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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In accordance with point 8.7.1 of column 2 of REACH Annex VIII, the screening for reproductive/developmental toxicity does not need to be conducted if a pre-natal developmental toxicity study is available.

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

Developmental toxicity /teratogenicity: NOAEC= 548.0 µg/m3, Not teratogenic (Read-Across, no guideline followed, not GLP, K, rel.2)

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:
key study
Justification for type of information:
See attached justification document
Reason / purpose:
read-across source
Specific details on test material used for the study:
4-chloroformylphthalic anhydride
Details on maternal toxic effects:
Maternal toxic effects: yes

Details on maternal toxic effects:
All rats sacrificed on gestation day 20 had lung foci. The mean number of lung foci was 115.9 with the range between 38 and 196. Rats sacrificed following weaning had lower numbers of foci, and only 5 were classed as having a positive response (10 lung foci or more). Rats sacrificed following weaning had a mean of 9.5 lung foci with the range between 0 and 35. The number of external haemorrhagic foci was significantly higher in the TMA-exposed rats relative to control rats at both time points. The number of lung foci in the filtered air control group ranged from 0 - 2 at both sacrifice timepoints.
Two of the seven guinea pig dams sacrificed on gestation day 62 had lung foci (one had 25 foci and the other had 43 foci). None of the guinea pig dams sacrificed following weaning had a positive response with respect to lung foci.
TMA-specific IgG antibody levels were significantly increased at the time of caesarean section and following parturition in the TMA-exposed rats compared to the controls.
Much lower levels of IgG antibody were detected in the guinea pig dams compared to the rat dams at the time of caesarean section and following parturition. Antibody levels were significantly higher than controls at both time points.
Dose descriptor:
LOAEC
Effect level:
0.548 mg/m³ air (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Based on:
test mat.
Basis for effect level:
other: Overall effects
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEC
Effect level:
548 other: µg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Overall effects
Remarks on result:
other:
Remarks:
No effects seen at the highest exposure concentration
Abnormalities:
no effects observed
Developmental effects observed:
no

No significant differences were detected in the gestating body weights or body weight gains between treated and control dams for either species. No significant differences were detected in gravid uterus weights or in corrected body weights (full-term body weight minus gravid uterus weight) between treated and control dams of either species. No significant differences were detected in the lactating bodyweights between treated and control dams for either species.

No significant differences in body weights were detected between the treated and control foetuses of either species at the time of Caesarean section, parturition, and/or following weaning. No significant differences in litter size or litter viability were detected between the control or treated groups of either species. No significant variations or malformations were observed in the gross external appearance, viscera, skeletal system, or in the development of the brain for either species. None of the foetuses of either species selected for visceral examination had lung foci.

A total of 16 rat pups (exposed in utero) were challenged with TMA. Two male and 3 female rat pups had a positive response of 10 or more lung foci. One male had 7 foci (higher than the concurrent control values). None of the non-challenged pups that were exposed in utero exhibited a positive lung foci response (10 or more). Also, none of the non-challenged filtered air controls had a positive lung foci response. The number of foci was significantly higher in the in utero exposed challenged offspring compared to both the filtered air challenged/non-challenged controls, and also compared to in utero exposed non-challenged pups.

Sixteen in utero exposed rats were challenged as adults with TMA. No treatment-related foci were observed in any of the adult challenged or non-challenged rats. Guinea pigs were not challenged as adults because no response was observed at the time of neonatal challenge.

All TMA in utero exposed rat and guinea pig foetuses had detectable TMA-specific antibody levels. The antibody levels for the majority of the guinea pig foetuses were much lower than rat foetuses. Almost all male and female in utero exposed rat neonates had TMA-specific antibodies. The antibody levels were similar for the TMA in utero exposed challenged and nonchallenged neonates. None of the filtered air controls had antibodies to TMA. None of the guinea pig pups (challenged, non-challenged, TMA-exposed or filtered air controls) sacrificed at approximately 4 weeks of age had TMA-specific antibody. One challenged rat had a barely perceptible level of TMA-specific IgG antibody.

