Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No studies were available which are directly related to this endpoint (e.g. OECD Guideline 415, 416, or 422). However, no studies are needed because it is not to be expected, that formaldehyde reaches the reproductive organs and there is no evidence for effects on fertility and gonads in experimental animals after long-term oral or inhalation exposure. Toxicokinetic data (see summary end discussion Toxicokinetics) suggested only local effects at the site of entry.

Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
other justification
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Additional information

Effects on fertility

In a two-years drinking-water study in rats comparable with OECD Guideline 453 (Til et al., 1989, Section Repeated dose toxicity: oral) no adverse effects on the reproductive organs were recorded even at the high dose level of 109 mg/kg bw/day in females and 82 mg/kg bw/day in males that induced local effects in the stomach. These negative results for reproductive organs are confirmed by the long-term drinking water study of Tobe et al. (1989; Section Repeated dose toxicity: oral) in rats or a chronic inhalation study in rats and mice (CIIT, 1981; Section Repeated dose toxicity: inhalation) comparable to OECD Guideline 453 and further oral and inhalation studies in rats, mice and dogs (see waiving Section Effects on fertility). This lack of systemic effects to reproductive organs (independent on the route of exposure) are in accord with toxicokinetic data (see endpoint summary of section repeated dose toxicity) suggesting only local effects at the site of entry.

No conclusions can be drawn from the limited data in humans (see waiving Section Effects on fertility).

A short summary and evaluation on reproductive effects is also presented in a recent review by IARC (2006); details are given in the following Section of the endpoint summary.

Effects on developmental toxicity

Description of key information
There is no evidence for adverse effects of formaldehyde on embryo and fetal development at dose levels inducing  local maternal effects and secondary decrease in body weights and growth.
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Acceptable with some restrictions: No data about purity of the test substance or stability in food; only low dose tested without maternal toxicity; some evaporation of formaldehyde prior to consumption presumed (resulting in lower dose levels). Study limited to a restricted number of parameters (e.g. data on visceral or skeletal alterations only in stillborn pups or pups which died later in post natal observation period, no data on maternal weight gain). No statistical analysis.
Principles of method if other than guideline:
Teratogenic effects in dogs after oral exposure via the food.
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Specification
40% formalin (presumably stabilized with 10% methanol)
Species:
other: dog
Strain:
other: Beagle
Details on test animals and environmental conditions:
- Source: Closed breeding colony of the same laboratory
- Sex: Female
- Age/weight at study initiation: no data / ca. 12 kg
- Dogs received certified diet (dog pellets, Nafag AG, Gossau, Switzerland).
- 4-5 pregnant dogs in one indoor cubicle plus outdoor run; animals single in whelping rooms 1 week before term.
Route of administration:
oral: feed
Vehicle:
other: Solution of the required daily dose in 2 ml were prepared weekly and sprayed on the pellets prior to feeding. Pellets were consumed within 5-10 min (authors statement: no volatilization; comment: some evaporation expected).
Details on exposure:
Concentration in food: 0, 125 and 375 ppm (0, 0.012, 0.037%)
food consumption per day: 300 g per animal per day corresponding to 0, 3.1, or 9.4 mg/kg bw/day (authors calculation).
Controls received the plain diet.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
No details
Duration of treatment / exposure:
Day 4 after mating up to day 56
Frequency of treatment:
once daily
Duration of test:
Normal birth. Pups observed up to 9 months after birth
Dose / conc.:
125 ppm
Remarks:
- 0.012%
- 3.1 mg/kg bw/day
Dose / conc.:
375 ppm
Remarks:
- 0.037%
- 9.4 mg/kg bw/day
No. of animals per sex per dose:
9-10 pregnant bitches (10-11 mated bitches)
Control animals:
yes, concurrent vehicle
Maternal examinations:
- Body weight Yes, maternal weight determined at weekly intervals.
- Food consumption See above
- Clinical signs No data
Ovaries and uterine content:
No data
Fetal examinations:
External malformations examined immediately after birth and after 8 weeks. Autopsy of stillborn pups and those lost before weaning. Further parameters: total pups at birth, total live pups at birth, total pups at weaning, mean live (or total) pups per litter at birth and at weaning, mean litter size, sex ratio, mean pup weight (measured daily after birth for 8 days).
Skeletal and visceral malformations examined only in stillborn or pups who died postnatal.
Statistics:
no
Indices:
no data
Historical control data:
no data
Details on maternal toxic effects:
No effects.

