(23)
---------------------------------------------------------
*Positive Control: 250.0 mg/kg
**Number of surviving dams in parentheses (c.f. Table 1)
***Of pregnant dams

Conclusions:
In this study conducted similar to OECD TG 414, oral administration of calcium chloride given once a day to Wistar rat dams from Day 6 to 15 of gestation was well tolerated of up to the highest dose applied of 176 mg/kg bw/day. As no adverse results were observed in any examined parameter, the NOAEL for reproductive/developmental and maternal toxicity is considered to be greater than 176 mg/kg bw/day.
Executive summary:

In a developmental toxicity study conducted similar to OECD TG 414, calcium chloride was administered to groups of 25 pregnant adult female Wistar rats/dose by gavage at dose levels of 0, 1.76, 8.18, 38.0 and 176.0 mg/kg bw/day from day 6 through day 15 of gestation. The animals were sacrificed on gestation day 20.

No treatment-related effects were seen in maternal or offspring survival and no maternal/foetal toxicity was observed. In addition, no differences were seen in either soft or skeletal examinations of the fetuses. As no adverse results were observed in any examined parameter, the NOAEL for reproductive/developmental and maternal toxicity is considered to be greater than 176 mg/kg bw/day.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Abnormalilics seen during exposure were confined to visually increased breathing rate in animals exposed lo 600 mg/m³ during Ihe entire treatment period and occasionally in rats exposed lo 200 mg/m3. One animal of the control group (A 101) lost part of its tail due to a mechanical trauma. Daily clinical observations did not reveal any noticeable differences in the animals' appearance, general condition or behaviour amongst the various groups.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal of the low dose group died on day 11 of gestation because it turned around in the inhalation tube and subsequently suffocated. All other females survived until scheduled Caesarian section.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no significant differences in body weight or body weight change between the control group and the groups exposed to the test substance.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The food consumption of the high dose group was statistically significantly decreased when compared to the control group throughout the exposure period. The food consumption of the 200 mg/m³ was slightly decreased during the exposure period, but increased thereafter.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Gross examination at autopsy did not reveal any significant differences of the maternal organs and tissues among the various groups.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Uterus and ovary weights:
Mean reproductive organ weights and net maternal body weight change during gestation were evaluated. No statistically significant differences in gravid and empty uterus weight, ovary weight, carcass weight and the net weight change (body weight gain from day 0 to 21 of gestation minus gravid uterine weight) were observed between the control group and he groups treated to 2-ethylhexyl lactate.
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between the control group and the groups exposed to the test substance in the numbers of corpora lutea, implantations, live and dead foetuses and early and late resorptions nor in pre- and post-implantation loss or in the sex ratio of the foetuses.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between the control group and the groups exposed to the test substance in the numbers of corpora lutea, implantations, live and dead foetuses and early and late resorptions nor in pre- and post-implantation loss or in the sex ratio of the foetuses.
Early or late resorptions:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between the control group and the groups exposed to the test substance in the numbers of corpora lutea, implantations, live and dead foetuses and early and late resorptions nor in pre- and post-implantation loss or in the sex ratio of the foetuses.
Dead fetuses:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between the control group and the groups exposed to the test substance in the numbers of corpora lutea, implantations, live and dead foetuses and early and late resorptions nor in pre- and post-implantation loss or in the sex ratio of the foetuses.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
From the 12 mated female rats per group, 11 of each group were pregnant.
Other effects:
not examined
Details on maternal toxic effects:
Details on maternal toxic effects:
Clinical signs and mortality:
One animal of the low dose group died on day 11 of gestation because it turned around in the inhalation tube and subsequnetly suffocated. Daily clinical observations did not reveal any differences between dose and control group animals.

Maternal body weight and body weight change:
There were no significant differences in body weight or body weight change between the control group and the groups exposed to the test substance.

Food consumption:
The food consumption of the high dose group was statistically significantly decreased when compared to the control group throughout the exposure period. The food consumption of the 200 mg/m³ was slightly decreased during the exposure period, but increased thereafter.

Parental necropsy observations:
Gross examination at autopsy did not reveal any significant differences of the maternal organs and tissues among the various groups.