Conclusions:
By analogy, maternal and fetal NOAEC of 4-chloroformylphthalic anhydride (TMAC) were estimated to be 548.0 µg/m3. There were no treatment-related effects observed in maternal, foetal or offspring body weights or litter viability in the rat or guinea pig. It can therefore be concluded that there were no teratogenic effects of TMAC in rats and in guinea pigs.
Executive summary:

This developmental toxicity study was performed to assess the toxicological effects of the test substance on development in rats and guinea pigs (parents, fetus and offsprings). The study did not followed any guidelines and was not GLP compliance. However, the study appears to be well conducted and the methods were scientifically acceptable.

In this study,the test substance was administered to 27 pregnant rats and 14 pregnant guinea pigs via inhalation at a concentration of 500 µg/m³. A group of similar size was exposed to filtered air and served as a sham control. During the period of major organogenesis, the species were exposed for 6 hours per day. In the rat, the period of major organogenesis was gestation days 6 through 15 and for the guinea pig, it was gestation days 6 through 26. Half of each species per group were used for teratological evaluation while the remaining animals were allowed a natural parturition. Offspring of both species were challenged with a single 6-hour Trimellitic Anhydride exposure.

No treatment-related effects were observed on maternal, foetal or offspring body weights. In addition to this, there were no teratogenic effects or effects on litter viability in either species. No teratogenic effects were seen in either species. Lung foci and substance-specific IgG antibody were observed in dams of both species. Substance-specific IgG antibody was detected in serum from in utero exposed rat and guinea pig foetuses. Lung foci response, of challenged neonatal rat offspring, was variable. Foci were observed in only the challenged offspring whose mothers had not completely recovered from the original exposure. No treatment-related lung foci were observed in neonatal guinea pigs or adult rat offspring.

By analogy, after applying the correcting factor based on molecular weights, maternal and fetal NOAEC of 4-chloroformylphthalic anhydride (TMAC) were estimated to be 548.0µg/m³. As there were no treatment-related effects observed in maternal, foetal or offspring body weights or litter viability in the rat or guinea pig, it can therefore be concluded that there were no teratogenic effects of TMAC in rats and in guinea pigs.