No data about clinical symptoms and maternal weight gain. No effects on number of pregnant bitches, number of litters and mean length of gestation (range or SD not given). No local maternal effects in the gastro-intestinal tract expected (max. concentration 0.037% in the diet)
Dose descriptor:
LOAEL
Effect level:
> 9.4 mg/kg bw/day (nominal)
Basis for effect level:
other: study not sufficient for identifying a NOAEL, no local effects expected (max. concentration in the diet: 0.037%)
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
No effects.

No effects on parameters listed above. Mean values given but no data on SD, SE or range. No skeletal or visceral malformation in stillborn pups or pups which died later (no further details).
Dose descriptor:
LOAEL
Effect level:
> 9.4 mg/kg bw/day (nominal)
Basis for effect level:
other: study not sufficient for identifying a NOAEL
Abnormalities:
not specified
Developmental effects observed:
not specified

No effects on behaviour, appearance, motility and muscular co-ordination in dogs observed for a more prolonged period.

Conclusions:
No developmental effects in dogs exposed via the diet to doses up to 9.4 mg/kg bw/day but limited number of parameters examined.
Executive summary:

Study meets generally accepted scientific standards but limited number of parameters examined. Further deficiencies: No data about purity of the test substance; only low dose tested without maternal toxicity; some evaporation of formaldehyde prior to consumption presumed (resulting in lower dose levels). Study limited to a restricted number of parameters (e.g. data on visceral or skeletal alterations only in stillborn pups or pups which died later in post natal observation period, no data on maternal weight gain). No statistical analysis.

Pregnant Beagle dogs (9-10 pregnant bitches per dose) were exposed from day 4 after mating up to day 56 to a diet containing formaldehyde at dose levels of 0, 3.1, or 9.4 mg/kg bw/day. The dose levels (max. 9.4 mg/kg bw) and concentrations (max. 0.037% in the diet) were relative low (no local effects expected). No toxic effects were reported in the bitches (but no data on body weight gain). External malformations were examined immediately after birth and after 8 weeks. Autopsy was performed on stillborn pups and those lost before weaning. Further parameters: total pups at birth, total live pups at birth, total pups at weaning, mean live (or total) pups per litter at birth and at weaning, mean litter size, sex ratio, mean pup weight (measured daily after birth for 8 days). Concerning the investigated parameters no developmental toxicity was detected.