Uterus and ovary weights:
Mean reproductive organ weights and net maternal body weight change during gestation were evaluated. No statistically significant differences in gravid and empty uterus weight, ovary weight, carcass weight and the net weight change (body weight gain from day 0 to 21 of gestation minus gravid uterine weight) were observed between the control group and the groups treated to 2-ethylhexyl lactate.
Key result
Dose descriptor:
NOAEC
Effect level:
600 mg/m³ air (nominal)
Based on:
test mat.
Basis for effect level:
other: No differences in clinical signs, maternal body weight or body weight change and necropsy seen in treated animals in comparison to control animals.
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
See box “Details on embryotoxic / teratogenic effects” below.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
See box “Details on embryotoxic / teratogenic effects” below.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
See box “Details on embryotoxic / teratogenic effects” below.
Skeletal malformations:
no effects observed
Description (incidence and severity):
See box “Details on embryotoxic / teratogenic effects” below.
Visceral malformations:
no effects observed
Description (incidence and severity):
See box “Details on embryotoxic / teratogenic effects” below.
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
Reproduction and litter data at Caesarian section:
From the 12 mated female rats per group, 11 of each group were pregnant.
Reproduction and litter data revealed no treatment-related changes either as evidenced by the absence of statistically significant differences between the
control group and the groups exposed to the test substance in the numbers of corpora lutea, implantations, live and dead foetuses and early and late resorptions nor in pre- and
post-implantation loss or in the sex ratio of the foetuses.

Foetal external observations:
No statistically significant differences were observed for the individual findings. When compared with the control group, the total number of fetal external
observations was slightly albeit statistically significantly increased in the high concentration group. This difference was mainly due to the low number of foetal
observations in the control group: Only one foetus with a small haemorrhage on the head in the control group versus 4 dysmature foetuses from 4 litters (i.e. foetus weight < 75 % of the mean foetal body weight in the control group) and three large foetuses (i.e. foetus weight > 125 % of the mean foetal body weight) plus one foetus with a flexed limb from one litter of the 600 mg/m³ group. Considering the nature of the findings and the low number in the control group, this difference is not considered treatment related.

Findings of the placenta:
Findings of the placenta were limited to two fused placenta in four fetuses of one female control group animal.

Foetal weight and placental weight:
No significant differences in mean foetal body weights were observed between the control group and the groups exposed to the test substance. Mean placental
weight of the 200 mg/m³ group was increased (statistically significantly for both sexes combined). Mean placental weights in of the 600 mg/m³ were comparable to these in the control group.

Visceral examination:
Examination of foetal soft tissues was limited to the control group and the high concentration group.
Visceral malformations:
No visceral malformations were seen in the control group and the high concentration group.
Visceral anomalies:
No visceral variations were observed in the control and the high-concentration group.

Skeletal examinations:
Skeletal examinations were conducted in all groups.
Skeletal malformations:
None of the fetuses showed skeletal malformations
Skeletal anomalies:
Skeletal anomalies were limited to wavy ribs in 3 foetuses out of 2 litters in the high-concentration groups. The incidence in the high-concentration group did not differ significantly from that in the control group.
Skeletal variations:
No statistically significant differences were observed for the individual findings.
Variations in the ossification of the skeletons
When compared with the control group, the 200 and 600 mg/m³ groups showed the following differences: Increase in the number of foetuses and litters with an incompletely ossified frontalis and unossified metatarsals, which was significant in the 200 mg/m³ group. Furthermore, a delay in the ossification of the hind limb phalanges was observed in the 200 and 600 mg/m³ group. The slightly retarded ossification as observed at 200 and 600 mg/m3, was considered to be a minor developmental effect, most attributable to the stress conditions. No teratogenic effects were observed in this study.
Key result
Dose descriptor:
NOAEC
Effect level:
600 mg/m³ air (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Key result
Abnormalities:
no effects observed
Developmental effects observed:
no

Gravimetric analysis:

The mean actual concentrations of 2-ethylhexyl lactate in the test atmospheres (and their standard deviations) were 230 (± 16) and 594 (± 48) mg/m³.

Nominal concentration:

The daily mean airflow through the exposure units were 26.5, 55.9, and 70.4 L/min for the control, low, and high concentration level, respectively. The nominal concentrations were 378 and 751 mg/m³, indicating generation efficiencies of 61 and 79 % for the low and high concentration level, respectively.

Particle size measurement:

Particle size measurement showed that almost all particles in the animals' breathing zone were respirable, viz. they were smaller than or equal to 4.2 µm. The mean mass median aerodynamic siameter (MMAD) was 2.7 and 1.7 µm for the low and high exposure level, respectively. The mean geometric standard deviation was 1.5 for the low concentration level and 1.6 for the high concentration level.