Endpoint:
developmental toxicity
Type of information:
other: Research study
Adequacy of study:
key study
Study period:
Not documented
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is a research investigation, the methods are scientifically acceptable and the study appears well conducted.
Reason / purpose:
read-across: supporting information
Qualifier:
no guideline followed
Principles of method if other than guideline:
Teratological evaluation of TMA in rats and guinea pigs
GLP compliance:
no
Limit test:
yes
Specific details on test material used for the study:
Trimellitic anhydride
Species:
other: rat and guinea pig
Strain:
other: Sprague Dawley rats and Hartley guinea pigs
Details on test animals and environmental conditions:
The animals were first generation offspring (rats born in-house) from Caesarean derived Sprague-Dawley rats (Charles River Breeding Laboratories, MI) and Hartley guinea pigs (Murphy Breeding Laboratories, IN) were used for this study.
Animals (that had successfully mated) were housed individually in polycarbonate shoe-box cages with corn cob bedding. Animals were transferred to stainless steel wire mesh cages for the 6 hour inhalation exposure periods.
Purina Rodent Chow 5001 or Guinea Pig Chow 5025 (Ralston Purina) and reverse-osmosis purified water were provided ad libitum except during exposure.
The animal rooms were maintained at 22°C and 40% relative humidity. Fluorescent lighting was provided on a 12 hour light/dark cycle.
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
The animals were split into two groups, the first group were exposed via inhalation to 500 µg/m³ (nominal), while the other group was exposed to filtered air only.
TMA flakes were ground to micron-sized particles using a jet-mill. Respirable-sized particles of TMA were generated in a modified TSI fluidised bed aerosol generator and blown by means of a transvector jet into a 1 m³ inhalation chamber. A minimum flow of 12-15 air changes per hour was maintained in the chamber.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A Lambda 5 UV/VIS spectrophotometer was used to determine chamber concentrations. The TMA exposure chamber was sampled 2-5 times per day, and the filtered air control chamber was sampled once per day. Samples were collected on glass fibre filters, and extracted with acetonitrile in water. Particle size was determined weekly during the study using a Portable Continuous Aerosol Monitor. The average particle size was 2.73-2.85 microns, and 99.99% of the particles were less than 10 microns.
Details on mating procedure:
The animals were mated two females to one male. Animals were checked daily to determine if mating had occurred; mating was confirmed by the presence of a vaginal plug or sperm positive vaginal smear. The day mating was confirmed was designated as day 0.
Duration of treatment / exposure:
10 exposure days (gestation days 6 through 15)
Frequency of treatment:
6 hours/day for 10 consecutive days (gestation days 6 through 15)
Duration of test:
Rats were sacrificed on gestation day 20 or after weaning. Guinea pigs were sacrificed on gestation day 62 or after weaning.
Dose / conc.:
0.5 mg/m³ air (nominal)
No. of animals per sex per dose:
27 female rats per dose
15 guinea pigs per dose
Control animals:
yes, sham-exposed
Details on study design:
Approximately one half of the animals in the treated and control groups were sacrificed one day prior to parturition and the offspring were used for teratologic investigation. In the case of the rats sacrifice was gestation day 20, whereas in the guinea pigs it was gestation day 62. The remaining dams were allowed a natural parturition and their offspring were used to evaluate the response (IgG antibody and grossly observed lesions) to a challenge exposure. Dams allowed a natural parturition were sacrificed at the time of neonatal challenge. At the time of challenge, the offspring were subdivided into non-challenge and challenge groups.
Maternal examinations:
Rats were weighed on gestation days 0, 6, 11, 16 and 20. Rats that were allowed a natural parturition were weighed weekly after gestation day 20. Guinea pigs were weighed on gestation days 0, 6, 11, 16, 20, 26 and weekly thereafter.
A gross examination of all maternal organs was performed at sacrifice.
Ovaries and uterine content:
All dams sacrificed prior to parturition underwent a caesarean section. The uterus was removed from each dam, trimmed of excess adherent fat and weighed. The foetuses were removed and examined (see below). The uterus was inspected for tissue resorptions and foetal deaths
Fetal examinations:
Offspring from both species of dams allowed a natural parturition were weighed on day 0 (day of parturition), 5 (day of culling), 7, 14 and at weaning on day 21. Following weaning the offspring were weighed once every two weeks.

The foetuses were removed from the uteri of sacrificed dams. The foetuses were counted, sexed, weighed and given a gross external examination.

One half of each rat's litter was decapitated and utilized for visceral examination. The heads were fixed in Bouins solution and examined separately from the body. A modified Staples' technique was used to examine the thoracic and abdominal viscera, while the heads were serially sectioned and the brain development examined using a modified Wilson's technique. The remaining half of each litter was processed for skeletal evaluation. The same procedures were used for the guinea pigs, however, because of the smaller litter size, all pups underwent a visceral examination and the torso of the decapitated pups were also processed for visceral evaluation.

Rat foetuses were fixed in 70% ethanol for a minimum of one week, gutted, stained with Alizarin Red in 2% aqueous KOH solution for 48 hours and then cleared in glycerin. Guinea pig foetuses were fixed in 70% ethanol for a minimum of one week and then switched to 90% ethanol for an additional week. Prior to staining (with 4% aqueous KOH Alizarin Red solution) and clearing (with glycerin), guinea pig foetuses were macerated for 48 hours in 4% aqueous KOH solution.
Statistics:
A T-test was performed on all data. When sex was a factor, a 2-way analysis of variance (ANOVA) was performed. Maternal body weight data were log-transformed and the data analysed by a multivariate analysis of variance for repeated measures. A mean litter weight was used and not individual foetal or pup weights as litter weights were dependent on the litter size. A minimum significance level of p<0.05 was used in all comparisons. All statistical analyses were performed on a Zenith X-200 PC/AT using SYSTAT.
Indices:
Indices were not calculated.
Historical control data:
No information available.
Details on maternal toxic effects:
Maternal toxic effects: yes

Details on maternal toxic effects:

RAT
All rats sacrificed on gestation day 20 had lung foci. The mean number of lung foci was 115.9 with the range between 38 and 196. Rats sacrificed following weaning had lower numbers of foci, and only 5 were classed as having a positive response (10 lung foci or more). Rats sacrificed following weaning had a mean of 9.5 lung foci with the range between 0 and 35. The number of external haemorrhagic foci was significantly higher in the TMA-exposed rats relative to control rats at both time points. The number of lung foci in the filtered air control group ranged from 0 - 2 at both sacrifice timepoints.