Conclusion: no developmental effects in dogs exposed via the diet to doses up to 9.4 mg/kg bw/day but limited number of parameters examined.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Comparable to OECD guideline 414 with acceptable restrictions [partly without details on results (irritation, symptoms, necropsy); co-application of methanol (used for stabilisation of formalin solution)].
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
Aqueous formaldehyde solution containing 12-15% methanol (presumably formalin); source: Fisher Scientific Co.
No further data
Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
- Source: Charles-River Breeding Labs, Wilmington, Mass., USA
- Sex: emale (virgin) & male
- Age/weight at study initiation: 60-90 days-old mice, no further data
- Housing conditions:
housed individually, certified diet and tape water ad libitum; 22-24°C; rel. air humidity 45-50%; 12 h light/12 h dark.
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Stock solution diluted with destilled water. Intubation of the dose on a 1% body weight basis (v/w). Thus, 1 mL formaldehyde per 100 g bw was applied. Concentrations: 0, 0.7, 1.5, 1.8%.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Mating period 1 day; no further details
Duration of treatment / exposure:
Gestation day 6-15
Frequency of treatment:
once daily
Duration of test:
Termination at day 19 of gestation.
Dose / conc.:
74 mg/kg bw/day
Remarks:
[0.7%] of applied solution
Dose / conc.:
148 mg/kg bw/day
Remarks:
[1.5%] of applied solution
Dose / conc.:
185 mg/kg bw/day
Remarks:
[1.8%] of applied solution
No. of animals per sex per dose:
29-76 dams
Control animals:
yes, sham-exposed
Maternal examinations:
- Body weight: Yes
- Food consumption: No data
- Clinical signs: Only data on mortality
- Necropsy: no data (comment: local effects in the gastro-intestinal tract expected)
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- General: Live fetuses, litter size, Nr. of live and dead foetuses, foetal weight, Sex ratio, pre and post-implantation loss;
- Skelet: Yes
- Soft tissue: Yes
- External: yes
Statistics:
Suitable methods used for statistical analysis ((Mann-Whitney U Test, Fisher exact test), level of significance p<0.05.
Indices:
No data
Historical control data:
No data
Details on maternal toxic effects:
Decreased body weight gain, but significant only in the low dose group. High dose was lethal to 22 out of 34 dams. One out of 35 dams died at the mid dose level. No mortality at 74 mg/kg bw. Data on repeated oral dose toxicity in Section 7.5.1 suggested local effects in the gastro-intestinal tract even at the low dose level (concentration 0.7%).
Dose descriptor:
LOAEL
Effect level:
74 mg/kg bw/day (nominal)
Basis for effect level:
body weight and weight gain
Abnormalities:
effects observed, treatment-related
Localisation:
other: decreased body weight
Details on embryotoxic / teratogenic effects:
No statistically significant effects on examined developmental parameters. However, at 185 mg/kg bw/day the average of resorptions/litter was doubled compared to concurrent control (but not significant). External, visceral and skeletal examinations of foetuses revealed no teratogenic effects (details presented in a Table) although the high dose resulted in high mortality rate of dams.
Dose descriptor:
NOAEL
Effect level:
185 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: highest dose level tested, also no malformations
Abnormalities:
no effects observed
Developmental effects observed:
no

Developmental effects of formaldehyde in mice after oral exposure via gavage

Tested parameter

Control

Dose in mg/kg bw/day

Vehicle

74

148

185

No. of dams receiving the test substance

76

29

35

34

No. of dams alive on day 18

76

29

34

12

Number of pregnant dams

69

26

28

8

Average weight gain day 6-17

17.9+-0.42

16.5+-0.46*

17.2+-0.74

16.6+-1.04

Mean number of implants/dam

13.2

13.0

13.5

12.5

Number of resorptions

69

25

37

15

Average % of resorptions/litter

7.5

7.4

9.8

15.0

Average % of foetal deaths/litter

1.4

0.59

1.6

2.0

Sex ratio

403/428

137/174

169/166

40/43

Number of stunted fetuses

2

2

2

1

Average no. of live fetuses/dam

12.1

12.0

12.0

10.4

Average foetal weight in g

0.969+-0.012

0.954+-0.018

0.992+-0.021

0.953+-0.036

*: significant

Conclusions:
No developmental toxicity in mice at dose levels inducing maternal toxicity after oral exposure via gavage.
Executive summary:

Study is comparable to OECD guideline 414 with acceptable restrictions [partly without details on results (irritation, symptoms, necropsy); co-application of methanol (used for stabilisation of formalin solution)].

In this gavage study 29 -76 pregnant mice per dose group were exposed to 0, 74, 148, 185 mg/kg bw/day formaldehyde (concentration of applied solution: 0, 0.7, 1.5, 1.8%) once daily at gestation day 6-15 (termination at gestation day 19). Maternal toxicity was obvious at 74 mg/kg bw/day (decreased body weight gain); data on local effects in the gastro-intestinal tract are not available, however, these effects are expected even at the low dose level (compare with data in Section 7.5.1). No embryo- or fetotoxic effects and no teratogenic effects were reported at any dose level, although 185 mg/kg bw/day resulted in a high mortality rate in pregnant mice.