Temperature and relative humidity:

The daily mean temperature was 22.7 ± 0.6 °C, 22.6 ± 0.4 °C and 22.6 ± 0.4 °C for the control, low and high concentration level. respectively. The daily relalive humidity was 56 ± 6%, 52 ± 5% and 52 ± 6 %, respectively.

Conclusions:
In conclusion, no treatment-related effects in developmental parameters or maternal parameters were detected in a developmental toxicity study (OECD 414) after inhalation of 2-ethylhexyl lactate, except slightly retarded ossification. This is considered to be a minor developmental effect, most attributable to the stress conditions. Therefore, it can be stated that no teratogenic effects were observed in this study and the maternal and developmental NOAEC is considered to be 600 mg/m³.
Executive summary:

In a developmental toxicity study (OECD 414), 2-ethylhexyl lactate (98.2% purity) was administered to 12 female Wistar rats per dose level in clean air (nose-only exposure for 6 hours/day) at concentration levels of 0, 200 and 600 mg/m³ from day 6 through day 15 of gestation. On day 21 of gestation the animals were sacrificed. There were no treatment-related effects on mortality, clinical signs, body weight or Casarean parameters. Food consumption of the groups was statistically significantly decreased in comparison to the control group animals. As no differences were noticed in body weight change between control and treated animals this effect was classified as not biologically adverse. Based on the results, the maternal NOAEC is considered to be 600 mg/m³. Moreover, no treatment related effects were noted in developmental parameters, except slightly retarded ossification. This is considered to be a minor developmental effect, most attributable to the stress conditions. Thus, the developmental NOAEC is 600 mg/m³. This developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rat.

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Endpoint:
developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Species:
rat
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
GLP guideline study
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No data is available for the target substance Calcium (S)-lactate itself. Due to complete dissociation of Calcium (S)-lactate into Ca2+ ions and lactate under aqueous and/or physiological conditions, the toxicology of Calcium (S)-lactate can be understood in terms of effects of the dissociation products. The calcium moiety of Calcium (S)-lactate is considered to be devoid of any reproductive/developmental properties, based on the physiological role of calcium ions: calcium is an essential bulk element for the human body. This observation is common textbook knowledge hence can be considered as adequately and reliably documented, fulfilling the criteria of REACH Annex XI, section 1.1. Additional experimental evidence supporting the lack of potential developmental and/or reproductive effects of calcium (thus also Calcium (S)-lactate) is scientifically not necessary. Lactic acid is a ubiquitous and essential molecule of life, found in all higher animals and many micro-organisms. It is also found in many food items. Reproductive/developmental toxicity is not a relevant endpoint for such a substance since there is no way of lowering exposure below minimum required levels or normal (or even abnormal) internal levels. The toxicity of lactic acid is specifically described in IUCLID section 7.1 (Sterenborg, 2007). Nevertheless, available data from the suitable read-across partner calcium chloride and ethylhexyl lactate was used to assess the potential of Calcium (S)-lactate to induce reproductive/developmental effects. For justification of the read-across approach please refer to IUCLID section 13.

In a developmental toxicity study, female CD-1 mice were orally exposed to calcium chloride at doses of up to 189 mg/kg bw/day (corresponding to 372 mg/kg bw/day Calcium (S)-lactate) and female Wistar rats were orally exposed to doses of up to 176 mg/kg bw/day (corresponding to 346 mg/kg bw/day Calcium (S)-lactate) between gestation day 6 and 15. In a third study, female rabbits

were orally exposed to calcium chloride at doses up to 169 mg/kg bw/day (corresponding to 327 mg/kg bw/day Calcium (S)-lactate) between gestation day 6 and 18. In all three studies, no adverse effects were observed.

In another developmental toxicity study conducted according to OECD 414, no treatment-related effects on developmental or maternal parameters were detected in rats after inhalation of ethylhexyl lactate. Therefore, it can be stated that no teratogenic effects were observed in this study and the maternal and developmental NOAEC is considered to be 600 mg/m³. 

In conclusion, based on the assessment of the available data in a weight-of-evidence approach, no classification for developmental/reproductive toxicity is warranted for the target substance Calcium (S)-lactate.

Justification for classification or non-classification

Based on the assessment of the available data in a weight-of-evidence approach and by way of read-across, no classification for developmental/reproductive toxicity is warranted for Calcium (S)-lactate.

Additional information