GUINEA PIG
Two of the seven guinea pig dams sacrificed on gestation day 62 had lung foci (one had 25 foci and the other had 43 foci). None of the guinea pig dams sacrificed following weaning had a positive response with respect to lung foci.

IgG ANTIBODY
TMA-specific IgG antibody levels were significantly increased at the time of caesarean section and following parturition in the TMA-exposed rats compared to the controls.
Much lower levels of IgG antibody were detected in the guinea pig dams compared to the rat dams at the time of caesarean section and following parturition. Antibody levels were significantly higher than controls at both time points.
Dose descriptor:
LOAEC
Effect level:
500 other: ug/m³ air (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Based on:
test mat.
Basis for effect level:
other: Overall effects
Remarks on result:
not determinable
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: no effects
Dose descriptor:
NOAEC
Effect level:
500 other: ug/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Overall effects
Remarks on result:
other:
Remarks:
No effects seen at the highest exposure concentration
Abnormalities:
no effects observed
Developmental effects observed:
not specified

No significant differences were detected in the gestating body weights or body weight gains between treated and control dams for either species. No significant differences were detected in gravid uterus weights or in corrected body weights (full-term body weight minus gravid uterus weight) between treated and control dams of either species. No significant differences were detected in the lactating bodyweights between treated and control dams for either species.

No significant differences in body weights were detected between the treated and control foetuses of either species at the time of Caesarean section, parturition, and/or following weaning. No significant differences in litter size or litter viability were detected between the control or treated groups of either species. No significant variations or malformations were observed in the gross external appearance, viscera, skeletal system, or in the development of the brain for either species. None of the foetuses of either species selected for visceral examination had lung foci.

A total of 16 rat pups (exposed in utero) were challenged with TMA. Two male and 3 female rat pups had a positive response of 10 or more lung foci. One male had 7 foci (higher than the concurrent control values). None of the non-challenged pups that were exposed in utero exhibited a positive lung foci response (10 or more). Also, none of the non-challenged filtered air controls had a positive lung foci response. The number of foci was significantly higher in the in utero exposed challenged offspring compared to both the filtered air challenged/non-challenged controls, and also compared to in utero exposed non-challenged pups.

Sixteen in utero exposed rats were challenged as adults with TMA. No treatment-related foci were observed in any of the adult challenged or non-challenged rats. Guinea pigs were not challenged as adults because no response was observed at the time of neonatal challenge.

All TMA in utero exposed rat and guinea pig foetuses had detectable TMA-specific antibody levels. The antibody levels for the majority of the guinea pig foetuses were much lower than rat foetuses. Almost all male and female in utero exposed rat neonates had TMA-specific antibodies. The antibody levels were similar for the TMA in utero exposed challenged and nonchallenged neonates. None of the filtered air controls had antibodies to TMA. None of the guinea pig pups (challenged, non-challenged, TMA-exposed or filtered air controls) sacrificed at approximately 4 weeks of age had TMA-specific antibody. One challenged rat had a barely perceptible level of TMA-specific IgG antibody.

Conclusions:
Under the conditions of this study, there were no treatment-related effects observed in maternal, foetal or offspring body weights or litter viability in the rat or guinea pig. It can therefore be concluded that there were no teratogenic effects of Trimellitic Anhydride observed in either species.
Executive summary:

Trimellitic Anhydride was administered to 27 pregnant rats and 14 pregnant guinea pigs via inhalation at a concentration of 500 µg/m³. A group of similar size was exposed to filtered air and served as a sham control. During the period of major organogenesis, the species were exposed for 6 hours per day. In the rat, the period of major organogenesis was gestation days 6 through 15 and for the guinea pig, it was gestation days 6 through 26. Half of each species per group were used for teratological evaluation while the remaining animals were allowed a natural parturition. Offspring of both species were challenged with a single 6-hour Trimellitic Anhydride exposure.