Conclusion: No developmental toxicity in mice at dose levels inducing maternal toxicity after oral exposure via gavage.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Comparable to OECD guideline 414 with acceptable restriction (exposure restricted to gestation day 6-15; virus infection in dams of all groups)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Remarks:
(BIO-RESEARCH LABORATORIES LTD)
Limit test:
no
Specific details on test material used for the study:
paraformaldehyde (T-353)
Batch No. 732540 from Fischer Scientific Co.
Purity: 95%, with the majority of the remaining 5% being water with a trace of formic acid
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
- Age/weight at study initiation: 13 weeks / 221-277 g
- Housing conditions: housed individually, certified diet and tape water ad libitum; 18-24°C; rel. air humidity 30-70%; 12 h light/12 h dark.
- diet and water not during exposure
Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
Exposure chamber 600 l volume; equilibration period 0.5 h each day followed by further 5.5 h exposure; formaldehyde gas was generated by depolymerizing paraformaldehyde at a temperature of 80°C and pressure 2 psi; formaldehyde gas was carried from the generator at a rate of 0.5 L/min into a heated manifold and diluted with 4.5 L/min of dehumidified campressed air.
Gas metered into the inhalation chambers of the 3 treated groups to achieve the desired chamber concentrations. Mean chamber temperature ranged from 17 to 23°C, and mean relative humidity ranged from 48 to 77%.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
3 samples per day (3 x 1.75 h); samples analyzed by the chromotropic acid method.
Details on mating procedure:
Mating:placing 1 female with 1 male overnight; mating determined by the presence af spermatozoa in the vaginal lavage; the day of positive identification af spermatozaa termed day 0 of gestation.
Duration of treatment / exposure:
day 6 to day 15 of gestation
Frequency of treatment:
6 h/day
Duration of test:
Sacrifice and caesarian section at gestation day 20 (GD20).
Dose / conc.:
2 ppm
Dose / conc.:
5 ppm
Dose / conc.:
10 ppm
No. of animals per sex per dose:
25
Control animals:
yes, concurrent no treatment
yes, sham-exposed
Maternal examinations:
- Body weight: weighed on days 0, 6, 9, 13, 16 and 20 of gestation
- Food consumption: measured between days 0 to 6, 6 to 9, 9 to 13, 13 to 16 and 16 to 20 of gestation
- Clinical signs: at least once each day
- Necropsy: at termination full gross pathological examination
Ovaries and uterine content:
The reproductive tract dissected out, the ovaries removed and the corpora lutea counted; uterus weighed and uterine contents examined and the number and position of live fetuses, dead fetuses, early (endometrial gland with or without some placental tissue), middle (discernible placental and fetal tissue present) and late (fetal structure apparent) resorptions were recorded.
The fetuses were removed from the uterus and given s.c. T61 euthanasia solution; uterus of each animal judged to be nonpregnant stained with 10% aq (vlv) ammonium suiphide solution and examined for implantation sites.
Fetal examinations:
Each fetus examined for external malformations; fetal weight and sex determined.
Visceral malformations examined in approximately 50% of the fetuses in each litter, heads of these fetuses removed and fixed in Bouin's fluid for examination by the technique of Wilson; the other 50% of each liter examined for skeletal malformations after staining with Alizarin Red S.
Abnormalities classified as major malformations, minor anomalies or common variants.
Statistics:
Suitable methods used for statistical analysis (one-way analysis of variance, Mann-Whitney U- test, Fisher exact test, Student's t- test), level of significance p<0.05.
Indices:
No details
Historical control data:
No data
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight: Significantly decreased body weight gain (GD 9-12) and body weights (GD 13 & 16) at 10 ppm
Corrected body weight (minus gravid uterine weight): weight gain GD 6-20 and weight at GD20 were sigificantly lower at 10 ppm
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
at 10 ppm sigificant decrease at GD 6-16
Description (incidence and severity):
yellow fur (no adverse effect), no further effects reported. No evidence of maternal toxicity at 2 and 5 ppm (no data about local irritation)
Details on maternal toxic effects:
No data on local effects in the upper respiratory tract available, however, effects expected at >= 5 ppm
Dose descriptor:
NOAEC
Effect level:
5 ppm (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Details on embryotoxic / teratogenic effects:
No effects on parameters listed in material and methods except significantly increased incidence in reduced ossification of the pubic and ischial bones (variation) at the mid and high dose level compared to shame exposed control but not untreated control (within historical range or ischial bone slightly above historical range). This effect was considered to be related to the larger litter size and slightly lower fetal weights at these dose levels.
Dose descriptor:
NOAEC
Effect level:
10 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: highest dose level tested
Abnormalities:
no effects observed
Developmental effects observed:
no