No treatment-related effects were observed on maternal, foetal or offspring body weights. In addition to this, there were no teratogenic effects or effects on litter viability in either species. No teratogenic effects were seen in either species. Lung foci and TMA-specific IgG antibody were observed in dams of both species. TMA-specific IgG antibody was detected in serum from in utero exposed rat and guinea pig foetuses. TMA-specific IgG antibody was found in only the neonatal rats. Lung foci response, of challenged neonatal rat offspring, was variable. Foci were observed in only the challenged offspring whose mothers had not completely recovered from the original TMA exposure. No treatment-related lung foci were observed in neonatal guinea pigs or adult rat offspring.

It can be concluded that exposure to trimellitic anhydride at a concentration of 500 µg/m³ in air during the period of major organogenesis was not teratogenic to rats and guinea pigs.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
548 µg/m³
Study duration:
subacute
Species:
other: rat and guinea pig
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Effect on developmental toxicity - via inhalation:

One key study was identified for the developmental toxicity assessment via inhalation. This study (School of Advanced Studies of Illinois Institute of Technology, 1988, Rel.2) was performed with 1,3 -dioxo-2 -benzofuran-5 -carboxylic acid (trimellitic anhydride, TMA),an analogous of the test item, to assess the toxicological effects of the test substance on development in rats and guinea pigs (parents, fetus and offsprings). This developmental toxicitystudy did not followed any guidelines and was not GLP compliance. However, the study appears to be well conducted and the methods were scientifically acceptable. In this study,Trimellitic Anhydride was administered to 27 pregnant rats and 14 pregnant guinea pigs via inhalation at a concentration of 500µg/m³. A group of similar size was exposed to filtered air and served as a sham control. During the period of major organogenesis, the species were exposed for 6 hours per day. In the rat, the period of major organogenesis was gestation days 6 through 15 and for the guinea pig, it was gestation days 6 through 26. Half of each species per group were used for teratological evaluation while the remaining animals were allowed a natural parturition. Offspring of both species were challenged with a single 6-hour Trimellitic Anhydride exposure.

No treatment-related effects were observed on maternal, foetal or offspring body weights. In addition to this, there were no teratogenic effects or effects on litter viability in either species. No teratogenic effects were seen in either species. Lung foci and TMA-specific IgG antibody were observed in dams of both species. TMA-specific IgG antibody was detected in serum fromin uteroexposed rat and guinea pig foetuses. TMA-specific IgG antibody was found in only the neonatal rats. Lung foci response, of challenged neonatal rat offspring, was variable. Foci were observed in only the challenged offspring whose mothers had not completely recovered from the original TMA exposure. No treatment-related lung foci were observed in neonatal guinea pigs or adult rat offspring.

It can be concluded that exposure to trimellitic anhydride at a concentration of 500 µg/m³ in air during the period of major organogenesis was not teratogenic to rats and guinea pigs.

By analogy, after applying the correcting factor based on molecular weights, maternal and fetal NOAEC of 4-chloroformylphthalic anhydride (TMAC) were estimated to be 548.0µg/m³. As there were no treatment-related effects observed in maternal, foetal or offspring body weights or litter viability in the rat or guinea pig, it can therefore be concluded that there were no teratogenic effects of TMAC in rats and in guinea pigs.

The rational for the choice of this low concentration is based on the corrosivity of the substance.

Effect on developmental toxicity - via oral route:

No data was available regarding the developmental toxicity assessment via oral route, therefore the substance should not be classified due to the lack of data.

Effect on developmental toxicity - via dermal route:

No data was available regarding the developmental toxicity assessment via dermal route, therefore the substance should not be classified due to the lack of data.

Justification for classification or non-classification

Harmonized classification:

Trimellitic anhydride mono-chloride does not have an harmonized classification according to the Regulation (EC) No. 1272/2008.

Self-classification:

Developmental toxicity:

The substance is not classified for the developmental toxicity according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).

Toxicity on fertility:

No information was available regarding the assessment of effects on fertility irrespective of the route of exposure.