At a dose level of >=5 ppm local effects in the nasal cavity of dams are expected (compare with data in Section 7.5.3 and endpoint summary in Section 7.5). It can be speculated that 2 ppm is the NOAEC for maternal toxicity (related to these local effects).

Conclusions:
No embryo- or fetotoxic effects in rats at concentrations inducing maternal toxicity.
Executive summary:

The study is comparable to OECD guideline 414 with acceptable restriction (exposure restricted to gestation day 6-15; virus infection in dams of all groups).

Pregnant Sprague-Dawley rats (25 per dose level) were exposed at gestation day (GD) 6 -15 for 6 h/day to 0, 2, 5, 10 ppm. The study was terminated at GD20. Maternal toxicity was detected only at 10 ppm (decreased body weight gain and food consumption; no data about irritation but local effects in the nasal cavity expected at >= 5 ppm). No effects of toxicological relevance were found on parameters of developmental toxicity, the NOAEC was 10 ppm.

Conclusion: No embryo- or fetotoxic effects in rats at concentrations inducing maternal toxicity.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Requirements of OECD guideline 414 fulfilled except data on maternal toxicity (no data on food consumption, body weight during exposure period and clinical symptoms or local effects in the nasal cavity).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
37% formalin (stabilized with 10% methanol)
No further data
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
- Source: IFFA-Credo breeding laboratories, France
- Age/weight at study initiation: No data / 180-220 g (acclimatization period at least 5 days)
- Housing conditions:
certified diet and tape water ad libitum; 22-24°C; rel. air humidity 45-55%; 12 h light/12 h dark.
Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
Whole body exposure in a 200 l inhalation chamber with air flow 10-20 m³/h
Generation of test atmosphere: air 21-25°C and rel. humidity 45-55%; air flow through a flask containing the test substance; concentration varied by passing air amount.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis by spectrophotometry; periodically samples collected (no further details).
Details on mating procedure:
3 females caged with one male overnight.
Duration of treatment / exposure:
day 6 to day 20 of gestation
Frequency of treatment:
6 h/day
Duration of test:
Termination at gestation day 21
No. of animals per sex per dose:
25 females treated (21-24 pregnant rats for evaluation)
Control animals:
yes, sham-exposed
Maternal examinations:
- Body weight: Yes, at day 0, 6 and 21 (not during exposure period)
- Food consumption: No data
- Clinical signs: No data
Ovaries and uterine content:
- Examination of uterine content
Gravid uterine weight determined
Number of corpora lutea
Number of implantations/resorptions
Fetal examinations:
Examination of foetuses
- General: Live fetuses, litter size, Nr. of live and dead foetuses, foetal weight, Sex Ratio, pre and post-implantation loss
- Skelet: Yes (one half of viable foetuses)
- Soft tissue: Yes (one half of viable foetuses)
- External malformations examined.
Statistics:
Suitable methods used for statistical analysis (Yates' corrected chi squared test, Students's t-test, Mann-Whitney U test); level of significance p<0.05.
Indices:
no
Historical control data:
not documented
Clinical signs:
not specified
Description (incidence and severity):
No data
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significant effects on maternal body weight only at the high dose level (determined gestation day 6 and 21). But no measurement during exposure period (at least every 3rd day of exposure period recommended).
Food consumption and compound intake (if feeding study):
not specified
Description (incidence and severity):
No data
Dose descriptor:
NOAEC
Effect level:
5 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEC
Effect level:
10 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
10 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
LOAEC
Effect level:
20 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
No effects on parameters listed in section 3 except decreased fetal weight of males and females in the high dose group. A slight but significant decrease in foetal weight of males at 20 ppm was also reported. Also no effects on skeletal or visceral variations.
Dose descriptor:
NOAEC
Effect level:
40 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEC
Effect level:
10 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: overall effects
Dose descriptor:
LOAEC
Effect level:
20 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: decrease in weight
Abnormalities:
not specified
Developmental effects observed:
not specified

Developmental effects in rats exposed via inhalation for 6 h/day on gestation day 6-20
Mean +- SD

Parameter

0 ppm

5 ppm

10 ppm

20 ppm

40 ppm

Number of pregnant females

24

21

23

21

24

Incidence of pregnancy (%)

96

84

92

84

96

Body weight gain of dams (g)

104+-21

111+-24

106+-18

104+-15

51+-25**

Implantation sites per litter

14.1+-3.3

13.4+-3.6

14.1+-2.2

15.0+-2.0

15.0+-2.0

Total foetal loss per litter

0.6+-0.7

0.4+-0.6

0.6+-0.7

0.6+-0.9

0.6+-1.1

Resorption sites per litter

0.6+-0.7

0.4+-0.6

0.6+-0.7

0.6+-0.7

0.6+-1.1

Live foetuses per litter

13.5+-3.2

13.0+-3.3

13.7+-2.2

14.4+-1.9

14.3+-2.7

Foetal sex ratio

0.89

1.16

1.06

1.01

0.91

Mean weight of male pups

5.61+-0.06

5.54+-0.06

5.52+-0.08

5.35+-0.06*

4.42+-0.09**

Mean weight of female pups

5.24+-0.06

5.31+-0.06

5.22+-0.07

5.09+-0.06

4.27+-0.09**

* : p<0.05; ** : p<0.01;

Conclusions:
No teratogenic effects in rats after inhalation exposure; effects on fetal weight at >= 20 ppm are considered to be due to maternal toxicity.
Executive summary:

In this study the requirements of the OECD guideline 414 were fulfilled except data on maternal toxicity (no data on food consumption, body weight during exposure period and clinical symptoms[local effects expected]).

21 -24 pregnant Sprague-Dawley rats per dose level were exposed via inhalation for 6 h/day on day 6 to day 20 of gestation to 0, 5, 10, 20, or 40 ppm and sacrificed at gestation day 21. Significant effects on maternal body weight were detected only at the high dose level (determined only gestation day 6 and 21). However, maternal toxicity due to local effects in the nasal cavity are expected at >= 10 ppm (compare with data in Section 7.5.3). No developmental effects were found except decreased fetal weight of males and females in the high dose group and a slight but significant decrease in foetal weight of males at 20 ppm.

Conclusion: No teratogenic effects; effects on fetal weight at >= 20 ppm might be due to maternal toxicity.

Additional information

Developmental toxicity

In a study comparable to OECD Guideline 414 (with acceptable restrictions) pregnant Sprague-Dawley rats (25 per dose level) were exposed at gestation day (GD) 6 -15 for 6 h/day to 0, 2, 5, 10 ppm (Martin, 1990; FCC, 1985). The study was terminated at GD20. Maternal toxicity was detected onlyat 10 ppm (decreased body weight gain and food consumption; no data about irritation). At the 5 and 10 ppm levels, an apparently significant concentration-related decrease in ossification was detected in the bones of the pelvic girdle, but this was associated with larger litter sizes with decreased fetal weights in both these groups. The slightly lower fetal weights were considered to be due to the larger litter sizes. Since noeffects of toxicological relevance were found on parameters of developmental toxicity, the developmental toxicity NOAEC was 10 ppm (Martin, 1990; FCC, 1985). In conclusion, no embryo- or fetotoxic effects were detected in rats at concentrations inducing maternal toxicity.

In a further teratogenicity study in rats (Saillenfait et al., 1989) no teratogenic effects were detected even at inhaled concentrations up to 40 ppm (0, 5, 10, 20, 40 ppm; 6 h/days at gestation day 6-20). Only effects on fetal weight were reported at ≥ 20 ppm. Significant reduction in body weight and absolute weight gain of dams was found at 40 ppm. No data were reported on clinical signs or local effects; however, local irritant effects are clearly to be expected at ≥ 10 ppm (compare with data in Section Repeated dose toxicity)

In an oral developmental toxicity study (Marks, 1980) pregnant mice were exposed via gavage to 0, 74, 148, or 185 mg/kg bw/day formaldehyde (concentration of applied solution: 0, 0.7, 1.5, 1.8%) at gestation day 6-15. Maternal toxicity was reported at 74 mg/kg bw/day or greater (lethality and decreased body weight gain); data on local effects in the gastro-intestinal tract are not available; however, these local effects are expected even at the low dose level/concentration in dams (compare with data in Section Repeated dose toxicity: oral). No embryo- or fetotoxic effects and no teratogenic effects were reported at any dose level, although 185 mg/kg bw/day resulted in a high mortality rate in dams. In conclusion, no developmental toxicity was found in mice at dose levels inducing maternal toxicity after oral exposure via gavage.

There were inconsistent findings in epidemiological studies on spontaneous abortions; however, no conclusion can be drawn due to limitations of these studies (see IUCLID Section 7.10.2; WHO, 1989; developmental toxicity).

A summary and evaluation on reproductive and developmental effects is also presented in a recent review by IARC (2006): “Eleven epidemiological studies have evaluated directly or indirectly the reproductive effects of occupational exposures to formaldehyde. The outcomes examined in these studies included spontaneous abortions, congenital malformations, birth weights, infertility and endometriosis. Inconsistent reports of higher rates of spontaneous abortion and lowered birth weights were reported among women occupationally exposed to formaldehyde. Studies of inhalation exposure to formaldehyde in animal models have evaluated the effects of formaldehyde on pregnancy and fetal development, which have not been clearly shown to occur at exposures below maternally toxic doses. ”

A review on reproductive effects was identified in the literature update up to April 20, 2015.

Dong et al. (2011, supporting) reviewed the literature on reproductive effects in humans and animals starting from 450 references including studies published iin Chinese language mostly in peer reviewed journals. Animal studies by all routes of exposure were included. After removal of abstacts, animal studies dating from before 1980, and non-English publications (except Chinese and human studies), 18 human and 46 animal studies were reviewed in detail. By a metaanalysis of the mainly retrospective human studies the authors observed an increased risk for spontaneous abortions (1.76, 95% CI 1.20-2.59; p=0.002) and all adverse pregnancy outcomes (1.54, 95% CI 1.27-1.88; p<0.001) for formaldehyde exposed women. But differential recall, selection bias, or confounding cannot be ruled out. Animal studies suggest positive associations between formaldehyde exposure and reproductive toxicity, mostly in males. Potential mecchanisms are offered, like genotoxicity, oxidative stress apoptosis, and alterations of enzymes, hormones, or proteins. This review is a valuable collection of literature, including studies from China, but as a critique, generally no effort is made to analyse strengths and weaknesses of the single publications in order to arrive at some weight of evidence assessment.

Justification for classification or non-classification

The available data on toxicity for reproductiondo not trigger classification and labeling according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008).